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 amendment and arguments in the reply filed on 26 March 2026 are acknowledged and have been fully considered. Claims 1-3, 5-7, 9-14, 24-25, 32-35, 66, and 68 are pending. Claims 1-3, 5-7, 9-14, 24-25, 32-35, and 66 are under consideration in the instant office action. Claim 68 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claims. Claims 4, 8, 15-23, 26-31, 36-65, 67, and 69 are canceled.
Information Disclosure Statement
The information disclosure statement (IDSs) submitted on 26 March 2026 and 08 January 2026 are noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the information disclosure statement. Signed copies are attached herein.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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, 5-7, 9-14, 24, 32, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over FANG et al. (WO2020247352, previously cited) in view of PRATER et al. (WO02096394, previously cited) and Davis et al. (US Patent No. 5,670,158, previously cited).
Applicant Claims
Applicant claims a softgel capsule comprising a fill material and a shell composition and the other features as recited. Dependent claims thereof further define the different components.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
FANG et al. teach delayed release softgel capsules comprise a fill material and a pH dependent shell composition, characterized in that the delayed release nature of the capsules may be achieved without a pH dependent coating or added conventional pH dependent polymers (see abstract). A delayed release softgel capsule comprising: (a) a fill material; and (b) a pH dependent shell composition, wherein the fill material comprises at least one pharmaceutically active ingredient, and wherein the pH dependent shell composition comprises gelatin, pectin, and dextrose (see claim 1). The delayed release softgel capsule of claim 1, wherein the pH dependent shell composition further comprises a plasticizer (see claim 2). The delayed release softgel capsule of any one of the preceding claims, wherein the pectin is low methoxyl pectin (see claim 3). The delayed release softgel capsule of any one of the preceding claims, wherein the pectin is selected from the group consisting of amidated pectin, non-amidated pectin and combinations thereof (see claim 4). The delayed release softgel capsule of any one of the preceding claims, wherein the pH dependent shell composition comprises about 40 wt% to about 80 wt% of a gelatin, based on the dry pH dependent shell composition weight (see claim 5). The delayed release softgel capsule of any one of the preceding claims, wherein the pH dependent shell composition comprises about 2 wt% to about 20 wt% of pectin, based on the dry pH dependent shell composition weight (see claim 6). The delayed release softgel capsule of any one of the preceding claims, wherein the pH dependent shell composition comprises about 0.01 wt% to about 4 wt% of dextrose, based on the dry pH dependent shell composition weight (see claim 7). The delayed release softgel capsule of any one of claims 2-7, wherein the pH dependent shell composition comprises about 15 wt% to about 40 wt% of a plasticizer, based on the dry pH dependent shell composition weight (see claim 8). In certain embodiments, the pH dependent shell composition comprises a stabilizer and/or a binder comprising gellan gum. In certain embodiments, the ratio of pectin to stabilizer and/or binder (e.g., gellan gum) is about 1: 10 to about 50: 1; about 1:5 to about 40: 1; about 1: 1 to about 25: 1 or about 10: 1 to about 24: 1 (paragraph 0052). In certain embodiments, the amount of stabilizer and/or binder (e.g., gellan gum) in the pH dependent shell composition is about 0.05 wt% to about 5 wt%, about 0.1 wt% to about 3 wt%, or about 0.2 wt% to about 2 wt% of stabilizer and/or binder (e.g., gellan gum), or any single value or sub-range therein, based on total weight of the dry capsule shell composition (paragraph 0053). In certain embodiments, the amount of the various components (e.g., pectin, dextrose, gelatin, plasticizer) and the ratio of the various components are tuned to control the dissolution and/or disintegration properties of the softgel capsule across various pH ranges (paragraph 0058).
Fang teaches as used herein, “conventional pH dependent polymers” refer to, but are not limited to, acrylic and methacrylic acid polymers, which may be available under the tradename EUDRAGIT® and other conventional acid insoluble polymers, e.g., methyl acrylate- methacrylic acid copolymers. Other conventional acid insoluble polymers include, without limitation, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypermellose acetate succinate), polyvinyl acetate phthalate (PVAP), algenic acid salts such as sodium alginate and potassium alginate, stearic acid, and shellac. Pectin and pectin derivatives are not considered to be conventional pH dependent polymers (paragraph 0035). The delayed release softgel capsule of any one of claims 1-27, further comprising a conventional pH dependent polymer (see claim 45). Pectin and pectin derivatives are not considered to be conventional pH dependent polymers. In some embodiments, the pH dependent shell composition of the present invention does not include an acid insoluble polymer.” The examiner notes that the above polymers are the same polymers that Applicant in the instant application recites as enteric polymers. In an embodiment, the gelatin in the pH dependent shell composition may include Type A gelatin, Type B gelatin, a hide or skin gelatin (e.g., calf skin, pig skin) and/or a bone gelatin (e.g., calf bone, pig bone) used alone or in combination. In one embodiment, the gelatin is a 250 Bloom gelatin. In another embodiment, there is only one type of gelatin. In yet another embodiment, the gelatin is a combination of at least two types of gelatins. In an embodiment, the amount of gelatin in the pH dependent shell composition is from about 30 wt% to about 85 wt%, from about 30 wt% to about 75 wt%, from about 30 wt% to about 65 wt%, from about 30 wt% to about 55 wt%, from about 30 wt% to about 40 wt%, about 40 wt% to about 80 wt%, from about 45 wt% to about 65 wt%, from about 45 wt% to about 75 wt%, or from about 50 wt% to about 70 wt%, or any single value or sub-range therein, based on total weight of the dry capsule shell composition (paragraph 0045). In an embodiment, an amount of pectin in the pH dependent shell composition is about 2 wt% to about 20 wt%, from about 3 wt% to about 15 wt%, from about 3 wt% to about 5.5 wt%, from about 4 wt% to about 11 wt%, from about 7 wt% to about 12 wt%, from about 8 wt% to about 13 wt%, or from about 5 wt% to about 10 wt%, or any single value or sub-range therein, based on total weight of the dry capsule shell composition (see paragraph 0050). This teaching is equally applicable for the amount of methyl acrylic acid copolymer as the pectin and methyl acrylic acid copolymer are taught as equivalent pH dependent polymers. In an embodiment, the pH dependent shell composition comprises: (a) about 30 wt% to about 85 wt%, about 30 wt% to about 75 wt%, about 30 wt% to about 65 wt%, about 30 wt% to about 55 wt%, about 30 wt% to about 40 wt%, about 40 wt% to about 80 wt%, about 45 wt% to about 65 wt%, about 45 wt% to about 75 wt%, or about 50 wt% to about 70 wt% gelatin, (b) about 0.01 wt% to about 4 wt%, or from about 0.1 wt% to about 3 wt%, from about 0.2 wt% to about 2 wt%, or from about 0.01 wt% to about 0.1 wt%, or from about 0.05 wt% to about 0.5 wt%, or from about 0.1 wt% to about 0.2 wt% dextrose, (c) about 2 wt% to about 20 wt%, about 3 wt% to about 15 wt%, about 7 wt% to about 15 wt%, about 3 wt% to about 5.5 wt%, or about 7 wt% to about 12 wt% of a pH dependent polymer (e.g., pectin such as a low methoxy pectin), (d) about 15 wt% to about 45 wt%, about 15 wt% to about 40 wt%, about 20 wt% to about 35 wt%, or about 25 wt% to about 30 wt% of a plasticizer, and optionally (e) about 0.05 wt% to about 5 wt%, about 0.1 wt% to about 3 wt%, or about 0.2 wt% to about 2 wt% of stabilizer and/or binder (e.g., gellan gum). All wt% being based on the total weight of the dry pH dependent shell composition. In an embodiment, the pH dependent shell composition consists essentially of: (a) about 30 wt% to about 85 wt%, about 30 wt% to about 75 wt%, about 30 wt% to about 65 wt%, about 30 wt% to about 55 wt%, about 30 wt% to about 40 wt%, about 40 wt% to about 80 wt%, about 45 wt% to about 65 wt%, about 45 wt% to about 75 wt%, or about 50 wt% to about 70 wt% gelatin, (b) about 0.01 wt% to about 4 wt%, or from about 0.1 wt% to about 3 wt%, or from about 0.2 wt% to about 2 wt%, or from about 0.01 wt% to about 0.1 wt%, or from about 0.05 wt% to about 0.5 wt%, or from about 0.1 wt% to about 0.2 wt% dextrose, (c) about 2 wt% to about 20 wt%, about 3 wt% to about 15 wt%, about 7 wt% to about 15 wt%, or about 3 wt% to about 5.5 wt%, or about 7 wt% to about 12 wt% of a pH dependent polymer (e.g., pectin such as a low methoxy pectin), (d) about 15 wt% to about 45 wt%, about 15 wt% to about 40 wt%, about 20 wt% to about 35 wt%, or about 25 wt% to about 30 wt% of a plasticizer, and optionally (e) about 0.05 wt% to about 5 wt%, about 0.1 wt% to about 3 wt%, or about 0.2 wt% to about 2 wt% of stabilizer and/or binder (e.g., gellan gum). All wt% being based on the total weight of the dry pH dependent shell composition. In an embodiment, the pH dependent shell composition consists of: (a) about 30 wt% to about 85 wt%, about 30 wt% to about 75 wt%, about 30 wt% to about 65 wt%, about 30 wt% to about 55 wt%, about 30 wt% to about 40 wt%, about 40 wt% to about 80 wt%, about 45 wt% to about 65 wt%, about 45 wt% to about 75 wt%, or about 50 wt% to about 70 wt% gelatin, (b) about 0.01 wt% to about 4 wt%, or from about 0.1 wt% to about 3 wt%, or from about 0.2 wt% to about 2 wt%, or from about 0.01 wt% to about 0.1 wt%, or from about 0.05 wt% to about 0.5 wt%, or from about 0.1 wt% to about 0.2 wt% dextrose, (c) about 2 wt% to about 20 wt%, about 3 wt% to about 15 wt%, about 7 wt% to about 15 wt%, or about 3 wt% to about 5.5 wt%, or about 7 wt% to about 12 wt% of a pH dependent polymer (e.g., pectin such as a low methoxy pectin), (d) about 15 wt% to about 45 wt%, about 15 wt% to about 40 wt%, about 20 wt% to about 35 wt%, or about 25 wt% to about 30 wt% of a plasticizer, and optionally (e) about 0.05 wt% to about 5 wt%, about 0.1 wt% to about 3 wt%, or about 0.2 wt% to about 2 wt% of stabilizer and/or binder (e.g., gellan gum). All wt% being based on the total weight of the dry pH dependent shell composition (paragraphs 0098-0100). As used herein, “pharmaceutically active ingredient,” “active agents” refers to a drug or compound that may be used in the diagnosis, cure, mitigation, treatment, or prevention of a condition. In certain embodiments, suitable “active agents” include nutraceuticals, such as, vitamins, minerals, and supplements (VMS). Exemplary delayed release softgel capsules may include, without limitations, capsules containing lactic acid bacteria, probiotics, fish oil capsules, valproic acid, garlic, peppermint oil, polyethylene glycol, ibuprofen solution or suspension, proton pump inhibitors, aspirin and similar products (paragraph 0016). As used herein, the term "active ingredient" refers to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. This term with respect to a specific agent includes the pharmaceutically active agent, and all pharmaceutically acceptable salts, solvates and crystalline forms thereof, where the salts, solvates and crystalline forms are pharmaceutically active (paragraph 0018). Any pharmaceutically active ingredient may be used for purposes of the present invention, including both those that are water-soluble and those that are poorly soluble in water. Suitable pharmaceutically active ingredients include, without limitation, analgesics and anti-inflammatory agents (e.g., ibuprofen, naproxen sodium, aspirin), antacids, anthelmintic, anti-arrhythmic agents, anti-bacterial agents, anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheal, anti-epileptics, anti-fungal agents, anti-gout agents, anti hypertensive agents, anti-malarial, anti-migraine agents, anti-muscarinic agents, anti neoplastic agents and immunosuppressants, anti -protozoal agents, anti-rheumatics, anti thyroid agents, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, cough suppressants, cytotoxics, decongestants, diuretics, enzymes, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and anti-anginal agents, nutritional agents, opioid analgesics, anticonvulsant agents (e.g., valporic acid), oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof (paragraph 0019). In an embodiment, the pH dependent shell composition may optionally comprise additional agents such as stabilizers or binders (e.g., gellan gum), coloring agents, flavorings agents, sweetening agents, fillers, antioxidants, diluents, pH modifiers or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides (paragraph 0067). With regard to the limitation of claim 66 FANG et al. do not teach the presence of any impurities in its composition.
With regard to the new limitation wherein the fill material in addition to the active contains lipid, FANG et al. teach in some embodiments, the lipids in the dosage form may be selected, without limitations, from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, colza oil, com oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, peppermint oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oil and fats may include, but not be limited to, fish oil (omega-3), krill oil, animal or vegetable fats, e.g., in their hydrogenated form, free fatty acids and mono-, di-, and tri-glycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20- and C22-fatty acids, fatty acid esters like EPA and DHA 3and combinations thereof (see paragraph 0021). . A method of reducing incidence of belching comprising, administering to a subject in need thereof a delayed release softgel capsule comprising: (a) a fill material; and (b) a pH dependent shell composition, wherein the fill material comprises at least one pharmaceutically active ingredient, and wherein the pH dependent shell composition comprises gelatin, pectin, and dextrose (see claim 42). The method of claim 42, wherein the fill material comprises fish oil, krill oil, garlic oil, or a combination thereof (see claim 43).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
FANG et al. do not specifically teach the inclusion of bisacodyl or a pharmaceutically acceptable salt thereof with the fill material. Furthermore FANG et al. is silent with regard to the bisacodyl or a pharmaceutically acceptable salt thereof is dissolved or suspended in the lipid. These deficiencies are cured by the teachings of PRATER et al.
PRATER et al. teach stool softener and enteric coated bisacodyl form a pharmaceutical composition (see abstract). PRATER et al. in the background section teach Bisacodyl is a diphenylmethane stimulant laxative used for the treatment of constipation and bowel evacuation. It acts mainly in the large intestine within 6-12 hours following oral administration. Bisacodyl was recently subjected to carcinogenicity testing and was shown to be free of carcinogenic/ mutagenic potential and therefore, from a safety perspective, is the stimulant laxative of choice. However bisacodyl is directly irritant to the intestinal mucosa of the upper intestine and can cause griping and epigastric pain. To reduce the incidence of such effects bisacodyl is conventionally administered as enteric-coated tablets (e.g. Dulcolax, Boehringer), in doses of 5-15 mg daily. Due to the reported irritant nature of the active compound and the drug sensitivity to the low pH of the gastric environment, tablets have to be swallowed whole and not within one hour of milk or antacids. Bisacodyl is also available as suppositories, with onset of action within 20 -60 minutes, but not as a commercially available oral liquid or sachet (see pages 1-2).
Davis et al. teach Bisacodyl is an inactive prodrug that is hydrolyzed by intestinal brush border enzymes and colonic bacteria to desacetyl bisacodyl which is the active species. Contact of the desacetyl bisacodyl with the mucosa of the colon stimulates sensory nerve endings to produce increased propulsive peristaltic contractions of the colon which accelerate movement of contents through the colon. Administration of bisacodyl has also been shown to promote fluid and ion accumulation in the colon, which increases its laxative effect. Both bisacodyl and desacetyl bisacodyl are poorly water soluble with absorption reported from both the small intestine and colon. Absorption from the small intestine may be greater than from the colon. Davis et al. teach pharmaceutical compositions in dosage unit form, for peroral administration of bisacodyl to a human or lower animal having a gastrointestinal tract, with a lumen therethrough, with a small intestine and a colon with a junction therebetween, comprising: (a) a safe and effective amount of rapidly-dissolving bisacodyl means; and (b) a delivery means which prevents the release of bisacodyl from the dosage form into the lumen of the gastrointestinal tract during transport of the dosage form through the lumen until the dosage form is near the junction between the small intestine and the colon or in the colon, and which then releases the bisacodyl in the lumen near the junction between the small intestine and the colon or within the colon, The subject invention also involves methods for providing laxation for humans and lower animals in need thereof by peroral administration of such compositions (see abstract). Another preferred rapidly-dissolving bisacodyl means is a self-emulsifying or self-dispersing lipid solution of bisacodyl. Preferably substantially all of the bisacodyl in certain compositions of the subject invention is incorporated in such lipid solutions. The lipid in which bisacodyl is dissolved comprises, preferably consists essentially of, a surfactant or mixture of surfactants, the lipid having the following properties: (a) being a homogeneous liquid at 37° C., (b) having an HLB of from about 6 to about 18, and (c) forming a stable dispersion in water at 20° C. at a concentration of 10%. Preferred lipids also have the following properties: (d) being soluble in isopropanol at 20° C. at a concentration of 10%, and (e) being soluble in cottonseed oil at 20° C. at a concentration of 1% (column 5, lines 7-9). Preferred bisacodyl means of the subject invention which comprise liquid forms of bisacodyl described above, e.g., bisacodyl in a water-miscible liquid solvent, bisacodyl in a lipid solution, or a melted solid dispersion of bisacodyl, are filled into hard or soft elastic gelatin (SEG) capsules using conventional equipment and processes (column 6 lines 49-54).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to utilize in the pH dependent softgel capsule formulations of FANG et al. for the delivery of bisacodyl or a pharmaceutically acceptable salt thereof as an active agent because PRATER et al. teach Stool softener and enteric coated bisacodyl form a pharmaceutical composition (see abstract). One of ordinary skill in the art would have been motivated to do so because PRATER et al. in the background section teach Bisacodyl is a diphenylmethane stimulant laxative used for the treatment of constipation and bowel evacuation. It acts mainly in the large intestine within 6-12 hours following oral administration. Bisacodyl was recently subjected to carcinogenicity testing and was shown to be free of carcinogenic/ mutagenic potential and therefore, from a safety perspective, is the stimulant laxative of choice. However bisacodyl is directly irritant to the intestinal mucosa of the upper intestine and can cause griping and epigastric pain. To reduce the incidence of such effects bisacodyl is conventionally administered as enteric-coated tablets (e.g. Dulcolax, Boehringer), in doses of 5-15 mg daily. Due to the reported irritant nature of the active compound and the drug sensitivity to the low pH of the gastric environment, tablets have to be swallowed whole and not within one hour of milk or antacids. Bisacodyl is also available as suppositories, with onset of action within 20 -60 minutes, but not as a commercially available oral liquid or sachet (see pages 1-2). Furthermore, it should be noticed that FANG et al. teach that as used herein, “pharmaceutically active ingredient,” “active agents” refers to a drug or compound that may be used in the diagnosis, cure, mitigation, treatment, or prevention of a condition. In certain embodiments, suitable “active agents” include nutraceuticals, such as, vitamins, minerals, and supplements (VMS). Exemplary delayed release softgel capsules may include, without limitations, capsules containing lactic acid bacteria, probiotics, fish oil capsules, valproic acid, garlic, peppermint oil, polyethylene glycol, ibuprofen solution or suspension, proton pump inhibitors, aspirin and similar products (paragraph 0016). As used herein, the term "active ingredient" refers to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. This term with respect to a specific agent includes the pharmaceutically active agent, and all pharmaceutically acceptable salts, solvates and crystalline forms thereof, where the salts, solvates and crystalline forms are pharmaceutically active (paragraph 0018). Any pharmaceutically active ingredient may be used for purposes of the present invention, including both those that are water-soluble and those that are poorly soluble in water. Suitable pharmaceutically active ingredients include, without limitation, analgesics and anti-inflammatory agents (e.g., ibuprofen, naproxen sodium, aspirin), antacids, anthelmintic, anti-arrhythmic agents, anti-bacterial agents, anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheal, anti-epileptics, anti-fungal agents, anti-gout agents, anti hypertensive agents, anti-malarial, anti-migraine agents, anti-muscarinic agents, anti neoplastic agents and immunosuppressants, anti -protozoal agents, anti-rheumatics, anti thyroid agents, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, cough suppressants, cytotoxics, decongestants, diuretics, enzymes, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and anti-anginal agents, nutritional agents, opioid analgesics, anticonvulsant agents (e.g., valporic acid), oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof (paragraph 0019).
One of ordinary skill in the art would have been motivated to dissolve or suspend bisacodyl or salt thereof taught by PRATER et al. and also poorly water soluble drugs taught by FANG et al. in a lipid because Davis et al. teach that Bisacodyl is an inactive prodrug that is hydrolyzed by intestinal brush border enzymes and colonic bacteria to desacetyl bisacodyl which is the active species. Contact of the desacetyl bisacodyl with the mucosa of the colon stimulates sensory nerve endings to produce increased propulsive peristaltic contractions of the colon which accelerate movement of contents through the colon. Administration of bisacodyl has also been shown to promote fluid and ion accumulation in the colon, which increases its laxative effect. Both bisacodyl and desacetyl bisacodyl are poorly water soluble with absorption reported from both the small intestine and colon. Absorption from the small intestine may be greater than from the colon. Davis et al. teach pharmaceutical compositions in dosage unit form, for peroral administration of bisacodyl to a human or lower animal having a gastrointestinal tract, with a lumen therethrough, with a small intestine and a colon with a junction therebetween, comprising: (a) a safe and effective amount of rapidly-dissolving bisacodyl means; and (b) a delivery means which prevents the release of bisacodyl from the dosage form into the lumen of the gastrointestinal tract during transport of the dosage form through the lumen until the dosage form is near the junction between the small intestine and the colon or in the colon, and which then releases the bisacodyl in the lumen near the junction between the small intestine and the colon or within the colon, The subject invention also involves methods for providing laxation for humans and lower animals in need thereof by peroral administration of such compositions (see abstract). Another preferred rapidly-dissolving bisacodyl means is a self-emulsifying or self-dispersing lipid solution of bisacodyl. Preferably substantially all of the bisacodyl in certain compositions of the subject invention is incorporated in such lipid solutions. The lipid in which bisacodyl is dissolved comprises, preferably consists essentially of, a surfactant or mixture of surfactants, the lipid having the following properties: (a) being a homogeneous liquid at 37° C., (b) having an HLB of from about 6 to about 18, and (c) forming a stable dispersion in water at 20° C. at a concentration of 10%. Preferred lipids also have the following properties: (d) being soluble in isopropanol at 20° C. at a concentration of 10%, and (e) being soluble in cottonseed oil at 20° C. at a concentration of 1% (column 5, lines 7-9). Preferred bisacodyl means of the subject invention which comprise liquid forms of bisacodyl described above, e.g., bisacodyl in a water-miscible liquid solvent, bisacodyl in a lipid solution, or a melted solid dispersion of bisacodyl, are filled into hard or soft elastic gelatin (SEG) capsules using conventional equipment and processes (column 6 lines 49-54).
In the case where the claimed amounts of ingredients and actives "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). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or amount 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 FANG et al., PRATER et al., and Davis et al. because all of the references teach enteric coated pharmaceutical compositions.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded 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) 25 and 33-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over FANG et al. (WO2020247352, previously cited) in view of PRATER et al. (WO02096394, previously cited) and Davis et al. (US Patent No. 5,670,158, newly cited) as applied to claims 1-3, 5-7, 9-14, 24, 32, and 66 above, and further in view of YOON et al. (WO 01/22942, previously cited).
Applicant Claims
Applicant claims a softgel capsule comprising a fill material and a shell composition, wherein the fill material comprises bisacodyl or a pharmaceutically acceptable salt dissolved or suspending in a lipid, and wherein the shell composition comprises a film forming material and an enteric polymer. Dependent claims thereof further define the different components.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
The teachings of FANG et al., PRATER et al., and Davis et al. are described in detail above and are incorporated herein by reference.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
FANG et al., PRATER et al., and Davis et al. do not specifically teach the antioxidants recited in claim 25 and their amounts as recited in claims 33-35. These deficiencies are cured by the teachings of YOON et al.
YOON et al. teach a carrier systems useful in preparing pharmaceutical formulations, the systems comprising, by weight percentage, from about 1 % to about 20 %, preferably from about 5 % to about 12 %, of a surfactant component; from about 55 % to about 93 %, preferably from about 60 % to about 85 %, of a component of one or more polyethylene glycols (PEG); and from about 1 % to about 25 %, preferably from about 5 % to about 15 %, of one or more sucrose fatty acid esters or polyvinylpyrrolidone (PVP) with a K value between about 15 and about 90, preferably with a K value of from about 16 to about 18, most preferably about 17, as defined in USP/NF, or a combination of one or more sucrose fatty acid esters or PVP, and, optionally, one or more pharmaceutically acceptable preservatives or antioxidants, such as BHA, BHT, ascorbyl palmitate or benzyl alcohol (see abstract). In addition to these components, other enhancing or protective pharmaceutically acceptable antioxidants or preservatives may be added to the compositions of this invention, preferably accounting for from about 0.1% to about 4% by weight of the composition, more preferably from about 0.1% to about 3% of the composition. Examples may include ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc. Examples of these components in the present formulations would include BHA at a concentration from about 0.3% to about 2.5% (% w/w) and BHT at a concentration from about 0.005% to about 0.15% (% w/w), preferably with a mixture of BHA and BHT within these ranges. Preferred amounts of BHA are from about 0.5% to about 2.0% or from about 0.75% to about 1.5%. Preferred amounts of BHT are from about 0.005% to about 0.02% or from about 0.075% to about 1.5%. Further embodiments are those wherein about 0.2% BHT is included (see pages 7-8). It will be understood that the percentages of the compounds in each of the formulations of these carrier or excipient systems will equal 100%, without taking into account an active pharmacological agent or other pharmacological components, such as coloring agents, fillers, pharmaceutically acceptable adjuvants, encapsulating or coating components, etc. In a preferred embodiment of this invention, the carrier system above is combined with a pharmacologically active agent and then encapsulated, such as with a hard or soft gelatin capsule (see page 8).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of FANG et al., PRATER et al., and Davis et al. by incorporating the antioxidants recited in claim 25 and their amounts as recited in claims 33-35 because YOON et al. teach a carrier systems useful in preparing pharmaceutical formulations, the systems comprising, by weight percentage, from about 1 % to about 20 %, preferably from about 5 % to about 12 %, of a surfactant component; from about 55 % to about 93 %, preferably from about 60 % to about 85 %, of a component of one or more polyethylene glycols (PEG); and from about 1 % to about 25 %, preferably from about 5 % to about 15 %, of one or more sucrose fatty acid esters or polyvinylpyrrolidone (PVP) with a K value between about 15 and about 90, preferably with a K value of from about 16 to about 18, most preferably about 17, as defined in USP/NF, or a combination of one or more sucrose fatty acid esters or PVP, and, optionally, one or more pharmaceutically acceptable preservatives or antioxidants, such as BHA, BHT, ascorbyl palmitate or benzyl alcohol (see abstract). One of ordinary skill in the art would have been motivated to do so because YOON et al. teach that in addition to these components, other enhancing or protective pharmaceutically acceptable antioxidants or preservatives may be added to the compositions of this invention, preferably accounting for from about 0.1% to about 4% by weight of the composition, more preferably from about 0.1% to about 3% of the composition. Examples may include ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc. Examples of these components in the present formulations would include BHA at a concentration from about 0.3% to about 2.5% (% w/w) and BHT at a concentration from about 0.005% to about 0.15% (% w/w), preferably with a mixture of BHA and BHT within these ranges. Preferred amounts of BHA are from about 0.5% to about 2.0% or from about 0.75% to about 1.5%. Preferred amounts of BHT are from about 0.005% to about 0.02% or from about 0.075% to about 1.5%. Further embodiments are those wherein about 0.2% BHT is included (see pages 7-8). It will be understood that the percentages of the compounds in each of the formulations of these carrier or excipient systems will equal 100%, without taking into account an active pharmacological agent or other pharmacological components, such as coloring agents, fillers, pharmaceutically acceptable adjuvants, encapsulating or coating components, etc. In a preferred embodiment of this invention, the carrier system above is combined with a pharmacologically active agent and then encapsulated, such as with a hard or soft gelatin capsule (see page 8). Furthermore, one of ordinary skill in the art would have been motivated to do so because antioxidants are functionally equivalent. 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.) In the case where the claimed amounts of ingredients and actives "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). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or amount 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 FANG et al., PRATER et al., Davis et al., and YOON et al. because all of the references teach active containing softgel capsule pharmaceutical compositions.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded 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.
Response to Arguments
Applicant's arguments filed on 26 March 2026 have been fully considered but they are not persuasive.
Applicant argues that there is no motivation in the combination of Fang, Prater and Davis to arrive at the claimed shell composition where the enteric material comprises methyl acrylic acid polymer. In fact, Fang teaches away from including methyl acrylic acid copolymer in the shell composition. Fang teaches "the pH dependent shell composition of the present invention does not include an acid insoluble polymer. In other words, in certain embodiments, the pH dependent shell composition and the pH dependent softgel capsule are 'free or substantially free of conventional pH dependent polymers" [0035] of Fang. Fang then defines "conventional pH dependent polymers" to include "acrylic and methacrylic acid polymers Further, Fang identified a specific problem with conventional pH dependent polymers stating "the addition of conventional pH dependent polymers can lead to capsules that are prone to leaking due to insufficient sealing." [0005] of Fang. Fang states that it is an object to avoid these polymer, "[t]he delayed release softgel capsules according to the present invention do not require either a pH dependent coating or an added conventional pH dependent polymer." [0007] of Fang. Additionally, the Action alleged that "the pectin and methyl acrylic acid copolymer are taught as equivalent pH dependent polymers." Page 7 of the Action. Applicant disagrees and submits this is a mischaracterization based on the teachings of Fang. Rather, Fang teaches "[p]ectin and pectin derivatives are not considered to be conventional pH dependent polymers." [0035] of Fang. Therefore, pectin and methyl acrylic acid copolymer cannot reasonably be considered equivalent because Fang explicitly distinguishes pectin from conventional pH dependent polymers like the claimed methyl acrylic acid copolymer. Thus, one of skill in the art would understand that these materials are not interchangeable. Because Fang teaches away from methyl acrylic acid copolymer, there would be no motivation for one of skill in the art to modify Fang to arrive at the claimed invention. Prater and Davis do not cure the deficiencies of Fang. In fact, Prater fails to teach a softgel composition but is directed to a solid dosage form, and Davis includes methyl acrylic acid copolymer as a coating material, not as part of the shell composition. Accordingly, for the reasons presented herein and made of record, Applicant requests withdrawal of the present obviousness rejections.
The above assertions are not found persuasive because Fang does not teach away from the claimed invention. Applicant selectively quotes Fang paragraphs 0005 and 0035 regarding certain embodiments in which pH dependent shell does not include an acid insoluble polymer or is free or substantially free of conventional pH dependent polymers, and the statement that addition of conventional pH-dependent polymers can lead to leaking due to insufficient sealing, with an object of avoiding those polymers in certain delayed release softgels. The examiner indicates that this doe not constitute a teaching away. Teaching way requires that the reference criticize, discredit, or otherwise discourage the claimed solution or combination (see In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004); In re Gurley 27 F.3d 551, 553 (FED Cir. 1994). Fang’s statements are limited to preferred or certain embodiments that achieve pH dependence via alternative materials (e.g., pectin based systems) without conventional acid insoluble polymers. Fang does not state that methyl acrylic acid copolymers cannot be used, are unsuitable in all softgel shells, or that their use would be inoperative. Disclosure of preferred embodiments or alternatives does not teach away from the workable embodiments within the broader disclosure or the knowledge of one of ordinary skill in the art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Fang identifies a potential sealing/leaking issue
With conventional polymers in its particular shell formulations. This is a known challenge that one of ordinary skill in the art would address through routine optimization of polymer grade/amount, plasticizers, film forming materials, processing conditions (temperature, humidity, sealing parameters), or co use of known fil formers-precisely the type of modification contemplated by combining with Prater and Davis. Fang’s recognition of a problem does not discourage solutions rather it provides motivation to solve it using established enteric polymers known to provide reliable pH dependent release. One of ordinary skill in the art seeking an enteric sofgel for bisacodyl (to achieve colonic delivery and minimize upper GI release/absorption, as taught by Davis) would have been motivated to use a shell comprising a film forming material plus a conventional enteric polymer such as a methyl acrylic acid copolymer. Methyl acrylic acid copolymers (e.g., Eudragit L-type polymers) were well known, commercially available and routinely used for enteric protection of capsules and softgels because they remain insoluble at gastric pH and dissolve at intestinal pH. Prater supplies teachings on softgel shell compositions compatible with enteric functionality. Davis confirms the desirability of enteric/colonic delivery specifically for bisacodyl and the suitability of polymethacrylate coatings for that purpose. Combining Fang’s softgel architecture and delayed release concept with the enteric polymer teachings or Prater/Davis would have been obvious. The fill material (bisacodyl in lipid) is conventional for softgels and aligns with Davis focus on bisacodyl. Any sealing concerns noted in Fang would have been viewed as solvable by one of ordinary skill by optimizing the conditions described above in detail yielding a reasonable expectation of success. The claimed shell is simply the predictable result of applying a known enteric polymer to a softgel platform for a known active requiring delayed/colonic release. Furthermore, the examiner reminds Applicant that a prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). Fang teaches as used herein, “conventional pH dependent polymers” refer to, but are not limited to, acrylic and methacrylic acid polymers, which may be available under the tradename EUDRAGIT® and other conventional acid insoluble polymers, e.g., methyl acrylate- methacrylic acid copolymers. Other conventional acid insoluble polymers include, without limitation, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypermellose acetate succinate), polyvinyl acetate phthalate (PVAP), algenic acid salts such as sodium alginate and potassium alginate, stearic acid, and shellac. Pectin and pectin derivatives are not considered to be conventional pH dependent polymers (paragraph 0035). The delayed release softgel capsule of any one of claims 1-27, further comprising a conventional pH dependent polymer (see claim 45).
Conclusions
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619
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