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 .
Information Disclosure Statement
The submitted information disclosure statement (IDS) was filed on 03/13/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Application
Applicants' arguments/remarks filed 02/23/2026 are acknowledged. Claim(s) 1 is/are currently amended. Claims 1-11 are examined on the merits within and are currently pending.
Modified Rejections
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 non-obviousness.
Claims 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Nangia et al. (US 9744137 B2) in view of Belgamwar et al. (Belgamwar et al., Formulation and Evaluation of Oral Mucoadhesive Multiparticulate System Containing Metoprolol Tartarate: An In Vitro – Ex Vivo Characterization. Current Drug Delivery, 2009, 6, 113-121).
Claims 1-3 and 7-8,
Nangia et al. teach:
Pharmaceutical compositions (Abs), refer to pellets, particles, microparticles, or minitablets or any combination thereof (Col. 16, lines 37-40). Certain delayed release (DR) pellets may be coated with EUDRAGIT® L30D-55, which dissolves at about pH 5.5-6.0, i.e., in the upper intestines. (Col. 23, line 15-17). Dosage forms of the invention can be retained in the small intestine (or one or two portions thereof, selected from the duodenum, the jejunum and the ileum) for at least 6 hours, at least 8 hours or at least 12 hours, such as from 16 to 18 hours. (Col. 47, lines 37-41). The upper intestine is the duodenum area. The composition contains a core and an enteric coating surrounding the core. (Col. 1, line 15-17).
The cores or starting seeds can be, sugar spheres or spheres made from microcrystalline cellulose or silicon dioxide or various salt crystals such as sodium citrate. (Col 20, lines 63-67), which are hydrophilic components. The immediate release composition may contain one or more binders to give the pellets cohesiveness. (col. 20, lines 17-18). In certain embodiments, at least a portion of the pellets are individually coated with both the bioadhesive polymer and the enteric coating. (Col 14, line 35-37). In some embodiments, an unbanded capsule is sealed with a sufficient amount of sealing composition. Such sealing compositions comprise a film-forming material, a plasticizer and a filler. The sealed capsule may be further coated with at least one other coating. (col 40, line 25-29).
In another aspect, a pharmaceutical composition comprises suitable pharmaceutically acceptable polymeric carriers include polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), (col. 26, lines 1-2). Preferred polymeric carriers are one or more of polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG), wherein a more preferred polymeric carrier is polyvinylpyrrolidone (PVP) having an average molecular weight of about 2,500 to about 3,000,000. A most preferred polymeric carrier is polyvinylpyrrolidone (PVP) having an average molecular weight of from about 10,000 to about 450,000. (Col. 26, lines 5-19). They are examples of channel forming agents and they include low molecular weight from as low as 2500 Dalton. Dalton unit (col. 54, line 67).
The modification to the polymer or monomer can performed in the coupling reaction with a crosslinker, carbodiimide (col. 58, line 26-42). The dosage form matrix can be made by procedures known to the polymer art with a cross-linking agent. A suitable polymer backbone can be a known bioadhesive polymer that is hydrophilic or hydrophobic. Hydrophilic polymers include CARBOPOL™, polycarbophil, cellulose esters, and dextran. (Col. 57, lines 6-10). Two classes of polymers have shown useful bioadhesive properties, hydrophilic polymers and hydrogels. In the large class of hydrophilic polymers, those containing carboxylic groups ( e.g., polyacrylic acid) exhibit the best bioadhesive properties, (Col. 48, lines 62-66), while hydrogels are formed by crosslinking. Some polymers derivatives of polyacrylic acids are also taught by Nangia: The step is repeated for each successive layer. Representative polymers suitable for manufacturing the dosage form include poly(methyl acrylate), poly(isobutyl methacrylate ), poly(alginate).(col 39, lines 51-67). Suitable film-forming materials include water-soluble synthetic polymers like poly acrylic acids (Col. 40 lines 30, 49), which are actually also bioadhesive polymers, (Col. 51, line 41; Col. 52, line 62).
Nangia et al. do not teach cross-linker is not active prior to exposure to an aqueous
environment exposure to said aqueous environment causes said cross-linker to become active and to induce intermolecular cross-linking within said film forming polymer thereby forming an in-situ cross-linked film.
Belgamwar et al. teach the in vitro release profiles of metoprolol tartarate from microparticles in phosphate buffer of pH 7.2 shown that as the concentration of sodium alginate increases in the formulation, the release of the metoprolol tartarate from the polymer matrix was retarded. The formulation extended the release of the drug for 12 hours. Increasing the concentration of calcium chloride solution also increases the crosslinking of the COOH groups of alginate molecule and thus retards the release of the drug from the alginate matrix. The drug release data of these optimized batches was then explored for the type of release mechanism that they followed. (pg. 120, right col., 2nd par.), to release the drug in a controlled manner, (pg. 114, left col., 2nd. par.)
It would have been obvious to one of ordinary skills in the art before the effective filing date of the invention to prepare the pharmaceutical compositions microparticles containing a core, coated with both the bioadhesive polymer and a film-forming material, especially with hydrophilic polymer containing carboxylic groups polyacrylic acid, which can be crosslinked, to control release the drug in the upper intestines, taught by Nangia et al, and crosslinker when are exposed to the aqueous environment to induce crosslinking within film forming polymer to reduce drug release, taught by Belgamar et al., since they have taught it is possible to do so.
With regard to claim 4, Nangia et al. teach: in certain embodiments, the bioadhesive layer comprises one or more polymeric materials selected from polyvinyl alcohols, Carbopols, (col. 7, lines 13, 15, 20, 23). A suitable polymer backbone can be a known bioadhesive polymer that is hydrophilic or hydrophobic. Hydrophilic polymers include CARBOPOL™, polycarbophil, cellulose esters, and dextran. (Col. 57, lines 6-10). Cellulose esters, and dextran. are polysaccharides, which is common knowledge. Carbopol is a family of synthetic, high-molecular-weight acrylic acid polymers (also known as carbomers) that are cross-linked with polyalkenyl ethers or divinyl glycol. These polymers are known for their ability to create gels and other thick, clear formulations, and are used as rheology modifiers, suspending agents, and binders in pharmaceutical, personal care, and home care products. https://www.lubrizol.com/solutions/products/carbopol/pharmaceuticals
With regard to claim 5, Nangia et al. teach: "Bioadhesion" is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Polycarbophils and acrylic acid polymers usually have the best adhesive properties. (col 47, lines 1-2 & 10-11).
With regard to claim 6, Nangia et al. teach: the modification to the polymer or monomer can performed in the coupling reaction with a crosslinker, carbodiimide (col. 58, line 26-42).
With regard to claim 9, Nangia et al. teach: the term "particle" refers to particles that comprise topiramate or a pharmaceutically acceptable salt thereof in any suitable size and shape. Typically, particles have a diameter in the range of about 1 micron to about 300 microns. Examples of different particle shapes include rods, granules, planar structures and other regular or irregular shapes. (Col 16, lines 23-27), so products comprise microparticles of different diameters.
With regard to claim 10, Nangia et al. teach: in other embodiments, the topiramate is micronized and the pellet size is less than 5 microns. Particles are formulated to these sizes in order to enable high drug loading when needed. (col. 44, lines 62-65), so microparticles are of substantially similar diameter.
With regard to claim 11, Nangia et al. teach: Active pellets were prepared by extrusion spheronization. Topiramate was blended with Emcocel 90M, Hydroxypropylcellulose EF Pharm, dibasic sodium phosphate, sodium lauryl sulfate, and Povidone K-30 and wet granulated by addition of purified water while mixing in a Hobart mixer. The granulation was then extruded into rods using a Caleva (col. 71, line 62-67).
Response to Arguments
The applicant argues that Nangia does not suggest the claimed duodenum-targeted, in-situ crosslinking system and Belgamwar discloses a fundamentally different crosslinking architecture. the combination of Nangia and Belgamwar would require impermissible
reconstruction.
This argument has been fully considered, and is found persuasive that Nangia's design goal, in the context of its disclosed embodiments, is to protect the active ingredient from upper GI exposure and to delay its release. according to the previous office action. Nangia et al. teach: Pharmaceutical compositions (Abs), refer to pellets, particles, microparticles, or minitablets or any combination thereof (Col. 16, lines 37-40). Dosage forms of the invention can be retained in the small intestine (or one or two portions thereof, selected from the duodenum, the jejunum and the ileum) for 6-18 hours. (Col. 47, lines 37-41). And by delaying drug release in the upper GI exposue, it is to protect the active ingredient from upper GI area conditions, which is the same goal with the applicant which directs to a microparticle specifically configured for administration to the duodenum and comprising a coating layer designed to activate and undergo intermolecular crosslinking upon aqueous exposure, thereby forming an in-situ cross-linked film. The upper intestine is the duodenum area. The composition contains a core and an enteric coating surrounding the core. And Nangia teaches same with applicant’s design: The cores with hydrophilic components, binders, coated with both the bioadhesive polymer, a film-forming material; the polymer or monomer can perform in the coupling reaction with a crosslinker, carbodiimide, a cross-linking agent. Please see details of the rejection of claim 1 above.
With the amendment, the rejection of claim 1 is modified in this office action, in which, Belgamwar teaches the crosslinking of the polymer, by the crosslinking agent, to form more intact matrix which makes the drug release more difficult from microparticles, when in contact with the aqueous solution and extend the release of the drug for 12 hours. Increases in the amount of alginate increases the number of COOH groups which are crosslinked by Ca2+ ions resulting in a formation of more intact matrix to release the drug in a controlled manner. In addition, divalent cations like calcium2+ and other like mg2+ are present in the gastrointestinal (GI) tract even when fasting, although their concentration is significantly higher after eating or drinking. The drug release data of these optimized batches was then explored for the type of release mechanism that they followed. Applicant claims, in claim 1, a cross-linker is not active prior to exposure to an aqueous environment without distinction of stomach or intestinal area, so Belgamwar teaches what applicant claims. For 103 rejection, no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though the prior arts may teach more and may teach different things.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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