FINAL DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Receipt is acknowledged of claim amendments filed on 31 December 2025.
Claims 1, 8 and 10 have been amended.
Claims 2, 5-6, 20 and 27-46 are cancelled.
Claims 51-55 have been added.
Consequently, claims 1, 3-4, 7-19, 21-26 and 47-55 are examined herein to the extent that the composition is composition that is one combination and the compound stimulating enteroendocrine cells to release at least one enterokine is a carbohydrate, e.g., applicant's elected species.
Rejections Withdrawn
The rejection of claim 10 under U.S.C. 112(b), as being indefinite, is withdrawn in view of Applicant’s claim amendments filed 31 December 2025.
The rejection of claims 1-2, 5-14, 20-26 and 47-50 under 35 U.S.C. 103(a) as being unpatentable over BLEIEL (WO 2019/170840 A1, cited in IDS filed 12/12/2022) in view of NOEL (US 2020/0230067 A1, effective filing date of 31 March 2020) as evidenced by the instant specification, FOX (US 5,360,614) and CETIN (“Formulation and In vitro Characterization of Eudragit® L100 and Eudragit®L100-PLGA Nanoparticles Containing Diclofenac Sodium”, AAPS PharmSciTech, Volume 11, Number 3, September 2010), is withdrawn in view of the claim amendments filed 31 December 2025.
The rejection of claims 3-4 under 35 U.S.C. 103(a) as being unpatentable over Bleiel in view of Noel as evidenced by the instant specification, Fox and Cetin as applied to claims 1-2, 5-14, 20-26 and 47-50, and further in view of LEGRAND (US 2004/0234601 A1), is withdrawn in view of the claim amendments filed 31 December 2025.
The rejection of claims 15-17 under 35 U.S.C. 103(a) as being unpatentable over Bleiel in view of Noel as evidenced by the instant specification and Fox as applied to claims 1-2, 5-14, 20-26 and 47-50, and further in view of FAYAD (WO 2013/063527), is withdrawn in view of the claim amendments filed 31 December 2025.
The rejection of claims 18-19 under 35 U.S.C. 103(a) as being unpatentable over Bleiel in view of Noel as evidenced by the instant specification and Fox as applied to claims 1-2, 5-14, 20-26 and 47-50, and further in view of SPRENGER (WO 2017/129639 A1), is withdrawn in view of the claim amendments filed 31 December 2025.
The provisional rejection of claims 3-4, 13 and 49 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-11, 23 and 26 of ‘867 in view of Noel as applied to claims 1-2, 5-12, 14-26 and 35-46, and further in view of BLEIEL (WO 2019/170840 A1) and LEGRAND (US 2004/0234601 A1) as evidenced by FOX (US 5,360,614), is withdrawn in view of the claim amendments filed 31 December 2025.
Rejections Modified as Necessitated by the Claim Amendments
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
The rejection of claims 1, 7-14, 21-26 and 47-50 under 35 U.S.C. 103 as being unpatentable over BLEIEL (WO 2019/170840 A1, cited in IDS filed 12/12/2022) in view of NOEL (US 2020/0230067 A1, effective filing date of 31 March 2020) as evidenced by the instant specification, FOX (US 5,360,614) and CETIN (“Formulation and In vitro Characterization of Eudragit® L100 and Eudragit®L100-PLGA Nanoparticles Containing Diclofenac Sodium”, AAPS PharmSciTech, Volume 11, Number 3, September 2010) is maintained.
Bleiel is primarily directed towards a composition comprising microparticles comprising high glycaemic index (GI) carbohydrate contained within a gastric-resistant, ileal-sensitive, GLP-1 stimulative, non-porous carrier configured for release of the high GI carbohydrate in the ileum (abstract).
Regarding claims 1 and 8-11, Bleiel discloses sugar (carbohydrate) contained within a gastric-resistant carrier configured for transit through the stomach of a mammal and ileal release (page 2, lines 5-6). Bleiel discloses that the coated sugar is provided in the form of a microparticulate (e.g., size, with respect to the largest dimension, provides for entry into the intestine of a subject) (page 2, lines 18-19). Bleiel discloses including a composition comprising microparticles (e.g., multiple dosage forms) (page 4, lines 1-3 and 19-21). Bleiel discloses gastric-resistant and ileal-sensitive material is coated onto carbohydrate material to make the microparticles (e.g., multiple dosage forms) (page 5, lines 23-27; page 7, lines 25-29). Bleiel discloses that the sugar includes glucose (page 16, lines 25-28). Bleiel discloses that the micro-encapsulates have a diameter of approx. 250 µm (e.g., below 3 mm) (page 23, lines 12-14).
Regard claim 12, Bleiel discloses that at least 85% by weight of the microparticle is carbohydrate (e.g., glucose) (page 5, lines 8-9).
Regarding claims 13 and 49, Bleiel discloses that the amount of the carbohydrate (e.g., glucose) in the composition includes 10-200 Kcal (e.g., 2.5 g to 50 g) (page 17, lines 5-6). As evidenced by Fox, 100 Kcal/4 Kcal per gram = 25 g glucose (column 7, line 15).
Regarding claim 7, Bleiel discloses that the coating material includes enteric coating material further including methyl-(methyl acrylate-methacrylic acid copolymers) and cellulose acetate phthalate (page 16, lines 2-5).
Regarding claim 14, Bleiel discloses that the coated sugar is provided in the form of a microparticulate (e.g., size, with respect to the largest dimension, provides for entry into the intestine of a subject) (page 2, lines 18-19). Bleiel discloses that the sugar includes glucose (page 16, lines 25-28). The glucose (e.g., compound stimulating enteroendocrine cells to release at least one enterokine) disclosed by Bleiel is substantially the same as the instantly claimed “compound stimulating enteroendocrine cells to release at least one enterokine” (e.g., carbohydrate is applicant elected species), therefore, the glucose disclosed by Bleiel necessarily has the same characteristics as the instantly claimed “compound stimulating enteroendocrine cells to release at least one enterokine” (e.g., carbohydrate is applicant elected species), e.g., stimulates I cells, K cells or L cells.
Bleiel does not specifically teach that the composition further comprises one or more gelling agents. The deficiency is made up for by the teachings of Noel.
Noel is primarily directed towards a system and method of creating personalized doses of active pharmaceutical ingredients dispersed in a palatable oral formulation, wherein the active are encapsulated into microparticles that are dispersed with a thixotropic suspension vehicle to create a customized oral formulation (abstract).
Regarding claims 1, 21-22, 24 and 26, Noel teaches a suspension comprising a uniform dispersion of microparticles (e.g., a heterogeneous mixture), wherein each microparticle comprises a core and a coating, wherein the core comprises about 20-99 weight percent of at least one active pharmaceutical ingredient (paragraph [0028]). Noel teaches a semisolid thixotropic hydrocolloid suspension media (paragraph [0028]). Noel teaches that hydrocolloid is aqueous-based (e.g., contains aqueous solution/gelling composition) (paragraph [0077]). Noel teaches that hydrocolloid are molecules that are dispersible in water or an aqueous solution and includes alginate, xanthan gum and polyethylene glycol (e.g., gelling agents) (paragraph [0080]). As evidenced by the instant specification, gelling agents includes polysaccharides including alginates, xanthan gum and polyethylene glycols (page 5, lines 5-9). Noel teaches that system create a customized formulation that has desired including food substances, flavors and/or textures (paragraph [0096]).
Regarding claims 1, 7, 47 and 50, Noel teaches coatings including hydroxypropyl methyl cellulose phthalate and methacrylic acid copolymer (paragraph [0016]). Noel teaches microparticles having an average particle size of between about 100-1000 microns (paragraph [0021]). Noel teaches microparticle coating that dissolve with a pH of about 5-8 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject) (paragraph [0062]). Noel teaches coating including Eudragit® L100 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject) (paragraph [0113]). As evidenced by Cetin, Eudragit® L100 is an anionic copolymerization product of methacrylic acid and methyl methacrylate and is a pH-dependent polymer, that is soluble in intestinal fluid from pH 6 (page 1251, first column, first paragraph). Noel teaches that the microparticles comprises a disintegrant in the core (paragraph [0004]). Noel teaches that the disintegrant help break apart and release the API (paragraph [0065]).
Regarding claims 23 and 25, Noel teaches that components including pH regulating agents are added to the suspension (paragraph [0085]).
Regarding claim 48, Noel teaches that the coating comprises about 1-50 weight percent of the microparticle, based on the total weight of the microparticle (paragraph [0018]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the microparticles comprises a core comprising glucose and a disintegrant, and a coating that is gastric-resistant providing transit through the stomach of a mammal and ileal release; wherein the coating includes Eudragit® L100; wherein the suspension media further includes a pH regulating agent; wherein the microparticles have an average particle size of between about 100-1000 microns; wherein the coating includes Eudragit® L100 that dissolves with a pH of 6 and above (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject). The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain a composition that can provide different flavors and textures by including a suspension media comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that the microparticles are uniformly dispersed in; 2) obtain microparticles that break apart and release the API by including a disintegrant in the core of the microparticles; and 3) obtain microparticles that are gastric resistant by substituting known enteric coating of methyl-(methyl acrylate-methacrylic acid copolymers) including Eudragit® L100 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject). The person of ordinary skill in the art would have reasonably expected success because Bleiel discloses sugar (carbohydrate) contained within a gastric-resistant carrier configured for transit through the stomach of a mammal and ileal release (page 2, lines 5-6). Bleiel discloses that the coated sugar is provided in the form of a microparticulate (e.g., size, with respect to the largest dimension, provides for entry into the intestine of a subject) (page 2, lines 18-19). Bleiel discloses including a composition comprising microparticles (e.g., multiple dosage forms) (page 4, lines 1-3 and 19-21). Bleiel discloses gastric-resistant and ileal-sensitive material is coated onto carbohydrate material to make the microparticles (e.g., multiple dosage forms) (page 5, lines 23-27; page 7, lines 25-29). Bleiel discloses that the sugar includes glucose (page 16, lines 25-28). Noel teaches a suspension comprising a uniform dispersion of microparticles (e.g., a heterogeneous mixture), wherein each microparticle comprises a core and a coating, wherein the core comprises about 20-99 weight percent of at least one active pharmaceutical ingredient (paragraph [0028]). Noel teaches a semisolid thixotropic hydrocolloid suspension media (paragraph [0028]). Noel teaches that hydrocolloid is aqueous-based (e.g., contains aqueous solution/gelling composition) (paragraph [0077]). Noel teaches that hydrocolloid are molecules that are dispersible in water or an aqueous solution and includes alginate, xanthan gum and polyethylene glycol (e.g., gelling agents) (paragraph [0080]). As evidenced by the instant specification, gelling agents includes polysaccharides including alginates, xanthan gum and polyethylene glycols (page 5, lines 5-9). Noel teaches that system create a customized formulation that has desired including food substances, flavors and/or textures (paragraph [0096]). Noel teaches coatings including hydroxypropyl methyl cellulose phthalate and methacrylic acid copolymer (paragraph [0016]). Noel teaches microparticle coating that dissolve with a pH of about 5-8 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject) (paragraph [0062]). Noel teaches coating including Eudragit® L100 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject) (paragraph [0113]). As evidenced by Cetin, Eudragit® L100 is an anionic copolymerization product of methacrylic acid and methyl methacrylate and is a pH-dependent polymer, that is soluble in intestinal fluid from pH 6 (page 1251, first column, first paragraph).
The rejection of claims 3-4 under 35 U.S.C. 103 as being unpatentable over Bleiel in view of Noel as evidenced by the instant specification, Fox and Cetin as applied to claims 1, 7-14, 21-26 and 47-50 above, and further in view of LEGRAND (US 2004/0234601 A1) is maintained.
Regarding claims 3-4, the composition of claim 2 is described above in section 7. Bleiel discloses that the amount of the carbohydrate (e.g., glucose) in the composition includes 10-200 Kcal (e.g., 2.5 g to 50 g) (page 17, lines 5-6). As evidenced by Fox, 100 Kcal/4 Kcal per gram = 25 g glucose (column 7, line 15).
Bleiel and Noel do not specifically teach that the composition contains 10000 to 400000 or 20000 to 30000 microparticles. The deficiency is made up for by the teachings of Legrand.
Legrand is primarily directed towards a microparticulate system for releases of active principles (abstract).
Regarding claims 3-4, Legrand teaches in cases where the dose of active is high including 500 mg or more, a monolithic form is too large to be swallowed easily. It is then of particular value to have a microparticulate form (paragraph [0019]). Legrand teaches dose of active to be administered spread over a large number of microcapsules including typically 10,000 for a dose of 500 mg which has advantages including residence time of the microcapsules can be prolonged and variability of the gastric emptying is reduced because of the emptying (paragraphs [0128-0129]). Therefore, the size and number microparticles is an art-recognized result-effective variable, e.g., provides prolonged residence time of the microparticles and reduced variability of the gastric emptying, which a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention.
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the microparticles comprises a core comprising glucose and a disintegrant, and a coating that is gastric-resistant providing transit through the stomach of a mammal and ileal release; wherein the coating includes Eudragit® L100; wherein the suspension media further includes a pH regulating agent; wherein the microparticles have an average particle size of between about 100-1000 microns; wherein the coating includes Eudragit® L100 that dissolves with a pH of 6 and above (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject); and wherein the number of microparticles is optimized using a reference point of 10,000 microparticles for a dose of 500 mg. The person of ordinary skill in the art would have been motivated to make those modifications to in order to obtain a composition with desired prolong residence time and reduction is variability of the gastric emptying by optimizing the size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying. The person of ordinary skill in the art would have reasonably expected success because Bleiel discloses that the amount of the carbohydrate (e.g., glucose) in the composition includes 10-200 Kcal (e.g., 2.5 g to 50 g) (page 17, lines 5-6). As evidenced by Fox, 100 Kcal/4 Kcal per gram = 25 g glucose (column 7, line 15). Legrand teaches in cases where the dose of active is high including 500 mg or more, a monolithic form is too large to be swallowed easily. It is then of particular value to have a microparticulate form (paragraph [0019]). Legrand teaches dose of active to be administered spread over a large number of microcapsules including typically 10,000 for a dose of 500 mg which has advantages including residence time of the microcapsules can be prolonged and variability of the gastric emptying is reduced because of the emptying (paragraphs [0128-0129]).
The rejection of claims 15-17 under 35 U.S.C. 103 as being unpatentable over Bleiel in view of Noel as evidenced by the instant specification and Fox as applied to claims 1, 7-14, 21-26 and 47-50 above, and further in view of FAYAD (WO 2013/063527) is maintained.
Regarding claims 15-17, the composition of claim 1 is described above in section 7. Bleiel discloses that metabolic disorder characterized by dysregulated insulin production includes Type II diabetes, pre-diabetes, obesity and metabolic syndrome (page 11, lines 17-19; claim 5).
Bleiel and Noel do not specifically teach that the composition further comprises caffeine (e.g., substance that enhances release of GLP-1 and/or PYY by L cells). The deficiency is made up for by the teachings of Fayad.
Fayad is primarily directed towards composition and method for treatment of a variety of metabolic syndromes including T2D (e.g. type 2 diabetes) (abstract).
Regarding claims 15-17, Fayad teaches composition for treating including T2D (page 1, first paragraph). Fayad teaches combining traditional bioactive agents together with the core to deliver the content specifically to the ileum for targeted therapy avoiding side effects and increasing the yield of the therapy, and includes stimulants including caffeine (e.g., substance that enhances release of GLP-1 and/or PYY by L cells) (paragraph bridging pages 26 and 27).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the microparticles comprises a core comprising glucose, caffeine and a disintegrant, and a coating that is gastric-resistant providing transit through the stomach of a mammal and ileal release; wherein the coating includes Eudragit® L100; wherein the suspension media further includes a pH regulating agent; wherein the microparticles have an average particle size of between about 100-1000 microns; wherein the coating includes Eudragit® L100 that dissolves with a pH of 6 and above (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject); and wherein the suspension media further includes a pH regulating agent. The person of ordinary skill in the art would have been motivated to make those modifications to add stimulant actives to a composition for treating metabolic disorders including type 2 diabetes by combining caffeine as a stimulant in the core of the microparticles, as taught by Fayad. The person of ordinary skill in the art would have reasonably expected success because Bleiel discloses that the composition is for including subject having Type II diabetes (page 11, lines 17-18; claim 5). Fayad teaches composition for treating including T2D (page 1, first paragraph). Fayad teaches combining traditional bioactive agents together with the core to deliver the content specifically to the ileum for targeted therapy avoiding side effects and increasing the yield of the therapy, and includes stimulants including caffeine (e.g., substance that enhances release of GLP-1 and/or PYY by L cells) (paragraph bridging pages 26 and 27).
The rejection of claims 18-19 under 35 U.S.C. 103 as being unpatentable over Bleiel in view of Noel as evidenced by the instant specification and Fox as applied to claims 1, 7-14, 21-26 and 47-50 above, and further in view of SPRENGER (WO 2017/129639 A1) is maintained.
Regarding claims 18-19, the composition of claim 1 is described above in section 7. Bleiel discloses the composition is used for including a subject a metabolic disorder characterized by dysregulated insulin production (page 3, lines 11-13). Bleiel discloses that metabolic disorder characterized by dysregulated insulin production includes Type II diabetes, pre-diabetes, obesity and metabolic syndrome (page 11, lines 17-19).
Bleiel and Noel do not specifically teach that the composition further comprises human milk oligosaccharide (e.g., an enteroendocrine cell maturation agent). The deficiency is made up for by the teachings of Sprenger.
Sprenger is primarily directed towards a composition comprising at least one human milk oligosaccharide for use in preventing or treating a health disorder in an infant or young child by increasing GLP-1 in said infant or young child (abstract).
Regarding claims 18-19, Sprenger teaches a composition comprising at least one human milk oligosaccharide for use in preventing and/or treating a health disorder including obesity or type 2 diabetes in and infant or young child by increasing GLP-1 secretion in said infant or young child (page 1, lines7-10).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the microparticles comprises a core comprising glucose, a human milk oligosaccharide (e.g., an enteroendocrine cell maturation agent) and a disintegrant, and a coating that is gastric-resistant providing transit through the stomach of a mammal and ileal release; wherein the coating includes Eudragit® L100; wherein the suspension media further includes a pH regulating agent; wherein the microparticles have an average particle size of between about 100-1000 microns; wherein the coating includes Eudragit® L100 that dissolves with a pH of 6 and above (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject); and wherein the suspension media further includes a pH regulating agent. The person of ordinary skill in the art would have been motivated to make those modifications to include additional actives for treating obesity and/or type 2 diabetes by including human milk oligosaccharides (e.g., an enteroendocrine cell maturation agent) that can be used to treat including obesity or type 2 diabetes, as taught by Sprenger. The person of ordinary skill in the art would have reasonably expected success because Bleiel discloses the composition is used for including a subject a metabolic disorder characterized by dysregulated insulin production (page 3, lines 11-13). Bleiel discloses that metabolic disorder characterized by dysregulated insulin production includes Type II diabetes, pre-diabetes, obesity and metabolic syndrome (page 11, lines 17-19). Sprenger teaches a composition comprising at least one human milk oligosaccharide for use in preventing and/or treating a health disorder including obesity or type 2 diabetes in and infant or young child by increasing GLP-1 secretion in said infant or young child (page 1, lines7-10).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
The provisional rejection of claims 1, 7-12, 14-19, 21-26, 47-48 and 50 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-11, 23 and 26 of copending Application No. 17/433,867 (reference application, hereafter ‘867) in view of NOEL (US 2020/0230067 A1, filed 31 March 2020) is maintained.
Regarding instant claims 1, 8-12 and 15-17, claim 1 of ‘867 recites an oral dosage form comprising a core and a pH-sensitive enteric coating, wherein the core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine, and at least one disintegrant providing a burst release of the ingredients of the core when the coating is substantially degraded or dissolved, and wherein the coating is a pH sensitive polymer that substantially dissolves or is substantially degraded in the terminal jejunum of a subject. Claim 23 of ‘867 recites that the core contains glucose (e.g., compound stimulating enteroendocrine cells to release at least one enterokine) in an amount of 60 to 70% based on the total weight of the core and caffeine (e.g., substance that enhances release of GLP-1 and/or PYY by L cells). Claim 26 of ‘867 recites that the oral dosage form has a size of less than 3 mm. Claim 31 of ‘867 recites an oral dosage form comprising a core and a pH-sensitive enteric coating, wherein the core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine, and at least one disintegrant providing a burst release of the ingredients of the core when the coating is substantially degraded or dissolved, and wherein the coating is a pH sensitive polymer that substantially degrades and/or dissolves at a pH value of about 5.5 to about 7.5, wherein the dosage forms have a size of less than 3 mm, based on the largest dimension of the oral dosage forms, and release said nutrient compound in the terminal jejunum of a subject.
Regarding instant 50, claim 10 of ‘867 recites that the pH sensitive polymer substantially degrades and/or dissolves at a pH value of about 5.5 to about 7.5.
Regarding instant claim 7, claim 11 of ‘867 recites that the pH sensitive polymer is selected from the group consisting of hydroxypropylmethyl celluloses and anionic copolymers of methacrylic acid and metacrylmethacrylate.
Regarding claims 14 and 48, claim 23 of ‘867 recites that the core contains glucose (e.g., compound stimulating enteroendocrine cells to release at least one enterokine) in an amount of 60 to 70% based on the total weight of the core and caffeine (e.g., substance that enhances release of GLP-1 and/or PYY by L cells). The glucose (e.g., compound stimulating enteroendocrine cells to release at least one enterokine) in the claims of ‘867 is substantially the same as the instantly claimed “compound stimulating enteroendocrine cells to release at least one enterokine” (e.g., carbohydrate is applicant elected species), therefore, the glucose in the claims of ‘867 necessarily has the same characteristics as the instantly claimed “compound stimulating enteroendocrine cells to release at least one enterokine” (e.g., carbohydrate is applicant elected species), e.g., stimulates I cells, K cells or L cells.
Regarding instant claims 18-19, claim 8 and 9 of ‘867 recites that the core further contains an enteroendocrine cell maturation agent, wherein the maturation agent is a human milk oligosaccharide, respectively.
Regarding instant claim 47, claim 27 of ‘867 recites that the size is from about 0.6 mm to about 1.7 mm.
The claims of ‘867 do not specifically teach that the composition includes a gelling agent in a gelling composition and multiple dosage forms. The deficiency is made up for by the teachings of Noel.
Noel is primarily directed towards a system and method of creating personalized doses of active pharmaceutical ingredients dispersed in a palatable oral formulation, wherein the actives are encapsulated into microparticles that are dispersed with a thixotropic suspension vehicle to create a customized oral formulation (abstract).
Regarding claims 1, 21-22, 24 and 26, Noel teaches a suspension comprising a uniform dispersion of microparticles (e.g., a heterogeneous mixture), wherein each microparticle comprises a core and a coating, wherein the core comprises about 20-99 weight percent of at least one active pharmaceutical ingredient (paragraph [0028]). Noel teaches a semisolid thixotropic hydrocolloid suspension media (paragraph [0028]). Noel teaches that hydrocolloid is aqueous-based (e.g., contains aqueous solution/gelling composition) (paragraph [0077]). Noel teaches that hydrocolloid are molecules that are dispersible in water or an aqueous solution and includes alginate, xanthan gum and polyethylene glycol (e.g., gelling agents) (paragraph [0080]). As evidenced by the instant specification, gelling agents includes polysaccharides including alginates, xanthan gum and polyethylene glycols (page 5, lines 5-9). Noel teaches that system create a customized formulation that has desired including food substances, flavors and/or textures (paragraph [0096]).
Regarding claims 23 and 25, Noel teaches that components including pH regulating agents are added to the suspension (paragraph [0085]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles with a core and pH-sensitive enteric coating; wherein the microparticles are uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the core comprises glucose, caffeine, a human milk oligosaccharide and a disintegrant; wherein the coating comprises pH sensitive polymer is selected from the group consisting of hydroxypropylmethyl celluloses and anionic copolymers of methacrylic acid and metacrylmethacrylate; wherein the pH sensitive polymer substantially degrades and/or dissolves at a pH value of about 5.5 to about 7.5; and wherein the suspension media further includes a pH regulating agent. The person of ordinary skill in the art would have been motivated to make those modifications to obtain a composition that can provide different flavors and textures by including a suspension media comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents), that the microparticles are uniformly dispersed in.
The provisional rejection of claims 3-4, 13 and 49 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-11, 23 and 26 of ‘867 in view of Noel as applied to claims 1-2, 5-12, 14-26 and 35-46 above, and further in view of BLEIEL (WO 2019/170840 A1) and LEGRAND (US 2004/0234601 A1) as evidenced by FOX (US 5,360,614) is maintained.
Regarding claims 3-4, the composition of claim 2 is described above in section 18.
The claims of ‘867 do not specifically recite and Noel does not specifically teach that the composition contains 10000 to 400000 or 20000 to 30000 dosage/microparticles. The deficiency is made up for by the teachings of Bleiel and Legrand.
Bleiel is primarily directed towards a composition comprising microparticles comprising high glycaemic index (GI) carbohydrate contained within a gastric-resistant, ileal-sensitive, GLP-1 stimulative, non-porous carrier configured for release of the high GI carbohydrate in the ileum (abstract).
Regarding claims 13 and 49, Bleiel discloses sugar (carbohydrate) contained within a gastric-resistant carrier configured for transit through the stomach of a mammal and ileal release (page 2, lines 5-6). Bleiel discloses that the coated sugar is provided in the form of a microparticulate (e.g., size, with respect to the largest dimension, provides for entry into the intestine of a subject) (page 2, lines 18-19). Bleiel discloses including a composition comprising microparticles (e.g., multiple dosage forms) (page 4, lines 1-3 and 19-21). Bleiel discloses gastric-resistant and ileal-sensitive material is coated onto carbohydrate material to make the microparticles (e.g., multiple dosage forms) (page 5, lines 23-27; page 7, lines 25-29). Bleiel discloses that metabolic disorder characterized by dysregulated insulin production includes Type II diabetes, pre-diabetes, obesity and metabolic syndrome (page 11, lines 17-19; claim 5). Bleiel discloses that the sugar includes glucose (page 16, lines 25-28). Bleiel discloses that the amount of the carbohydrate (e.g., glucose) in the composition includes 10-200 Kcal (e.g., 2.5 g to 50 g) (page 17, lines 5-6). As evidenced by Fox, 100 Kcal/4 Kcal per gram = 25 g glucose (column 7, line 15).
Legrand is primarily directed towards a microparticulate system for releases of active principles (abstract).
Regarding claims 3-4, Legrand teaches in cases where the dose of active is high including 500 mg or more, a monolithic form is too large to be swallowed easily. It is then of particular value to have a microparticulate form (paragraph [0019]). Legrand teaches dose of active to be administered spread over a large number of microcapsules including typically 10,000 for a dose of 500 mg which has advantages including residence time of the microcapsules can be prolonged and variability of the gastric emptying is reduced because of the emptying (paragraphs [0128-0129]). Therefore, the size and number microparticles is an art-recognized result-effective variable, e.g., provides prolonged residence time of the microparticles and reduced variability of the gastric emptying, which a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention.
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles with a core and pH-sensitive enteric coating; wherein the microparticles are uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the core comprises glucose, caffeine, a human milk oligosaccharide and a disintegrant; wherein the coating comprises pH sensitive polymer is selected from the group consisting of hydroxypropylmethyl celluloses and anionic copolymers of methacrylic acid and metacrylmethacrylate; wherein the pH sensitive polymer substantially degrades and/or dissolves at a pH value of about 5.5 to about 7.5; wherein the suspension media further includes a pH regulating agent; wherein and the amount of the glucose in the composition includes 10-200 Kcal (e.g., 2.5 g to 50 g); and wherein the number of microparticles is optimized using a reference point of 10,000 microparticles for a dose of 500 mg. The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain a composition that is effective at treating metabolic disorder including Type II diabetes, pre-diabetes, obesity and metabolic syndrome by using the amount of carbohydrate including glucose of 10-200 Kcal (e.g., 2.5 g to 50 g) taught by Bleiel; and 2) obtain a composition with desired prolong residence time and reduction is variability of the gastric emptying by optimizing the size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000, a number taught by LEGRAND for 500 mg of drug) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying. The person of ordinary skill in the art would have reasonably expected success because Bleiel discloses that the amount of the carbohydrate (e.g., glucose) in the composition includes 10-200 Kcal (e.g., 2.5 g to 50 g) (page 17, lines 5-6). As evidenced by Fox, 100 Kcal/4 Kcal per gram = 25 g glucose (column 7, line 15). Legrand teaches in cases where the dose of active is high including 500 mg or more, a monolithic form is too large to be swallowed easily. It is then of particular value to have a microparticulate form (paragraph [0019]). Legrand teaches dose of active to be administered spread over a large number of microcapsules including typically 10,000 for a dose of 500 mg which has advantages including residence time of the microcapsules can be prolonged and variability of the gastric emptying is reduced because of the emptying (paragraphs [0128-0129]).
This is a provisional nonstatutory double patenting rejection.
New Grounds of Rejection Necessitated by the Claim Amendments
Claims 51-55 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over FAYAD (US 9,757,346 B2; patent date of 12 September 2017) in view of NOEL (US 2020/0230067 A1, effective filing date of 31 March 2020) and LEGRAND (US 2004/0234601 A1) as evidenced by the instant specification.
Fayad is primarily directed towards a dosage form comprising a controlled release composition, which comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance in vivo upon reaching the subject’s ileum (abstract).
Regarding claims 51-52, Fayad discloses a controlled release oral dosage form comprising an effective amount of a nutritional substance preferably D-glucose in an amount effective when released in the ileum to stimulate or inhibit the release of hormones in that portion of the small intestine of a subject (paragraph bridging columns 6 and 7). Fayad discloses that the that the nutritional component is coated using a polymeric, preferably aqueous pH-sensitive coating to effect a natural physiological response within the subject’s ileum with favorable results (column 8, lines 3-11). Fayad discloses D-glucose amount of including at least about 7.5 grams (column 9, lines 60-62). Fayad discloses that the nutritional substance including D-glucose is combined with including a delayed release component including copolymers of methacrylic acid and methylmethacrylate having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum, including Eudragit® S100 alone (column 10, lines 26-31). Fayad discloses that Eudragit® S100 dissolved at pH 7 and upwards (e.g., substantially dissolves or is substantially degraded at a pH value of about 7.2 to 7.3, provide release of the core in a terminal jejunum of a subject) (column 10, 36-37). Fayad discloses that dosage forms including multiparticulate systems (column 18, lines 11-14). Fayad discloses delayed release oral dosage form comprising a core containing an ileum hormonal-stimulating amount of a nutritional substance that is coated by an enteric coating (column 19, lines 43-46). Fayad discloses that the dosage form pharmaceutically acceptable additives (column 19, 59-60). Fayad discloses that pharmaceutically acceptable additives include disintegrating agents (column 20, line 4). The glucose (e.g., compound stimulating enteroendocrine cells to release at least one enterokine) coated with including Eudragit® S100 dissolved at pH 7 disclosed by Fayad is substantially the same as the instantly claimed “compound stimulating enteroendocrine cells to release at least one enterokine” (e.g., carbohydrate is applicant elected species), therefore, the glucose disclosed by Fayad necessarily has the same characteristics as the instantly claimed “compound stimulating enteroendocrine cells to release at least one enterokine” (e.g., carbohydrate is applicant elected species), e.g., stimulates I cells, K cells or L cells.
Fayad does not specifically teach that multiparticulate has a size of less than 3mm, 20000 to 30000 microparticulate, and that the composition further comprises one or more gelling agents. The deficiencies are made up for by the teachings of Noel and Legrand.
Noel is primarily directed towards a system and method of creating personalized doses of active pharmaceutical ingredients dispersed in a palatable oral formulation, wherein the active are encapsulated into microparticles that are dispersed with a thixotropic suspension vehicle to create a customized oral formulation (abstract).
Regarding claims 51 and 53-55, Noel teaches a suspension comprising a uniform dispersion of microparticles (e.g., a heterogeneous mixture), wherein each microparticle comprises a core and a coating, wherein the core comprises about 20-99 weight percent of at least one active pharmaceutical ingredient (paragraph [0028]). Noel teaches that the microparticles comprises a disintegrant in the core (paragraph [0004]). Noel teaches microparticles having an average particle size of between about 100-1000 microns (paragraph [0021]). Noel teaches a semisolid thixotropic hydrocolloid suspension media (paragraph [0028]). Noel teaches that hydrocolloid is aqueous-based (e.g., contains aqueous solution/gelling agent) (paragraph [0077]). Noel teaches that hydrocolloid are molecules that are dispersible in water or an aqueous solution and includes alginate, xanthan gum and polyethylene glycol (e.g., gelling agents) and combinations thereof (e.g., gelling composition) (paragraph [0080]). As evidenced by the instant specification, gelling agents includes polysaccharides including alginates, xanthan gum and polyethylene glycols (page 5, lines 5-9). Noel teaches that components including pH regulating agents are added to the suspension (paragraph [0085]). Noel teaches that dissolution of API during storage can be delayed by tailoring the pH and viscosity of the suspending media (paragraph [0091]). Noel teaches that system create a customized formulation that has desired including food substances, flavors and/or textures (paragraph [0096]).
Legrand is primarily directed towards a microparticulate system for releases of active principles (abstract).
Regarding claim 51, Legrand teaches in cases where the dose of active is high including 500 mg or more, a monolithic form is too large to be swallowed easily. It is then of particular value to have a microparticulate form (paragraph [0019]). Legrand teaches dose of active to be administered spread over a large number of microcapsules including typically 10,000 for a dose of 500 mg which has advantages including residence time of the microcapsules can be prolonged and variability of the gastric emptying is reduced because of the emptying (paragraphs [0128-0129]). Therefore, the size and number microparticles is an art-recognized result-effective variable, e.g., provides prolonged residence time of the microparticles and reduced variability of the gastric emptying, which a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention.
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles uniformly dispersed in a suspension media (e.g., gelling agent) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) and combinations thereof (e.g., gelling composition) that is in an aqueous solution; wherein the microparticles comprises a core comprising glucose and a disintegrant, and a coating comprising a polymer that provides ileal release; wherein the polymer includes Eudragit® S100 that dissolved at pH 7 and upwards (e.g., substantially dissolves or is substantially degraded at a pH value of about 7.2 to 7.3, provide release of the core in a terminal jejunum of a subject); wherein the microparticles have a size of between about 100-1000 microns (e.g., .1 to 1 mm); and wherein the suspension media further includes a pH regulating agent. The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain a composition that can provide different flavors and provides delayed dissolution of the active during storage by making microparticles uniformly dispersed in a suspension media comprising a hydrocolloid including alginates, xanthan gum, polyethylene glycols (e.g., gelling agents) and combination thereof (e.g., gelling composition) that is taught by Noel; and 2) obtain a composition with desired prolong residence time and reduction is variability of the gastric emptying by optimizing the size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying as taught by Legrand. The person of ordinary skill in the art would have reasonably expected success because Fayad discloses a controlled release oral dosage form comprising an effective amount of a nutritional substance preferably D-glucose in an amount effective when released in the ileum to stimulate or inhibit the release of hormones in that portion of the small intestine of a subject (paragraph bridging columns 6 and 7). Fayad discloses that the that the nutritional component is coated using a polymeric, preferably aqueous pH-sensitive coating to effect a natural physiological response within the subject’s ileum with favorable results (column 8, lines 3-11). Fayad discloses D-glucose amount of including at least about 7.5 grams (column 9, lines 60-62). Fayad discloses that the nutritional substance including D-glucose is combined with including a delayed release component including copolymers of methacrylic acid and methylmethacrylate having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum, including Eudragit® S100 alone (column 10, lines 26-31). Fayad discloses that Eudragit® S100 dissolved at pH 7 and upwards (e.g., substantially dissolves or is substantially degraded at a pH value of about 7.2 to 7.3, provide release of the core in a terminal jejunum of a subject) (column 10, 36-37). Fayad discloses that dosage forms including multiparticulate systems (column 18, lines 11-14). Fayad discloses delayed release oral dosage form comprising a core containing an ileum hormonal-stimulating amount of a nutritional substance that is coated by an enteric coating (column 19, lines 43-46). Fayad discloses that the dosage form pharmaceutically acceptable additives (column 19, 59-60). Fayad discloses that pharmaceutically acceptable additives include disintegrating agents (column 20, line 4). Noel teaches a suspension comprising a uniform dispersion of microparticles (e.g., a heterogeneous mixture), wherein each microparticle comprises a core and a coating, wherein the core comprises about 20-99 weight percent of at least one active pharmaceutical ingredient (paragraph [0028]). Noel teaches that the microparticles comprises a disintegrant in the core (paragraph [0004]). Noel teaches microparticles having an average particle size of between about 100-1000 microns (paragraph [0021]). Noel teaches a semisolid thixotropic hydrocolloid suspension media (paragraph [0028]). Noel teaches that hydrocolloid is aqueous-based (e.g., contains aqueous solution/gelling agent) (paragraph [0077]). Noel teaches that hydrocolloid are molecules that are dispersible in water or an aqueous solution and includes alginate, xanthan gum and polyethylene glycol (e.g., gelling agents) and combinations thereof (e.g., gelling composition) (paragraph [0080]). As evidenced by the instant specification, gelling agents includes polysaccharides including alginates, xanthan gum and polyethylene glycols (page 5, lines 5-9). Noel teaches that components including pH regulating agents are added to the suspension (paragraph [0085]). Noel teaches that dissolution of API during storage can be delayed by tailoring the pH and viscosity of the suspending media (paragraph [0091]). Noel teaches that system create a customized formulation that has desired including food substances, flavors and/or textures (paragraph [0096]). Legrand teaches in cases where the dose of active is high including 500 mg or more, a monolithic form is too large to be swallowed easily. It is then of particular value to have a microparticulate form (paragraph [0019]). Legrand teaches dose of active to be administered spread over a large number of microcapsules including typically 10,000 for a dose of 500 mg which has advantages including residence time of the microcapsules can be prolonged and variability of the gastric emptying is reduced because of the emptying (paragraphs [0128-0129]).
Claims 51-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-11, 23 and 26 of copending Application No. 17/433,867 (reference application, hereafter ‘867) in view of NOEL (US 2020/0230067 A1, filed 31 March 2020), FAYAD (US 9,757,346 B2; patent date of 12 September 2017) and LEGRAND (US 2004/0234601 A1) as evidenced by the instant specification.
Regarding instant claims 51, claim 1 of ‘867 recites an oral dosage form comprising a core and a pH-sensitive enteric coating, wherein the core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine, and at least one disintegrant providing a burst release of the ingredients of the core when the coating is substantially degraded or dissolved, and wherein the coating is a pH sensitive polymer that substantially dissolves or is substantially degraded in the terminal jejunum of a subject. Claim 23 of ‘867 recites that the core contains glucose (e.g., compound stimulating enteroendocrine cells to release at least one enterokine) in an amount of 60 to 70% based on the total weight of the core. Claim 26 of ‘867 recites that the oral dosage form has a size of less than 3 mm. Claim 27 of ‘867 recites that the size is from about 0.6 mm to about 1.7 mm. Claim 31 of ‘867 recites an oral dosage form comprising a core and a pH-sensitive enteric coating, wherein the core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine, and at least one disintegrant providing a burst release of the ingredients of the core when the coating is substantially degraded or dissolved, and wherein the coating is a pH sensitive polymer that substantially degrades and/or dissolves at a pH value of about 5.5 to about 7.5 (e.g., substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3), wherein the dosage forms have a size of less than 3 mm, based on the largest dimension of the oral dosage forms, and release said nutrient compound in the terminal jejunum of a subject.
Regarding instant claim 52, claim 11 of ‘867 recites that the pH sensitive polymer is selected from the group consisting of hydroxypropylmethyl celluloses and anionic copolymers of methacrylic acid and metacrylmethacrylate.
The claims of ‘867 do not specifically teach that the composition comprises 20000 to 30000 dosage forms with a largest dimension which is less than 3 mm, total weight of glucose in the composition being 7 g to 15 and includes a gelling agent. The deficiency is made up for by the teachings of Noel, Fayad and Legrand.
Noel is primarily directed towards a system and method of creating personalized doses of active pharmaceutical ingredients dispersed in a palatable oral formulation, wherein the actives are encapsulated into microparticles that are dispersed with a thixotropic suspension vehicle to create a customized oral formulation (abstract).
Regarding claims 51 and 53-55, Noel teaches a suspension comprising a uniform dispersion of microparticles (e.g., a heterogeneous mixture), wherein each microparticle comprises a core and a coating, wherein the core comprises about 20-99 weight percent of at least one active pharmaceutical ingredient (paragraph [0028]). Noel teaches a semisolid thixotropic hydrocolloid suspension media (paragraph [0028]). Noel teaches that hydrocolloid is aqueous-based (e.g., contains aqueous solution/gelling composition) (paragraph [0077]). Noel teaches that hydrocolloid are molecules that are dispersible in water or an aqueous solution and includes alginate, xanthan gum and polyethylene glycol (e.g., gelling agents) (paragraph [0080]). As evidenced by the instant specification, gelling agents includes polysaccharides including alginates, xanthan gum and polyethylene glycols (page 5, lines 5-9). Noel teaches that system create a customized formulation that has desired including food substances, flavors and/or textures (paragraph [0096]).
Fayad is primarily directed towards a dosage form comprising a controlled release composition, which comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance in vivo upon reaching the subject’s ileum, and for treatment of including diabetes and pre-diabetic symptoms (abstract).
Regarding claims 51, Fayad teaches treating including obesity, metabolic syndrome and type II diabetes (column 6, lines 50-53). Fayad discloses a controlled release oral dosage form comprising an effective amount of a nutritional substance preferably D-glucose in an amount effective when released in the ileum to stimulate or inhibit the release of hormones in that portion of the small intestine of a subject (paragraph bridging columns 6 and 7). Fayad discloses that the that the nutritional component is coated using a polymeric, preferably aqueous pH-sensitive coating to effect a natural physiological response within the subject’s ileum with favorable results (column 8, lines 3-11). Fayad discloses D-glucose amount of including at least about 7.5 grams (column 9, lines 60-62).
Legrand is primarily directed towards a microparticulate system for releases of active principles (abstract).
Regarding claim 51, Legrand teaches in cases where the dose of active is high including 500 mg or more, a monolithic form is too large to be swallowed easily. It is then of particular value to have a microparticulate form (paragraph [0019]). Legrand teaches dose of active to be administered spread over a large number of microcapsules including typically 10,000 for a dose of 500 mg which has advantages including residence time of the microcapsules can be prolonged and variability of the gastric emptying is reduced because of the emptying (paragraphs [0128-0129]). Therefore, the size and number microparticles is an art-recognized result-effective variable, e.g., provides prolonged residence time of the microparticles and reduced variability of the gastric emptying, which a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention.
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles with a core and pH-sensitive enteric coating; wherein the microparticles are uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the core comprises glucose, caffeine, a human milk oligosaccharide and a disintegrant; wherein the coating comprises pH sensitive polymer is selected from the group consisting of hydroxypropylmethyl celluloses and anionic copolymers of methacrylic acid and metacrylmethacrylate; wherein the pH sensitive polymer substantially degrades and/or dissolves at a pH value of about 5.5 to about 7.5; and wherein the suspension media further includes a pH regulating agent. The person of ordinary skill in the art would have been motivated to make those modifications to obtain: 1) a composition that can provide different flavors and provides delayed dissolution of the active during storage by making microparticles uniformly dispersed in a suspension media comprising a hydrocolloid including alginates, xanthan gum, polyethylene glycols (e.g., gelling agents) and combination thereof (e.g., gelling composition) that is taught by Noel; 2) obtain a composition that is effective at treating metabolic disorder including Type II diabetes, obesity and metabolic syndrome by using the amount of at least about 7.5 grams of glucose as taught by Fayad; and 3) obtain a composition with desired prolong residence time and reduction is variability of the gastric emptying by optimizing the size and number of microparticles (e.g., using number of microparticles of less than or greater than 10,000, a number taught by LEGRAND for 500 mg of drug) in order to obtain microparticles with desired prolong residence time and reduction is variability of the gastric emptying.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments and the Declaration
Applicant argues on page 10 of the response that while Bleiel proposes triggering a GLP-1 response by targeted release of high GI carbohydrate in the ileum, Bleiel’s data discloses in Bleiel’s example section does not support the conclusion that the release is confined to the ileum. Applicant points to Figure 10 of Bleiel and argues that it is shown that GLP-1 response upon oral administration of Bleiel’s composition results in the GLP-1 blood concentration almost immediately starts to rise after administration and reaches a first maximum at 60 minutes post administration. Applicant argues that the kinetic displayed in Figure 10 of Bleiel is typical for duodenal absorption. Applicant argues on page 11 of the response that Bleiel shows an increase in plasma glucose concentration paralleling the GLP-1 increase and points to Figure 3B of Bleiel. Applicant argues that Bleiel’s observed insulin responses are consistent with duodenal absorption of glucose and points to Figures 4A and 4B of Bleiel. Applicant argues on page 12 of the response that the concentration of insulin in the plasma of the treated subjects immediately starts to rise and reaches a peak at around 30 minutes after administration of the Bleiel composition. Applicant argues that the insulin concentration over time value for the microencapsulated composition and controls are parallel reaching a maximum at about 30 minutes. Applicant argues that Bleiel’s data is not consistent with the targeted delivery of glucose to the ileum. Applicant points out that as disclosed in the instant specification, the ileum is reached within about 3.8 hours after intake. Applicant argues that if the composition of Bleiel delivers the high glucose load to the ileum, the increase in GLP-1 and insulin would not have started until 3.5 hours after administration, however, at the 3.5 hour mark, in Bleiel, the value already on the downslope, which applicant references Figure 10 of Bleiel. Applicant argues that the data of Bleiel are consistent with direct stimulation of insulin secretion by the beta cells in the Langerhans islets in the pancreas through at least partial absorption of the administered glucose in the duodenum and the immediate increase of GLP-1 likely stems from the triggering of duodenal L-cells which are present in the uppermost part of the small intestine. Applicant argues that this is in stark contrast to the composition of the instant application in which the targeted burst release of the GLP-1 triggering compound from the core of the multiple dosage forms in the terminal jejunum in combination with the gelling composition leads to a GLP-1 increase starting at about 1.5 hours after administration and lasting about 4 hours and a peak GLP-1 between about 2.5 to about 3.5 hours with a low intra- and inter-patient variability, and pointing to Figure 1, page 37, and paragraph [0092] of the instant application. Applicant argues on page 15 of the response that the composition of the instant composition provides a targeted burst release of the API in the terminal jejunum, which delays the onset of insulin response, with a peak of insulin concentration at 2.5 hour after intake because the glucose released into the terminal jejunum is not absorbed but triggers enteroendocrine cells to release inter alia GLP-1 which in turn causes pancreatic beta cells to release insulin. Applicant argues that the blood glucose levels remained constant and points to Figure 1B of Deusch (publication with data related to instant application). Applicant argues that the release of insulin occurring at unchanged blood glucose levels indicates a sensitization of beta cells for glucose, which is a known effect of GLP-1. Applicant argues that the targeted burst release of the API according to the inventive combination of the small dosage forms and the gel composition according to the application suggests that GLP-1 released from L-cells in response to glucose released in the distally located terminal jejunum leads to a sensitization of the beta cells for blood glucose and the release of insulin which contrasts with the immediate release of insulin observed with the microparticles of Bleiel where an immediate insulin response is observed after intake of the microparticle composition due to at least partial absorption of the administered glucose which directly triggers beta cells of the Langerhans islets to release insulin. Applicant argues at the end of page 16 and into page 17 that Bleiel and Noel does not result in the claimed compositions with small dosage forms comprising an enteric coating providing a targeted burst release of the enterokin-releasing compound in the terminal jejunum of a subject. Applicant argues that Noel teaches coating preferably an enteric coating shielding the core from the highly acidic environment of the stomach but releases the API at a pH of above 4 such as at least 4.5, 5, 5.5 or 6. Applicant argues that the enteric coating taught by Noel would not result in a targeted burst release of the API in the terminal jejunum. Applicant argues that microparticles of Noel comprising enteric coating releasing the API at including pH 6 with Eudragit L100, and a core comprising a disintegrant together with the API being, as taught by Bleiel, a carbohydrate having a high GI such as glucose, would rapidly disintegrate in the duodenum and proximal jejunum where the glucose would be absorbed into the blood and the result blood glucose concentration curve would resemble the curve of composition C1 as shown in Figure 1B of Deusch which has a high peak of blood glucose early after administration. Applicant argues on page 18 that the proposed combination of Bleiel and Noel would result in a composition which when administered would reach the terminal jejunum with almost all glucose having been absorbed into the subject’s blood leading to a detrimental immediate direct insulin release by the beta cells of the Langerhans islets in the pancreas. Applicant argues that in case an obese or pre-diabetic subject would be given a suspension of Noel comprising 37.5 g or even 125 g glucose the subject would develop type 2 diabetes after repeated administration, requiring insulin treatment. Applicant argues on page 20 that Noels coating that dissolves at a pH of about 5-8 would not provide a targeted delivery of an API in the terminal jejunum because a coating that dissolves at a pH of about 5-8 would dissolve in or begin to dissolve in the duodenum not the terminal jejunum, which would have deleterious health effects on a diabetic subject. Applicant argues that Noel only discloses a coating which provides release of the API upon passage of the particle to the small intestine from the stomach. Applicant argues that the claimed composition provides superior results in that blood plasma GLP-1 levels are increased by oral consumption of the composition, but the claimed composition does not cause an increase in blood glucose levels or consequent increased insulin levels. Applicant argues that claimed composition allows blood glucose levels and related insulin levels to remain constant and that the increase in plasma insulin is caused by the increased GLP-1 levels which sensitize the pancreatic beta cells to glucose such that despite a constant glucose level, the pancreatic beta cells release more insulin. Applicant argues on page 21 that the superior results provided by the claimed composition are result of the combination of the claimed elements which include multiple dosage forms sized to be 3 mm or less and comprising a core with at least one disintegrant, and a coating which dissolve in a critical range, namely, that the “coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3.” Applicant argus on page 22 that Applicant’s invention recognizes that the pH dissolution range of the coating on the cores is a critical variable whereby, in combination with the presence of the disintegrant, the core is burst released into the terminal jejunum of the subject and provides for a peak of GLP-1 in the blood at between 2.5 to 3.5 hours after oral administration. Applicant argues that recognition of this result-effective variable which had not previously been recognized rebuts any prima facie case of obviousness. Applicant argues at the end of page 22 and into page 23 that the claimed composition provides a GLP-1 response without increasing blood glucose or causing glucose-triggered insulin spike. Applicant argues that the claimed composition is superior to the disclosure of Bleiel in combination with Fox, Noel, etc. Applicant argues that the composition of the instant composition is highly reproducible and points to the standard deviation of each point of measurement in Figure 1 of the instant specification.
Applicant's arguments filed 31 December 2025 have been fully considered but they are not persuasive. In response, Bleiel discloses release of sugar at the ileal, avoiding spikes in blood sugar levels, microparticulate form compositions, and a coating that is gastric resistant and ileal-sensitive (page 2, lines 5-21). Noel teaches a suspension comprising a uniform dispersion of microparticles (e.g., a heterogeneous mixture), wherein each microparticle comprises a core and a coating, wherein the core comprises about 20-99 weight percent of at least one active pharmaceutical ingredient (paragraph [0028]). Noel teaches a semisolid thixotropic hydrocolloid suspension media (paragraph [0028]). Noel teaches that hydrocolloid is aqueous-based (e.g., contains aqueous solution/gelling composition) (paragraph [0077]). Noel teaches that hydrocolloid are molecules that are dispersible in water or an aqueous solution and includes alginate, xanthan gum and polyethylene glycol (e.g., gelling agents) (paragraph [0080]). As evidenced by the instant specification, gelling agents includes polysaccharides including alginates, xanthan gum and polyethylene glycols (page 5, lines 5-9). Noel teaches that system create a customized formulation that has desired including food substances, flavors and/or textures (paragraph [0096]). Noel teaches coatings including hydroxypropyl methyl cellulose phthalate and methacrylic acid copolymer (paragraph [0016]). Noel teaches microparticle coating that dissolve with a pH of about 5-8 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject) (paragraph [0062]). Noel teaches coating including Eudragit® L100 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject) (paragraph [0113]). Thus, from the disclosure of Bleiel and the teachings of Noel, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a composition comprising microparticles uniformly dispersed in a suspension media (e.g., gelling composition) comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that is in an aqueous solution; wherein the microparticles comprises a core comprising glucose and a disintegrant, and a coating that is gastric-resistant provides transit through the stomach of a mammal and ileal release; wherein the coating includes Eudragit® L100; and wherein the suspension media further includes a pH regulating agent. The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain a composition that can provide different flavors and textures by including a suspension media comprising a hydrocolloid including alginates, xanthan gum and polyethylene glycols (e.g., gelling agents) that the microparticles are uniformly dispersed in; 2) obtain microparticles that break apart and release the API by including a disintegrant in the core of the microparticles; and 3) obtain microparticles that are gastric resistant by substituting known enteric coating of methyl-(methyl acrylate-methacrylic acid copolymers) including Eudragit® L100 (e.g., pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject). The Eudragit® L100 polymer taught by Noel reads on a pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3 such that the multiple dosage forms provide a targeted burst release of the core in a terminal jejunum of a subject because the polymer is able to dissolve or degrade at pH 6 and above and would provide a target burst release of the core if it was present in a subjects terminal jejunum, which can have a pH of about 7.3. The instant claims do not recite that the pH sensitive polymer only dissolves or degrades at a specific minimum pH. The instant claims only recite that the pH sensitive polymer substantially dissolves and/or is substantially degraded at a pH value of about 7.2 to 7.3. Therefore, polymers that reads on the instantly claimed pH sensitive polymer includes polymers that have a lower minimum pH that the polymers would begin to dissolve and/or degrade (e.g., begins to dissolve or degrade at pH 6).
Additionally, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., leads to a GLP-1 increase starting at about 1.5 hours after administration and lasting about 4 hours and a peak GLP-1 between about 2.5 to about 3.5 hours with a low intra- and inter-patient variability; delays the onset of insulin response, with a peak of insulin concentration at 2.5 hour after intake because the glucose released into the terminal jejunum is not absorbed; highly reproducible) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues on page 16 that Bleiel’s composition exerts an undesirable direct stimulation of insulin which is contraindicated in obese, pre-diabetic and diabetic patients. Applicant argues that the instantly claimed composition requires a comparatively low amount of API of 8 g per unit dose whereas the composition of Bleiel contains a very high glucose load of 37.5 g or even 125 g.
Applicant's arguments filed 31 December 2025 have been fully considered but they are not persuasive. In response, Bleiel discloses that they want to avoid spikes in blood sugar levels (page 2, lines 1-10) and Figure 3A of Bleiel shows that microparticulate carbohydrate for distal bowel release (e.g., with a gastric resistant coating) provides a constant plasma glucose concentration compared to a noncoated and stomach release microparticulate. Bleiel discloses that the amount of the carbohydrate (e.g., glucose) in the composition includes 10-200 Kcal (e.g., 2.5 g to 50 g) (page 17, lines 5-6). As evidenced by Fox, 100 Kcal/4 Kcal per gram = 25 g glucose (column 7, line 15). The amount of carbohydrate of 10-200 Kcal (e.g., 2.5 g to 50 g) disclosed by Bleiel overlaps the range of 0.5 g to 30 g glucose and 7 g to 15 g glucose recited in claims 13 and 50, respectively. Thus, the claims are rendered prima facie obvious. See 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). See also MPEP 2144.05.
Thus, for the reasons of record and for the reasons presented above claims 1, 3-4, 7-19, 21-26 and 47-55 are rejected under 35 U.S.C. 103(a) and provisionally rejected on the ground of nonstatutory double patenting.
Conclusion and Correspondence
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
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/JOHN P NGUYEN/
Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner., Art Unit 1600