DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Formal Matters
Applicant’s arguments along with the DECLARATION UNDER 37 C.F.R. §1.132 by Yigong Guo in the reply filed on 10 March 2026 are acknowledged and have been fully considered. Claims 1-27 are pending. Claims 1-20, 22-23, and new claim 27 are under consideration in the instant office action. Claims 21and 24-26 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims.
Information Disclosure Statement
The information disclosure statement (IDSs) submitted on 04 June 2026 are noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the information disclosure statement. A signed copy is attached herein.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20, 22-23, and newly added claim 27 remain rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (KR 20010105013, Google Patents English Machine Translation provided), Millotti et al. (Drug Delivery, 2011; 18(3): 190–197), and Vilhelmsen et al. (US 20150072926).
Note: The claims are examined with respect to the elected of species of ethylcellulose and polyacrylic acid cross-linked with allyl sucrose as the mucoadhesive layer; insulin as the drug in the peptide loading layer; Carbopol 934P NFTM as polyacrylic acid polymer; and ethylcellulose as the water impermeable layer.
Applicant Claims
Applicant claims a pharmaceutical dosage form comprising the components as recited in the claim.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Park et al. teach the present invention is 30 to 80 weight percent of hydroxypropyl cellulose, 5 to 50 weight percent of polyacrylic acid, 3 to 30 weight percent of polyethylene oxide, 3 to 30 weight percent of ethyl cellulose, and 5 to 30 weight percent of plasticizer. And it relates to a bilayer film-type oral mucoadhesive patch comprising an adhesive layer containing a drug as an essential component, a water-insoluble protective layer containing a water-insoluble polymer and a plasticizer as an essential component, and a manufacturing method thereof. When the film-type oral mucoadhesive patch of the present invention is applied to the oral mucosa with a thickness of 50 to 300㎛, it is thin and flexible, so that there is little foreign matter and can increase the patient's compliance. Release the drug continuously (abstract). An adhesion layer containing hydroxypropyl cellulose, polyacrylic acid, polyethylene oxide, ethyl cellulose, a plasticizer, and a drug as an essential component, and a protective layer including water-insoluble polymer, hydroxypropyl cellulose and a plasticizer as an essential component; Hydroxypropyl cellulose is 30 to 80 weight, polyacrylic acid is 5 to 50 weight, polyethylene oxide is 3 to 30 weight, ethyl cellulose is 3 to 30 weight and plasticizer is 5 to 30 weight. It has a thickness of 50 to 300 micrometers and the film-form oral mucosa patch (see claim 1). The method of claim 1, Polyacrylic acid is polycarbophil, carbomer or mixtures thereof Characterized Film-type oral mucosa patch (claim 2). The method of claim 1, Drugs include anti-inflammatory drugs, oral disease drugs, antihistamines, hormones, antihypertensive drugs, At least one selected from the group consisting of antibiotics, bronchodilators, Characterized in that it contains 0.05 to 50 weight of the total weight of the adhesion layer Film-type oral mucosa patch (see claim 3). The method of claim 1, The water-insoluble polymer constituting the protective layer is methacrylic acid copolymer, From the group consisting of ethylcellulose and hydroxypropylcellulose It is characterized by two or more kinds selected Film-type oral mucosa patch (claim 4). As the polyacrylic acid blended in the adhesive layer, polycarbophil, carbomer or a mixture thereof having excellent mucoadhesive property may be used. The polycarbophil is a polymer of acrylic acid crosslinked by divinyl glycol. Carbomer is a polymer of acrylic acid crosslinked by allyl sucrose or allyl pentaerythritol. In one embodiment, a carbonyl dimmer may be selected from commercially available under the trade names of Carbopol TM 910, 934 940, 941, 934P, 971P, 974P: BFGoodrich Company, USA) (see description section). The water-insoluble polymer constituting the protective layer of the present invention is at least two kinds selected from the group consisting of methacrylic acid copolymer, ethyl cellulose and hydroxypropyl cellulose, and the methacrylic acid copolymer among these water-insoluble polymers is a tablet or the like. Used as a coating agent, ethyl cellulose, a component of the protective layer and the adhesion layer, has been used as a water-insoluble coating agent for tablets and granules for the purpose of controlling release, masking taste, and improving stability (see description section). For the production of the film-type oral mucosa patch described above, hydroxypropyl cellulose is contained 30 to 80 weight, preferably 40 to 70 weight of the total weight of the adhesion layer, polyacrylic acid is 5 to 50 weight of the total weight of the adhesion layer , Preferably 10 to 40 wt%, polyethylene oxide is 3 to 30 wt%, preferably 5 to 20 wt% of the total weight of the adhesion layer, ethyl cellulose is 3 to 30 wt%, preferably the total weight of the adhesion layer 5 to 25 wt%, and the plasticizer is selected from triethyl citrate, polyethylene glycol, triacetin and the like to contain 5 to 30 wt% of the total weight of the adhesion layer. In addition, the content of the drug is different depending on the type of drug and the purpose of use, but is generally 0.05 to 50 weight, preferably 0.1 to 30 weight of the total weight of the adhesion layer (see description section). As for the thickness of the above-mentioned adhesion layer, 30-200 micrometers, and the thickness of a protective layer are 20-100 micrometers, 50-300 micrometers is preferable for the thickness of a film-type oral mucosa patch after all. When the thickness of the film-type oral mucosa patch of the present invention exceeds 300 μm, there is a foreign body feeling, and it is impossible to attach to the oral mucosa for a long time by being detached by the tongue, and when the thickness of the patch is less than 50 μm, You cannot mix enough. Table 4 shows formulations with higher mucoadhesive strength.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Park et al. do not specifically teach the drug in the instant case insulin in an insulin loading layer wherein the insulin is encapsulated via a mercaptonicotic (MNA)-thioglycolic acid-chitosan nanoparticles . These deficiency is cured by the teachings of Millotti et al.
Millotti et al. teach the aim of this study was to develop a novel nanoparticulate formulation and test its potential for oral peptide drug delivery. Chitosan-6-mercaptonicotinic acid is a novel thiolated chitosan with strong mucoadhesive properties. Nanoparticles were developed by an ionic gellation method. The obtained particles were characterized in terms of mucoadhesion, stability, toxicity, and in vitro release. Human insulin (HI) was chosen as a model peptide drug, incorporated in the particles and orally administered to rats. Human insulin was quantified in the blood by means of ELISA. The size of the obtained particles was in the range of 200–300 nm and the zeta potential was determined to be +8−+23 depending on the amount of thiol groups attached on the polymer. After 3h of incubation up to 60% of the thiolated chitosan nanoparticles remained attached to the mucosa in contrast to 20% of unmodified chitosan particles. The AUC of HI after oral administration of thiolated chitosan nanoparticles was 4-fold improved compared to unmodified chitosan nanoparticles. Due to these improvements, chitosan-6-mercaptonicotinic acid nanoparticles are promising vehicles for oral delivery of peptide drugs (see abstract). Peptide drug delivery is extensively studied because of the high therapeutic efficacy of this class of active pharmaceutical ingredients for treatments of many diseases. The improvements in biotechnology made it possible to produce peptides on a commercial scale. The oral administration of peptide drugs is one of the greatest challenges in pharmaceutical technology. When orally administered, peptide drugs are degraded in the low gastric pH as well as by different digestive enzymes in the stomach and small intestine. A promising strategy to tackle this problem is the use of nanoparticulate carriers. In particular, nanoparticles made from biodegradable polymers represent an exciting approach to improve the uptake of orally administered drugs (Cui et al., 2006). One polymer of choice is chitosan. Chitosan has the ability to gel spontaneously in contact with multivalent polyanions due to the formation of inter- and intra-molecular cross-linkages. Among poylanions, tripolyphosphate (TPP) is most commonly used because of its safety profile and quick gelling ability. Nanoparticles are formed immediately upon mixing of TPP and chitosan solution as ionic linkages are formed between TPP and chitosan (Gan et al., 2005). The advantageous features of chitosan-TPP systems include the formation under mild conditions, a positive surface charge, and a great capacity for the association of peptides, proteins, and oligonucleotides (Shu & Zhu, 2000). Indeed, the polymeric component of the particles such as chitosan should assure protection of the drug towards enzymatic degradation and controlled release (Sakuma et al., 1997). However, as the stability of these particles is provided by the addition of polyanionic excipients such as TPP, the positive charges of chitosan are neutralized. This results in loss of the mucoadhesive properties of chitosan. Mucoadhesion could alternatively be gained by the choice of specific polymers such as thiomers. Thiomers are thiolated polymers on which a thiol-bearing compound has been covalently attached. They are known to possess mucoadhesive, enzyme inhibition, permeation enhancing, and sustained release properties. Furthermore, thiol groups within these nanoparticles provide stability to such particles via the formation of intra- and intermolecular disulfide bonds. Recently a novel thiolated chitosan, called chitosan-6-mercaptonicotinamide (chitosan-6-MNA), has been synthesized and characterized (Millotti et al., 2009). This novel thiolated chitosan exhibits a pH-independent reactivity, comparatively high mucoadhesive properties, and biocompatibility. In order to combine these two promising strategies it was the aim of this study to develop a nanoparticulate drug delivery system based on chitosan-6-mercaptonicotinic acid and to evaluate whether these nanoparticles have potential for oral delivery of peptides. Because of already well established in vivo test systems, insulin was chosen as a representative model peptide drug (see introduction). Mucoadhesion and stability of the thiolated particles was significantly higher compared to unmodified chitosan particles. Furthermore, thiolated particles were more stable both in acidic as well as intestinal pH when compared to unmodified chitosan particles. These enhanced properties allowed to reach a significant plasma insulin concentration after oral administration. The advantages of this novel delivery system for the oral application are likely to be useful also for other peptides and could be a promising novel approach for their oral administration (conclusion).
Park et al. and Millotti et al. do not specifically teach inclusion of mannitol and sodium alginate with the encapsulated insulin nanoparticles containing loading layer. These deficiency is cured by the teachings of Vilhelmsen et al.
Vilhelmsen et al. teach compositions comprising pharmacologically active agents, such as GLP-1, and a delivery agent as well as processes for their preparation and use thereof in medicine (see paragraph 0001). In some embodiments the composition or granule comprises a filler, such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrins, dextrans, maltodextrins, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate, calcium carbonate, or sodium alginate. In some embodiments the filler is microcrystalline cellulose, such as Avicel PH 101 (paragraph 0026). In some embodiments the composition or granule comprises a binder, such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g., the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium lactate, calcium carbonate, acacia, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, PEG, or povidone. In some embodiments the binder is povidone, such as povidone K 90 (paragraph 0027).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Park et al. by incorporating an MNA-TG-chitosan encapsulated insulin in its own loading layer because Millotti et al. teach the aim of this study was to develop a novel nanoparticulate formulation and test its potential for oral peptide drug delivery. Chitosan-6-mercaptonicotinic acid is a novel thiolated chitosan with strong mucoadhesive properties. Nanoparticles were developed by an ionic gellation method. The obtained particles were characterized in terms of mucoadhesion, stability, toxicity, and in vitro release. Human insulin (HI) was chosen as a model peptide drug, incorporated in the particles and orally administered to rats. Human insulin was quantified in the blood by means of ELISA. The size of the obtained particles was in the range of 200–300 nm and the zeta potential was determined to be +8−+23 depending on the amount of thiol groups attached on the polymer. After 3h of incubation up to 60% of the thiolated chitosan nanoparticles remained attached to the mucosa in contrast to 20% of unmodified chitosan particles. The AUC of HI after oral administration of thiolated chitosan nanoparticles was 4-fold improved compared to unmodified chitosan nanoparticles. Due to these improvements, chitosan-6-mercaptonicotinic acid nanoparticles are promising vehicles for oral delivery of peptide drugs (see abstract). Peptide drug delivery is extensively studied because of the high therapeutic efficacy of this class of active pharmaceutical ingredients for treatments of many diseases. The improvements in biotechnology made it possible to produce peptides on a commercial scale. The oral administration of peptide drugs is one of the greatest challenges in pharmaceutical technology. When orally administered, peptide drugs are degraded in the low gastric pH as well as by different digestive enzymes in the stomach and small intestine. A promising strategy to tackle this problem is the use of nanoparticulate carriers. In particular, nanoparticles made from biodegradable polymers represent an exciting approach to improve the uptake of orally administered drugs (Cui et al., 2006). One polymer of choice is chitosan. Chitosan has the ability to gel spontaneously in contact with multivalent polyanions due to the formation of inter- and intra-molecular cross-linkages. Among poylanions, tripolyphosphate (TPP) is most commonly used because of its safety profile and quick gelling ability. Nanoparticles are formed immediately upon mixing of TPP and chitosan solution as ionic linkages are formed between TPP and chitosan (Gan et al., 2005). The advantageous features of chitosan-TPP systems include the formation under mild conditions, a positive surface charge, and a great capacity for the association of peptides, proteins, and oligonucleotides (Shu & Zhu, 2000). Indeed, the polymeric component of the particles such as chitosan should assure protection of the drug towards enzymatic degradation and controlled release (Sakuma et al., 1997). However, as the stability of these particles is provided by the addition of polyanionic excipients such as TPP, the positive charges of chitosan are neutralized. This results in loss of the mucoadhesive properties of chitosan. One of ordinary skill in the art would have been motivated to do so because Millotti et al. teach that by using MNA-TG-chitosan encapsulated insulin Mucoadhesion could alternatively be gained by the choice of specific polymers such as thiomers. Thiomers are thiolated polymers on which a thiol-bearing compound has been covalently attached. They are known to possess mucoadhesive, enzyme inhibition, permeation enhancing, and sustained release properties. Furthermore, thiol groups within these nanoparticles provide stability to such particles via the formation of intra- and intermolecular disulfide bonds. Recently a novel thiolated chitosan, called chitosan-6-mercaptonicotinamide (chitosan-6-MNA), has been synthesized and characterized (Millotti et al., 2009). This novel thiolated chitosan exhibits a pH-independent reactivity, comparatively high mucoadhesive properties, and biocompatibility. In order to combine these two promising strategies it was the aim of this study to develop a nanoparticulate drug delivery system based on chitosan-6-mercaptonicotinic acid and to evaluate whether these nanoparticles have potential for oral delivery of peptides. Because of already well established in vivo test systems, insulin was chosen as a representative model peptide drug (see introduction). Mucoadhesion and stability of the thiolated particles was significantly higher compared to unmodified chitosan particles. Furthermore, thiolated particles were more stable both in acidic as well as intestinal pH when compared to unmodified chitosan particles. These enhanced properties allowed to reach a significant plasma insulin concentration after oral administration. The advantages of this novel delivery system for the oral application are likely to be useful also for other peptides and could be a promising novel approach for their oral administration (conclusion). It should be noticed that Park et al. teach a mucoadhesive drug delivery device. In the case where the claimed ranges for amounts of ingredients, particle size, thickness, etc., "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Furthermore, a prima facie case of obviousness exists because differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. It is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233,235 (CCPA 1955)). An ordinary skilled in the artisan would have had a reasonable expectation of success in combining the teachings of Park et al. and Millotti et al. because both references teach mucoadhesive based drug delivery systems.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Park et al. and Millotti et al. by incorporating mannitol and sodium alginate in the peptide loading layer because Vilhelmsen et al. teach compositions comprising pharmacologically active agents, such as GLP-1, and a delivery agent as well as processes for their preparation and use thereof in medicine (see paragraph 0001). In some embodiments the composition or granule comprises a filler, such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrins, dextrans, maltodextrins, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate, calcium carbonate, or sodium alginate. In some embodiments the filler is microcrystalline cellulose, such as Avicel PH 101 (paragraph 0026). In some embodiments the composition or granule comprises a binder, such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g., the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium lactate, calcium carbonate, acacia, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, PEG, or povidone. In some embodiments the binder is povidone, such as povidone K 90 (paragraph 0027). One of ordinary skill in the art would have been motivated to do so because mannitol can help as sweetener and filler and the sodium alginate can serve as filler and binder as demonstrated by Vilhelmsen et al. in a peptide composition. An ordinary skilled in the artisan would have had a reasonable expectation of success in combining the teachings of Park et al., Millotti et al., and Vilhelmsen et al. because all references teach dosage forms comprising active agents, fillers, and binders.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Applicant’s Arguments
Applicant argues that the pharmaceutical dosage form recited in the present claims ("the Triple Layer System") demonstrates unexpectedly improved properties compared to the two-layer system taught by Park ("the Park Double Layer System"), as evidenced by the data submitted in the Second Guo Declaration. Applicant respectfully submits that the present claims are nonobvious over the cited references at least because of the following: 1) the evidence presented in the Second Guo Declaration demonstrates unexpected and unobvious results of both statistical and practical significance compared to the cited references; 2) this evidence of unexpected results outweighs the prima facie obviousness case; 3) these results are commensurate in scope with the claims (as discussed with respect to the additional data submitted in the Second Guo Declaration); 4) the. comparison data is consistent with the closest prior art or is closer than that applied by the Examiner; and 5) these results, together with the totality of the record, demonstrate the nonobviousness of the pending claims.
The above assertions are not found persuasive because the examiner maintains the rebuttal arguments that the data provided is not commensurate in scope with the claims. The examiner appreciates Applicant’s effort to provide experimental comparison data to establish unexpected results. To make the record very clear Applicant’s data is drawn to a narrower experiment. The declaration states that “In making the comparison both the triple layer buccal tablet and the double layer buccal tablet had the same a water impermeable layer of ethylcellulose. The double layer buccal tablet had a mucoadhesive layer comprised of Carbopol 934P, which is a type of polyacrylic acid, Insulin nanoparticles, sodium alginate, and mannitol. Whereas the triple layer buccal tablet had a mucoadhesive layer comprised of Carbopol 934P, sodium alginate, and mannitol, with a distinct insulin nanoparticle layer situated between the water impermeable layer of ethylcellulose and the mucoadhesive layer as shown below. The insulin nanoparticles used in both the triple layer tablet and the double layer tablet was the combination of chitosan, tripolyphosphate (TPP), insulin at the weight ratio of 2.5:0.5:1. The wt% for the components used in mucoadhesive layers was 12.5 mg of Carbopol 934P with 12.5 mg of ethylcellulose, 5 mg of sodium alginate and ethylcelluose. The data provided is a single data point in terms of the types of ingredients and active agent and the amounts of the ingredients and active agent in the composition while claim 1 is drawn to a broader range both in terms of the content of the mucoadhesive layer and the amount of the respective polymers in component (a); the type and amount of peptide in the peptide coating layer comprising an encapsulated peptide; and the amount and type of polymer used to make the water impermeable layer. The peptide elected is insulin while claim 1 is drawn to “wherein the encapsulated peptide is selected from one or more of the following: an insulin; an insulin derivative; an insulin analog; a pre-insulin; a pro-drug of insulin; a glucagon-like peptide 1 (GLP-1); a GLP-1 analog; a pre- GLP-1; or a pro-drug of GLP-1. Additionally, the data only presented encapsulate insulin nanoparticles at single data point. The examiner continues to remind Applicant that examination at this point is drawn to the elected species only. For instance, the declaration is not clear on the amount of ethyl cellulose used in the water impermeable layer, the amount of the peptide loading layer specifically chitosan encapsulated insulin nanoparticles in the composition. The declaration does not explain how one of ordinary skill in the art would extrapolate the single point data to the entire scope of claim 1 as currently written. Therefore, the examiner maintains that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (differences in sedative and anticholinergic effects between prior art and claimed antidepressants were not unexpected). In In re Waymouth, 499 F.2d 1273, 1276, 182 USPQ 290, 293 (CCPA 1974), the court held that unexpected results for a claimed range as compared with the range disclosed in the prior art had been shown by a demonstration of "a marked improvement, over the results achieved under other ratios, as to be classified as a difference in kind, rather than one of degree." Compare In re Wagner, 371 F.2d 877, 884, 152 USPQ 552, 560 (CCPA 1967) (differences in properties cannot be disregarded on the ground they are differences in degree rather than in kind); Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) ("we generally consider a discussion of results in terms of ‘differences in degree’ as compared to ‘differences in kind’ . . . to have very little meaning in a relevant legal sense"). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023) ("A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent."). The examiner further reminds applicant that the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Furthermore, "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989) (Claims at issue were directed to a process of sterilizing a polyolefinic composition which contains an antioxidant with high-energy radiation. Although evidence was presented in appellant’s specification showing that particular antioxidants are effective, the Board concluded that these beneficial results would have been expected because one of the references taught a claimed antioxidant is very efficient and provides better results compared with other prior art antioxidants.). Even furthermore, Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). Additionally, the examiner points that applicant alleging unexpected results should compare the claimed subject matter with the closest prior art. MPEP 716.02(e) states that in affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). The examiner contends that Applicant did not meet or show any of the above asserted points regarding the alleged unexpected results. Applicant’s arguments of unexpected results amount to an allegation with no objective evidence.
Applicant argues "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness of the claims at issue." M.P.E.P. § 716.02(a)(I). "The evidence relied upon should establish 'that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." M.P.E.P. § 716.02(b)(I). "Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims." M.P.E.P. § 716.02(b)(III). Accordingly, whereas the First Guo Declaration demonstrated the effectiveness of formulations "comprising: (a) a mucoadhesive layer, the mucoadhesive layer comprising: (i) an ethylcellulose and a polymer of acrylic acid cross-linked with allyl sucrose or allyl pentaerythritol," (referred to hereinafter as "F9"), the Second Guo Declaration demonstrates that this effectiveness is maintained for formulations "comprising: (a) a mucoadhesive layer, the mucoadhesive layer comprising: (ii) an ethylcellulose, a polymer of acrylic acid cross-linked with allyl sucrose or allyl pentaerythritol, and a hydroxypropyl methylcellulose (HPMC)" (referred to hereinafter as "F8"). Applicant then goes on to explain F9 and F8 formulations demonstrate unexpected results. Applicant states that The F9 and the F8 formulations (collectively, "the Test Triple Layer Systems") are compared in the Second Guo Declaration to analogous double layer buccal tablet (F9 Equivalent and F8 Equivalent, collectively, "the Test Double Layer Systems") formulated to be analogous to the Park Double Layer Systems. Notably, unlike the Park Double Layer Systems-which did not include chitosan encapsulated insulin, but rather included free drug-the Test Double Layer Systems (in both an "F8 Equivalent" form and an "F9 Equivalent" form) tested here include the drug in encapsulated form, as is allegedly taught by Millotti. Thus, the Test Double Layer Systems are presented to demonstrate how the Park Double Layer System would perform if already modified to include chitosan encapsulated insulin. As such these experiments represent a direct, or at least an indirect, comparison of the Triple Layer System of the pending claims with the closest prior art, as modified to be more directly comparable. In this regard, in these comparative experiments, "[a]ll of the two- and three-layer tablets have the same water impermeable layer of ethylcellulose." Second Guo Decl., 2. The F9 tablet includes a peptide loading layer with insulin nanoparticles, Mannitol, and sodium alginate as formulated in Table 1 of the specification, and a mucoadhesive layer with Carbopol 934P¹ and ethylcellulose, while the F9 Equivalent tablet includes a "combined mucoadhesive and peptide loading layer comprises Carbopol 934P (20mg), Insulin nanoparticles (5mg), and mannitol (30mg)"; the F8 tablet includes the same peptide loading layer as the F9 tablet and a mucoadhesive layer with Carbopol 934P, HPMC, and ethylcellulose, while the F8 Equivalent tablet includes a "combined mucoadhesive and peptide loading layer comprises Carbopol 934P (10mg), HPMC (10mg), Insulin nanoparticles (5mg), and mannitol (30mg). Applicant then goes on to explain the results with respect to uptake percentages; insulin loss; mucoadhesion strength; cell uptake of insulin and insulin uptake rate; effectiveness with Glp-1 encapsulated nanoparticles; effectiveness of range of water impermeable layer species in F9.
The above assertions are not found persuasive because first the examiner would like to make the record clear that the examiner does not dispute the fact that the presented data does show unexpected results to the extent of the single point data presented in Table 1. As explained in detail above the data provided in Table 1 is not commensurate in scope with claim 1 in terms of types of ingredients and peptide type and their respective amounts. One of ordinary skill in the art would not be able to extrapolate the single point data provided in Table 1 to the entire scope of claim 1. Furthermore, in terms of other water impermeable polymers tested it is not clear what amount of these polymers are used and the clear content of the composition and the amount of the respective ingredients. The same problem also exists with the Glp-1, it is unclear what Glp-1 drug is used and its amount and what other ingredients and their amounts are used in making the triple layer tablet.
Therefore, the examiner maintains that indeed the claimed limitations have been rendered obvious by the combination teachings of Park et al., Millotti et al. and Vilhelmsen et al. as described above. The examiner reminds Applicant that obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so. In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) (discussing rationale underlying the motivation-suggestion-teaching test as a guard against using hindsight in an obviousness analysis). Axonics, Inc. v. Medtronic, Inc., 73 F.4th 950, 957-58, 2023 USPQ2d 795 (Fed. Cir. 2023) (the court found an erroneous framing of the motivation inquiry led to an incorrect conclusion of nonobviousness). A "motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill." Zup v. Nash Mfg., 896 F.3d 1365, 1371, 127 USPQ2d 1423, 1427 (Fed. Cir. 2018) (quoting Plantronics, Inc. v. Aliph, Inc., 724 F.3d 1343, 1354 [107 USPQ2d 1706] (Fed. Cir. 2013) (citing Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1328 [92 USPQ2d 1849] (Fed. Cir. 2009) (quoting KSR, 550 U.S. at 418-21)). See MPEP § 2143 regarding the need to provide a reasoned explanation even in situations involving common sense or ordinary ingenuity. See also MPEP § 2144.05, subsection II, B. The examiner indeed provided rational and motivations why one of ordinary skill in the art would have been motivated to combine the references. The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below). The burden is on Applicant to explain why the motivations provided by the examiner to combine the references are not proper or acceptable motivations. It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Park et al. by incorporating an MNA-TG-chitosan encapsulated insulin in its own loading layer because Millotti et al. teach the aim of this study was to develop a novel nanoparticulate formulation and test its potential for oral peptide drug delivery. Chitosan-6-mercaptonicotinic acid is a novel thiolated chitosan with strong mucoadhesive properties. Nanoparticles were developed by an ionic gellation method. The obtained particles were characterized in terms of mucoadhesion, stability, toxicity, and in vitro release. Human insulin (HI) was chosen as a model peptide drug, incorporated in the particles and orally administered to rats. Human insulin was quantified in the blood by means of ELISA. The size of the obtained particles was in the range of 200–300 nm and the zeta potential was determined to be +8−+23 depending on the amount of thiol groups attached on the polymer. After 3h of incubation up to 60% of the thiolated chitosan nanoparticles remained attached to the mucosa in contrast to 20% of unmodified chitosan particles. The AUC of HI after oral administration of thiolated chitosan nanoparticles was 4-fold improved compared to unmodified chitosan nanoparticles. Due to these improvements, chitosan-6-mercaptonicotinic acid nanoparticles are promising vehicles for oral delivery of peptide drugs (see abstract). Peptide drug delivery is extensively studied because of the high therapeutic efficacy of this class of active pharmaceutical ingredients for treatments of many diseases. The improvements in biotechnology made it possible to produce peptides on a commercial scale. The oral administration of peptide drugs is one of the greatest challenges in pharmaceutical technology. When orally administered, peptide drugs are degraded in the low gastric pH as well as by different digestive enzymes in the stomach and small intestine. A promising strategy to tackle this problem is the use of nanoparticulate carriers. In particular, nanoparticles made from biodegradable polymers represent an exciting approach to improve the uptake of orally administered drugs (Cui et al., 2006). One polymer of choice is chitosan. Chitosan has the ability to gel spontaneously in contact with multivalent polyanions due to the formation of inter- and intra-molecular cross-linkages. Among poylanions, tripolyphosphate (TPP) is most commonly used because of its safety profile and quick gelling ability. Nanoparticles are formed immediately upon mixing of TPP and chitosan solution as ionic linkages are formed between TPP and chitosan (Gan et al., 2005). The advantageous features of chitosan-TPP systems include the formation under mild conditions, a positive surface charge, and a great capacity for the association of peptides, proteins, and oligonucleotides (Shu & Zhu, 2000). Indeed, the polymeric component of the particles such as chitosan should assure protection of the drug towards enzymatic degradation and controlled release (Sakuma et al., 1997). However, as the stability of these particles is provided by the addition of polyanionic excipients such as TPP, the positive charges of chitosan are neutralized. This results in loss of the mucoadhesive properties of chitosan. One of ordinary skill in the art would have been motivated to do so because Millotti et al. teach that by using MNA-TG-chitosan encapsulated insulin Mucoadhesion could alternatively be gained by the choice of specific polymers such as thiomers. Thiomers are thiolated polymers on which a thiol-bearing compound has been covalently attached. They are known to possess mucoadhesive, enzyme inhibition, permeation enhancing, and sustained release properties. Furthermore, thiol groups within these nanoparticles provide stability to such particles via the formation of intra- and intermolecular disulfide bonds. Recently a novel thiolated chitosan, called chitosan-6-mercaptonicotinamide (chitosan-6-MNA), has been synthesized and characterized (Millotti et al., 2009). This novel thiolated chitosan exhibits a pH-independent reactivity, comparatively high mucoadhesive properties, and biocompatibility. In order to combine these two promising strategies it was the aim of this study to develop a nanoparticulate drug delivery system based on chitosan-6-mercaptonicotinic acid and to evaluate whether these nanoparticles have potential for oral delivery of peptides. Because of already well established in vivo test systems, insulin was chosen as a representative model peptide drug (see introduction). Mucoadhesion and stability of the thiolated particles was significantly higher compared to unmodified chitosan particles. Furthermore, thiolated particles were more stable both in acidic as well as intestinal pH when compared to unmodified chitosan particles. These enhanced properties allowed to reach a significant plasma insulin concentration after oral administration. The advantages of this novel delivery system for the oral application are likely to be useful also for other peptides and could be a promising novel approach for their oral administration (conclusion). It should be noticed that Park et al. teach a mucoadhesive drug delivery device. In the case where the claimed ranges for amounts of ingredients, particle size, thickness, etc., "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Furthermore, a prima facie case of obviousness exists because differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. It is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233,235 (CCPA 1955)). An ordinary skilled in the artisan would have had a reasonable expectation of success in combining the teachings of Park et al. and Millotti et al. because both references teach mucoadhesive based drug delivery systems.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Park et al. and Millotti et al. by incorporating mannitol and sodium alginate in the peptide loading layer because Vilhelmsen et al. teach compositions comprising pharmacologically active agents, such as GLP-1, and a delivery agent as well as processes for their preparation and use thereof in medicine (see paragraph 0001). In some embodiments the composition or granule comprises a filler, such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrins, dextrans, maltodextrins, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate, calcium carbonate, or sodium alginate. In some embodiments the filler is microcrystalline cellulose, such as Avicel PH 101 (paragraph 0026). In some embodiments the composition or granule comprises a binder, such as lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g., the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium lactate, calcium carbonate, acacia, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, PEG, or povidone. In some embodiments the binder is povidone, such as povidone K 90 (paragraph 0027). One of ordinary skill in the art would have been motivated to do so because mannitol can help as sweetener and filler and the sodium alginate can serve as filler and binder as demonstrated by Vilhelmsen et al. in a peptide composition. An ordinary skilled in the artisan would have had a reasonable expectation of success in combining the teachings of Park et al., Millotti et al., and Vilhelmsen et al. because all references teach dosage forms comprising active agents, fillers, and binders.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIGABU KASSA whose telephone number is (571)270-5867. The examiner can normally be reached on 9 am-5 pm Monday-Friday.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619
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