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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/26/2025 has been entered.
Status of the Claims
This action is in response to papers filed 09/26/2025 in which claims 2, 6, 12, 39, 49, and 51 were canceled; claims 37-38 and 46-48 were withdrawn; and claim 1 was amended. All the amendments have been thoroughly reviewed and entered.
Claims 1, 3-5, 7-11, 13-36, 40-45 and 50 are under examination.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claims 1, 3, 5, 7-11, 13-20, 26-31, 33-36, 40-45, and 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pillay et al (19 December 2013; US 2013/0337022 A1) in view of Maggio (20 October 2011; US 2011/0257096 A1), Temtsin-Krayz et al (4 May 2017; US 2017/0119660 A1), Perricone (9 March 1999; US 5,879,690) and Hsu et al (3 July 2003; US 2003/0124176 A1), and as evidenced by Rani et al (BioResources, 5(4): 2765-2807).
Regarding claim 1, Pillay teaches an oral or buccal pharmaceutical dosage form comprising mucoadhesive membrane including therein a mucoadhesive layer in the form a film containing a polymeric membrane, at least one active agent and a permeation enhancer (abstract; [0001], [0003]-[0006], [0010]-[0018], [0051]-[0055] and [0057]; Figures 1 and 2; claims 34, 44, 45 and 53). Pillay teaches the polymeric membrane is selected from polyacrylic acid and chitosan ([0013]), thereby the polymeric membrane would be orally dissolvable or erodible and forming a gel-like structure when administered, as the film containing the polymeric membrane is buccally administered, and as evidenced by dependent claim 33 of the instant invention, polyacrylic acid and chitosan were defined as one of the suitable polymers of the polymer matrix. Furthermore, as evidenced by Rani, chitosan is a biodegradable polymer that also possesses gel-forming ability (Rani: pages 2765-2766). Thus, "[p]roducts of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Pillay further teaches the active agent include a peptide ([0016] and [0054]; claim 53). Pillay teaches the permeation enhancer is a surfactant ([0052]). Pillay teaches the permeation enhancer is in the polymeric membrane ([0052] and [0057]). Pillay teaches the permeation enhancers include chitosan and decyltrimethyl ammonium bromide (cationic surfactant) ([0052]).
However, Pillay does not teach octreotide as the active component; and the surfactant of claim 1.
Regarding octreotide as the active component of claim 1, Maggio teaches an oral or buccal pharmaceutical composition comprising a polymer matrix, a pharmaceutically active component including octreotide in the polymer matrix, and a permeation enhancer including a surfactant (abstract; [0005], [0011]-[0020], [0031]-[0052], [0085]-[0098], [0108]-[0112] and [0152]-[0169]). Maggio teaches the polymer matrix contains materials selected from polysaccharides, gum acacia, gelatin, starch, collagen, guar gum xanthan gum, polyvinylpyrrolidone and polypeptide/protein ([0074] and [0182]).
It would have been obvious to one of ordinary skill in the art to include octreotide as the peptide active agent in the mucoadhesive membrane of the oral or buccal pharmaceutical dosage form of Pillay, and produce the claimed invention. One of ordinary skill in the art would have been motivated do so because Maggio teaches octreotide is a peptide active agent that can be incorporated in a polymer matrix of an oral or buccal pharmaceutical composition containing a permeation enhancer so as to increase the bioavailability of the peptide administered to the oral cavity, thereby improving oral delivery of octreotide (Maggio: [0003], [0011], [0073] and [0086]). One of ordinary skill in the art would have reasonable expectation of success of including octreotide as the peptide active agent in the mucoadhesive membrane of the oral or buccal pharmaceutical dosage form of Pillay because Pillay is also drawn to the same objective of improving the oral or buccal bioavailability of drugs and pharmaceutical active agents (Pillay: [0001] and [0052]), the prior art in view of Temtsin-Krayz recognized that it is conventionally known in the art of pharmaceutical formulations that octreotide can be included as a drug in an oral pharmaceutical film of the oral or buccal pharmaceutical dosage form of Pillay so as improve the bioavailability of the drug when administered to the oral cavity (Temtsin-Krayz: Abstract; [0018], [0020], [0028]-[0029], [0054]-[0058], [0067]-[0068], [0089] and [0103]-[0111]; claim 4). Thus, an ordinary artisan provided the guidance from the prior art would have looked to including octreotide as the peptide active agent in the mucoadhesive membrane of the oral or buccal pharmaceutical dosage form of Pillay with a reasonable expectation of achieving a resultant pharmaceutical composition with improve the bioavailability of octreotide when administered to the oral cavity, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding the surfactant of claim 1, Perricone teaches a pharmaceutical composition containing a drug and penetration enhancers, wherein the suitable surfactants such as anionic surfactants, nonionic surfactants, and cationic surfactants including cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, dodecyltrimethylammonium chloride, and hexadecyltrimethylammonium chloride (column 4, lines 36-56; columns 6-7). Hsu teaches a pharmaceutical composition containing a drug such as octreotide and a penetration enhancers, wherein the suitable surfactants such as anionic surfactants, nonionic surfactants, and cationic surfactants including decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetradecyltrimethyl-ammonium chloride and dodecylammonium chloride ([0241]). It is noted that cationic surfactants such as cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium bromide, cetylpyridinium chloride, dodecyltrimethylammonium chloride/bromide or hexadecyltrimethylammonium chloride as taught by Perricone meet claimed quaternary ammonium surfactant as recited in claim 1.
It would have been obvious of ordinary skill in the art to include cationic surfactants such as cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium bromide, cetylpyridinium chloride, dodecyltrimethylammonium chloride/bromide or hexadecyltrimethylammonium chloride, as one of the surfactants used as the absorption/penetration enhancing agent of Pillay, and produce the claimed invention. One of ordinary skill in the art would have been motivate to do so because Perricone provided the guidance for including cationic surfactants as one of the absorption/penetration enhancing agent, as these cationic surfactants are conventional known absorption/penetration enhancing agents that are non-irritating and nontoxic and typically used as to enhance penetration capacity of the pharmaceutical composition (Perricone: column 4, lines 36-56), which is also the objective of Pillay ([0052]). Furthermore, Hsu provides the guidance for using the cationic surfactant disclosed in Perricone as the suitable surfactant/penetration enhancer for peptide drugs such as octreotide of Pillay and Maggio. Thus, an ordinary artisan would looked to select cationic surfactants from the list of known penetration enhancers in the prior art, and include them in the pharmaceutical compositions of Pillay and Maggio containing octreotide per guidance from Perricone and Hsu, with a reasonable expectation of achieving a pharmaceutical composition with enhanced penetration capacity of the peptide drug such as octreotide. As such, it is noted that The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
It is noted that the limitation of “the pharmaceutical composition useful to treat medical conditions including hormone producing tumors, diarrhea, and flushing episodes” as recited in claim 1, is a recitation of intended use of pharmaceutical composition. Maggio teaches octreotide is a cyclic octapeptide used for administration by deep subcutaneous (intrafat) or intravenous injection for treatment of acromegaly, metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease, and the treatment of the profuse watery diarrhea associated with VIP-secreting tumors (Maggio: [0085]). Since the pharmaceutical composition of claim 1 has been structurally rendered obvious by the combined teachings of Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu. The pharmaceutical composition containing octreotide of Pillay in view of Maggio, Temtsin-Krayz, Perricone, and Hsu would have been capable of performing the claimed intended use of “the pharmaceutical composition useful to treat medical conditions including hormone producing tumors, diarrhea, and flushing episodes.” It is noted that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Regarding claims 3, 5, 7 and 40-45, Perricone teaches a pharmaceutical composition containing a drug and penetration enhancers, wherein the suitable surfactants such as anionic surfactants, nonionic surfactants, and cationic surfactants including cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, dodecyltrimethylammonium chloride, and hexadecyltrimethylammonium chloride (column 4, lines 36-56; columns 6-7). Hsu teaches a pharmaceutical composition for application to a mucosal tissue containing a drug such as octreotide and a penetration enhancers, wherein the suitable surfactants such as anionic surfactants, nonionic surfactants, and cationic surfactants including decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetradecyltrimethyl-ammonium chloride and dodecylammonium chloride (Abstract; [0027], [0241]). It would have been obvious of ordinary skill in the art to include cationic surfactants such as cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium bromide, cetylpyridinium chloride, dodecyltrimethylammonium chloride/bromide or hexadecyltrimethylammonium chloride, as one of the surfactants used as the absorption/penetration enhancing agent of Pillay, and produce the claimed invention. One of ordinary skill in the art would have been motivate to do so because Perricone provided the guidance for including cationic surfactants as one of the absorption/penetration enhancing agent, as these cationic surfactants are conventional known absorption/penetration enhancing agents that are non-irritating and nontoxic and typically used as to enhance penetration capacity of the pharmaceutical composition (Perricone: column 4, lines 36-56), which is also the objective of Pillay ([0052]). Furthermore, Hsu provides the guidance for using the cationic surfactant disclosed in Perricone as the suitable surfactant/penetration enhancer for peptide drugs such as octreotide of Pillay and Maggio. Thus, an ordinary artisan would looked to select cationic surfactants from the list of known penetration enhancers in the prior art, and include them in the pharmaceutical compositions of Pillay and Maggio containing octreotide per guidance from Perricone and Hsu, with a reasonable expectation of achieving a pharmaceutical composition with enhanced penetration capacity of the peptide drug such as octreotide. As such, it is noted that The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
Regarding claim 8, Maggio teaches the composition further contains anionic surfactants ([0090]).
Regarding claims 9-11, Maggio teaches the composition further contains chelator, cyclodextrin and fatty acid ([0040]).
Regarding claim 13, Maggio teaches the composition contains nonionic alkyl glucoside, surfactants, fatty acids, cyclodextrin and chelator as the penetration enhancing agents ([0031]-[0044]).
Regarding claim 14, Pillay teaches the composition further contains a water insoluble outer layer (occlusive layer) ([0003]-[0009] and [0053]).
Regarding claim 15, as discussed above, Pillay teaches a mucoadhesive membrane including therein a mucoadhesive layer in the form a film containing a polymeric membrane, at least one active agent and a permeation enhancer ([0052], [0054] and [0055]).
Regarding claims 16-20, Perricone and Hsu teaches that the penetration enhancers including cationic surfactants such as dodecyltrimethylammonium bromide (Perricone: column 4, lines 36-56; columns 6-7; Hsu: [0241]), and Perricone teaches the penetration enhancer is present in the composition at a level of about 0.1% to about 10% (column 4, lines 36-56). Thus, it would have been customary for an artisan of ordinary skill to determine the optimum concentration of penetration enhancer such as dodecyltrimethylammonium bromide in the pharmaceutical composition so as to achieve desired penetration enhancement for octreotide. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the concentration of penetration enhancer such as dodecyltrimethylammonium bromide in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 (I)-(II).
Regarding claims 26-31, Maggio teaches the pharmaceutical composition containing octreotide provides a serum half-life of octreotide of from 23.6 to 53.1 min, following oral delivery (Example 16). It would have been obvious to one of ordinary skill in the art to determine the therapeutic window of the pharmaceutical composition by optimizing the concentrations of penetration enhancer and drug such as octreotide so as to achieve a desired pharmacokinetic (PK) profile that translate to a therapeutic window 300 minutes or less, or a therapeutic winder of 50-400 minutes, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Maggio provided the guidance to do so by teaching the optimizing of the concentrations of penetration enhancer and drug in the composition so as to achieve a PK profile including a serum half-life of octreotide of from 23.6 to 53.1 min following oral delivery, which would achieve a therapeutic window within the claimed 300 minutes or less, or the claimed 50-400 minutes. It is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05 I). As such, it would have been customary for an artisan of ordinary skill to determine the optimum therapeutic window based on optimizing the concentrations of penetration enhancer, octreotide and the PK profile so as to achieve the desired therapeutic effect upon oral delivery. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the therapeutic window would have been obvious before the effective filing date of Applicant’s invention. See MPEP 2144.05 (I)-(II).
Regarding claim 33, Pillay teaches the mucoadhesive layer comprises a polymeric membrane selected from polyacrylic acid and chitosan ([0013]). Maggio teaches the polymer matrix contains materials selected from polysaccharides, gum acacia, gelatin, starch, collagen, guar gum xanthan gum, polyvinylpyrrolidone and polypeptide/protein ([0074] and [0182]).
Regarding claim 34, Maggio teaches the composition further contains stabilizer ([0112]).
Regarding claims 35 and 36, Hsu teaches the polymer matrix include material selected from polyethylenes; polysiloxanes; polyisobutylenes; polyacrylates; polyacrylamides; polyurethanes; plasticized ethylene-vinyl acetate copolymers; and tacky rubbers such as polyisobutene, polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene) ([0116], [0251], [0258]). It would have been obvious to include dendritic polymer or hyperbranched polymer such as polyethylenes, polysiloxanes or polyisobutylenes as the material in the polymer matrix of Pillay and Maggio, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Hsu teaches that materials such as polyethylenes, polysiloxanes, or polyisobutylenes are suitable for use as the polymer matrix when formulating a pharmaceutical composition used for administration of a drug to the mucosal (i.e., buccal) containing peptidyl drug such as octreotide (Hsu: [0027], [0116], [0251], [0258]). Thus, an ordinary artisan provided the guidance from the prior art would have looked to including polyethylenes, polysiloxanes, or polyisobutylenes as one of the material in the polymer matrix of the pharmaceutical composition suitable for buccal administration of Pillay and Maggio per guidance from Hsu, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding claims 50, as discussed above, Pillay teaches the permeation enhancers include chitosan ([0052]), thereby meeting the claimed permeation enhancer is biocompatible.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 4 and 22-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pillay et al (19 December 2013; US 2013/0337022 A1) in view of Maggio (20 October 2011; US 2011/0257096 A1), Temtsin-Krayz et al (4 May 2017; US 2017/0119660 A1), Perricone (9 March 1999; US 5,879,690) and Hsu et al (3 July 2003; US 2003/0124176 A1), and as evidenced by Rani et al (BioResources, 5(4): 2765-2807), as applied claim 1 above, and further in view of Perusse et al (4 June 2015; WO 2015/078893 A1; citation and English translation via US 2017/0087077 A1).
The pharmaceutical composition of claim 1 is discussed above, and said discussion is incorporated herein in its entirety.
However, Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu do not teach the limitations of claims 4 and 22-25.
Regarding claim 4, Perusse teaches a pharmaceutical composition comprising alkyl polyglucosides and glycine betaine esters as penetration enhancers ([0005]-[0014], [0059]-[0074]; Examples 1-4).
It would have been obvious to one of ordinary skill in the art to include glycine betaine ester as the surfactant/penetration enhancer in the pharmaceutical composition of Pillay, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Perusse teaches that glycine betaine ester is nontoxic cationic surfactant that is suitable for use as one of penetration enhancers (Perusse: [0011]) and Pillay teaches that cationic surfactants can be added as the suitable permeation enhancers (Pillay: [0052]). Furthermore, Perusse teaches that glycine betaine ester also provide additional benefits such as preservatives and bactericidal properties (Perusse: [0011]). Thus, an ordinary artisan provided the guidance from Perusse would looked including glycine betaine esters as the permeation enhancer in the pharmaceutical composition of Pillay with a reasonable expectation of achieving a pharmaceutical composition with enhanced stability and penetration capacity, and achieve Applicant’s claimed invention with success.
Regarding claims 22-25, Perusse teaches the glycine betaine esters can be present in the composition at a concentration from 0.5% to 5% (Examples 1-4). Thus, it would have been customary for an artisan of ordinary skill to determine the optimum concentration of glycine betaine esters in the pharmaceutical composition so as to achieve desired penetration enhancement for octreotide. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the glycine betaine esters in the composition would have been obvious before the effective filing date of Applicant’s invention. “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 (I)-(II).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pillay et al (19 December 2013; US 2013/0337022 A1) in view of Maggio (20 October 2011; US 2011/0257096 A1), Temtsin-Krayz et al (4 May 2017; US 2017/0119660 A1), Perricone (9 March 1999; US 5,879,690) and Hsu et al (3 July 2003; US 2003/0124176 A1), and as evidenced by Rani et al (BioResources, 5(4): 2765-2807), as applied claim 1 above, and further in view of Banach et al (6 April 2006; US 2006/0073173 A1).
The pharmaceutical composition of claim 1 is discussed above, and said discussion is incorporated herein in its entirety.
However, Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu do not teach the limitation of claim 21.
Regarding claim 21, Banach teaches a pharmaceutical composition containing a drug and a surfactant, wherein the amount of surfactant is near the critical micelle concentration of 0.3% ([0016] and [0051]-[0053]).
It would have been obvious to one of ordinary in the art to include a surfactant at a concentration that is near the critical micelle concentration so as to achieve a composition with a critical micelle concentration of 0.3% per guidance from Banach, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Banach provided the guidance for using an amount of amount of surfactant is near the critical micelle concentration of 0.3% so as to achieve a composition with a desired surface tension and reduction in unwanted side effects such as irritations upon administration ([0016], [0051]-[0053] and [0164]). Thus, an ordinary artisan provided the guidance from Banach would looked to including a surfactant in an amount near a critical micelle concentration such 0.3% in the composition of Pillay so as to achieve a composition with a desired surface tension and reduction in unwanted side effects such as irritations upon administration to a mucosal surface, and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pillay et al (19 December 2013; US 2013/0337022 A1) in view of Maggio (20 October 2011; US 2011/0257096 A1), Temtsin-Krayz et al (4 May 2017; US 2017/0119660 A1), Perricone (9 March 1999; US 5,879,690) and Hsu et al (3 July 2003; US 2003/0124176 A1), and as evidenced by Rani et al (BioResources, 5(4): 2765-2807), as applied claim 1 above, and further in view of Deasy et al (4 April 2013; US 2013/0085105 A1).
The pharmaceutical composition of claim 1 is discussed above, and said discussion is incorporated herein in its entirety.
However, Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu do not teach the limitation of claim 32.
Regarding claim 32, Deasy teaches a pharmaceutical composition containing octreotide and penetration enhancers, wherein the absorption of the drug is from about 50 µg to about 500 ug ([0001], [0023], [0037] and [0300]-[0355]).
It would have been obvious to one of ordinary skill in the art to optimize the concentrations of octreotide and penetration enhancers in the pharmaceutical composition to achieve the desired content of octreotide permeation in the therapeutic window, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do with reasonable expectation of success because Deasy provide the guidance for optimizing the octreotide and penetration enhancers in the composition so as to achieve the desired absorption of the drug from about 50 µg to about 500 µg, which overlaps the amount of 50-600 µg of the claimed invention. Thus, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05 I). Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the amount of octreotide permeation in a therapeutic window would have been obvious before the effective filing date of Applicant’s invention. See MPEP 2144.05 (I)-(II).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 09/26/2025 have been fully considered but they are not persuasive.
Applicant argues that by alleging that “Maggio does not teach or suggest the claimed surfactants.” Applicant further alleges that “Temtsin-Krayz is directed to active lipophilic compounds generally, but contains no teaching regarding the claimed surfactants and octreotide specifically among many lipophilic compounds” and “Perricone contains no teaching to suggest or direct a person of ordinary skill to
octreotide, let alone as an active ingredient with the claimed surfactants.” Applicant further alleges “Hsu provides no specific selection of octreotide among hundreds of "peptidyl drugs," let alone with the claimed surfactants.” Applicant further alleges “Pillay teaches oral drug delivery, but contains no teaching regarding a pharmaceutically active component including octreotide in the polymeric matrix, and provides no motivation to select this particular active component with the claimed surfactants” and “Perusse provides no teaching regarding octreotide let alone with the claimed surfactants.” Thus, Applicant alleges “there is no reason to combine the references to arrive at the claimed subject matter apart from the teachings gleaned from Applicants' disclosure, which is impermissible hindsight.” (Remarks, page 11, paragraphs 2-4).
In response, the Examiner disagrees. The 103 obviousness rejection over independent claim 1 is based on the combined teachings of Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu (and as evidence by Rani).
As discussed above in the standing 103 rejection, Maggio in view of Temtsin-Krayz provide for the octreotide of claim 1, and Perricone in view of Hsu provides for the surfactant of claim 1 (see 103 rejection, pages 3-10 of this office action).
As discussed above in the standing 103 rejection, Maggio teaches octreotide is a peptide active agent that can be incorporated in a polymer matrix of an oral or buccal pharmaceutical composition containing a permeation enhancer so as to increase the bioavailability of the peptide administered to the oral cavity, thereby improving oral delivery of octreotide (Maggio: [0003], [0011], [0073] and [0086]); and Temtsin-Krayz recognized that it is conventionally known in the art of pharmaceutical formulations that octreotide can be included as a drug in an oral pharmaceutical film of the oral or buccal pharmaceutical dosage form of Pillay so as improve the bioavailability of the drug when administered to the oral cavity (Temtsin-Krayz: Abstract; [0018], [0020], [0028]-[0029], [0054]-[0058], [0067]-[0068], [0089] and [0103]-[0111]; claim 4). Thus, Maggio in view of Temtsin-Krayz renders obvious the inclusion of octreotide as the peptide active agent in the mucoadhesive membrane of the oral or buccal pharmaceutical dosage form of Pillay.
As discussed above in the standing 103 rejection, Perricone provided the guidance for including cationic surfactants as one of the absorption/penetration enhancing agent, as these cationic surfactants are conventional known absorption/penetration enhancing agents that are non-irritating and nontoxic and typically used as to enhance penetration capacity of the pharmaceutical composition (Perricone: column 4, lines 36-56), which is also the objective of Pillay ([0052]). Hsu provides the guidance for using the cationic surfactant disclosed in Perricone as the suitable surfactant/penetration enhancer for peptide drugs such as octreotide of Pillay and Maggio. Thus, Perricone in view of Hsu renders obvious the inclusion of cationic surfactants such as cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium bromide, cetylpyridinium chloride, dodecyltrimethylammonium chloride/bromide or hexadecyltrimethylammonium chloride, as one of the surfactants used as the absorption/penetration enhancing agent of Pillay.
Thus, Pillay is properly combined with Maggio, Temtsin-Krayz, Perricone, and Hsu to render obvious Applicant’s independent claim 1 because per KSR, a conclusion of obviousness has been adequately established by the Examiner, as there was some teaching, suggestion or motivation in the cited prior arts of Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu that would have led an ordinary artisan to modify or combine the cited prior art references to arrive at the claimed invention, and finding that there was reasonable expectation of success support a conclusion of obviousness. See MPEP §2143 (I)(G). As such, contrary to Applicant’s allegation, the obviousness analysis in the standing 103 rejection over the combined teachings of Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu was not based on hindsight analysis, as the obviousness analysis takes into account only knowledge gleaned from the combined teachings of the cited prior arts of Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu, and such reconstruction using the combined teachings of Pillay, Maggio, Temtsin-Krayz, Perricone, and Hsu was indeed proper to render obvious Applicant’s claimed invention.
Applicant argues:
“It is not enough to state that the combination of properties would render the claims obvious. It is critical to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does. MPEP 2143. The claimed subject matter is not directed to a mere aggregation of properties of components in an admixture. Rather, the functional interaction between the claimed features of the components achieves a combined technical effect that is greater than the sum of the technical effects of the individual features. Indeed, the pharmaceutical composition is based on applicants' discovery that the permeation enhancer (surfactant) enhances the permeation of octreotide from a pharmaceutical film, and that the surfactant is rendered systemically biodegradable. In short, the combination yields surprising and unexpected results, which is well supported in the Detailed Description.
For instance, Table 1 of the instant Application illustrates, cationic surfactants
surprisingly exhibited both strong octreotide compatibility and permeation enhancement, with a rank score of 3 (high permeation). Further, Figure 7 of the instant Application illustrates that DDTMAB is an effective permeation enhancer for octreotide in preclinical models. It also shows that absorption is more efficient through sublingual mucosa compared to buccal. Table 4 of the instant Application indicates that a quaternary amine moiety is critical for activity. Figure 8, shows an image of an exemplary pharmaceutical composition film. Figure 10 illustrates significant absorption of octreotide from a solution and film that was achieved in vivo. Figure 11A, illustrates the unexpected results of glycine betaine ester-C12 permeation activity. Figure 11 B shows the permeation activity is for glycine betaine esters with the effect of alkyl chains. Figure 12, shows a comparison of the permeation activity of GBE C12 with DDTMAB. Figure 13, shows the results of cetyl pyridium chloride (CPC) as a permeation enhancer in average flux (pg/cm2*min) as a function of time (mins). Figure 14 shows the results of tetrahexyl ammonium bromide which is a cationic surfactant with multiple long chain alkyl groups attached to the quaternary nitrogen as a permeation enhancer. Figure 15 shows the results of benzalkonium chloride (BAC) as a permeation enhancer. Example 16, figure 16 illustrates benzalkonium chloride and dodecyltrimethylammonium bromide as an efficient permeation enhancers with mean improved octreotide bioavailability.” (Remarks, page 11, 5th paragraph through page 12).
In response, the Examiner disagrees. First, it is noted the obviousness analysis in the standing 103 rejection over independent claim 1 was not based on “the combination of properties,” as alleged by Applicant. Rather, the obviousness analysis as discussed in the standing 103 rejection was based on i) how it would have been obvious include octreotide as the peptide active agent in the mucoadhesive membrane of the oral or buccal pharmaceutical dosage form of Pillay, per guidance from Maggio and Temtsin-Krayz (see 103 rejection, pages 4-6); and ii) how it would also have been obvious to include cationic surfactants such as cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium bromide, cetylpyridinium chloride, dodecyltrimethylammonium chloride/bromide or hexadecyltrimethylammonium chloride, as one of the surfactants used as the absorption/penetration enhancing agent of Pillay, per guidance from Perricone and Hsu (see 103 rejection, pages 6-10). Thus, Applicant’s allegations pertaining to how “[i]t is not enough to state that the combination of properties would render the claims obvious” and how “[t]he claimed subject matter is not directed to a mere aggregation of properties of components in an admixture” are not pertinent to the obviousness analysis in the standing 103 rejection as set forth in this office action.
Second, with respect to Applicant’s alleged argument and evidence of unexpected results as shown in the Specification, it is noted that Applicant’s alleged evidence of unexpected results with respect to enhanced permeation of octreotide and improved bioavailability of octreotide using cationic surfactants permeation enhancers, particularly, dodecyltrimethylammonium bromide, glycine betaine ester-C12, cetylpyridium chloride, tetrahexyl ammonium bromide, and benzalkonium chloride, are considered, but found insufficient to obviate standing 103 rejections as set forth in this office action. This is because the quaternary ammonium surfactant as recited in claim 1 is much broader than the particular permeation enhancers (dodecyltrimethylammonium bromide, glycine betaine ester-C12, cetylpyridium chloride, tetrahexyl ammonium bromide, and benzalkonium chloride) used in Applicant’s alleged evidence of unexpected results shown in Table 1, Figure 7, Table 4, Figure 8, Figure 10, Figures 11A-11B, and Figures 12-16. Furthermore, the results shown in Table 1, Figure 7, Table 4, Figure 8, Figure 10, Figures 11A-11B, and Figures 12-16 appeared to be concentration dependent. Thus, claim 1 is not commensurate in scope with the particular permeation enhancers and concentrations thereof allegedly used in showing the alleged unexpected results. It is noted that [w]hether 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." See MPEP §716.02(d).
Furthermore, even if claim 1 was to be amended so that it is commensurate in scope with the particular permeation enhancers and concentrations thereof allegedly used in showing the alleged unexpected results, said amendment commensurate in scope, may be not be sufficient to obviate the standing 103 rejections because it is well-established in the cited prior arts, dodecyltrimethylammonium bromide, glycine betaine ester-C12, cetylpyridium chloride, tetrahexyl ammonium bromide, and benzalkonium chloride are known cationic surfactant and permeation enhancers, and such cationic permeation enhancers, particularly quaternary ammonium surfactant, are known to be used to enhance penetration capacity of drugs including peptide drugs such as octreotide, thereby improving bioavailability of said drugs. See 103 rejections, pages 6-12 and 15-16. Thus, the Applicant’s alleged evidence of unexpected results with respect to enhance permeation of octreotide and improved bioavailability of octreotide using cationic surfactants permeation enhancers, appeared to be reasonably expected based on the teachings of the cited prior arts. As such, it is noted that "[e]xpected 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).
As a result, for at least the reasons discussed above, claims 1, 3-5, 7-11, 13-36, 40-45 and 50 remain rejected as being obvious and unpatentable over the combined teachings of the cited prior arts in the standing 103 rejections as set forth in this office action.
Conclusion
No claim is allowed.
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/DOAN T PHAN/ Primary Examiner, Art Unit 1613