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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application 18/276,918, filed 08/11/2023, is a 371 national stage entry of international patent application PCT/CA2022/050212, filed 02/14/2022, which claims benefit of U.S. provisional patent applications 63/149,215, filed 02/12/2021, 63/171524, filed 04/06/2021, 63/190,131, filed 05/18/2021, and 63/195,680, filed 06/01/2021.
Status of Action/Claims
Receipt of Remarks/Amendments filed on 1/26/2026 is acknowledged. Claims 1-2, 5-14, 17, 19-23, 25-27 are currently pending and are presented for examination on the merits for patentability.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
New/Maintained Claim Objection(s) / Rejection(s)
New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 20 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 20 and 23 recite a method for treating a condition selected from .. cluster headaches. The instant specification do not provide support for wherein the condition treated is specifically cluster headaches. The applicant also do not state wherein the specification there is support for this newly added limitation. Therefore, “cluster headaches” recited in claims 20 and 23 represents new matter.
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 1-2, 5-11, 13-14, 17, 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021003467 A1 (Arnold, C. M. et al) published 01/07/2021 (cited in PTO-892) in view of US 10,500,280 B2 (Shah, S. M. et al) published 12/10/2019 (cited in PTO-892) and US 2018/0360736 A1 (Obeid, R.; Paiement, N.) published 08/03/2017 (cited in IDS 11/24/2023), as evidenced by “Trehalose.” (n.d.). Calorie Control Council, https://caloriecontrol.org/trehalose/#:~:text=Trehalose%20is%20a%20multi%2Dfunctional,as%20sucrose%20or%20table%20sugar (cited in PTO-892) and Migliaccio, G. P. et al. (1981). “Comparison of Solution Conformational Preferences for the Hallucinogens Bufotenin and Psilocin Using 360-MHz Proton NMR Spectroscopy.” J. Med. Chem. 24(2), 206-209 (cited in PTO-892) and Bedosky (https://www.everydayhealth.com/diet-nutrition/maltitol/guide/; 2024).
Arnold teaches preparation of a psilocin sublingual thin film comprising 0-15% hydroxypropyl methylcellulose on a dry weight basis, 0-15% Eudragit on a dry weight basis, 0-25% polyvinyl alcohol on a dry weight basis, 0-25% glycerol on a dry weight basis, 0-15% sodium alginate on a dry weight basis, 0-60% trehalose on a dry weight basis, and 1.3% psilocin on a dry weight basis; the thin film yields a dose of 2 mg of psilocin to the oral cavity of the subject for sublingual administration ([0141] Example 8). As evidenced by the instant specification, psilocin is a tryptamine (instant specification [0051]). Thus, Arnold’s use of psilocin reads on the active agent recited in the oral film formulation of instant claims 1 and 22. As evidenced by the instant specification, glycerol is a plasticizer (see instant specification [0130]). Thus, Arnold’s use of 0-25% glycerol based on the dry weight of the thin film formulation reads on the plasticizer of instant claim 1, and the concentration range for plasticizer recited in instant claim 11. Arnold’s use of sodium alginate in an amount of 0-15% based on the dry weight of the thin film formulation reads on the mucoadhesive agent of claim 9, and overlaps and renders obvious the amount for mucoadhesive agent of claim 10. Arnold’s use of polyvinyl alcohol in an amount of 0-25% based on the dry weight of the formulations reads on the film forming polymer of instant claim 13, and renders obvious the amount of film forming polymer recited in instant claim 14. As evidenced by Calorie Control Council, trehalose is a sweetener (1st para). Thus, Arnold’s use of trehalose in the sublingual thin film reads on the sweetener of the oral film formulation, as recited in claim 19.
Arnold teaches that the “sublingual film” refers to a substrate containing the psychedelic compounds and hydrophilic material that dissolves in the mouth for transmucosal, buccal or sublingual administration of a dose; the film combines the psychedelic compound, hydrophilic polymers, and optionally one or more of a surfactant such as benzalkonium chloride, and a sweetener ([0091]). As evidenced by the instant claims, benzalkonium chloride is a penetration enhancer (instant claim 5). Arnold teaches application of an amount of the formulation to a subject for treating or mitigating a neurological, physiological, or mental health condition, wherein said mental health condition comprises: anxiety, post-traumatic stress disorder, attention deficit disorders, depression, memory loss, dementia, cognitive dysfunction, hearing loss, vision loss, neurologic pain, insomnia, erectile dysfunction, physiological pain or discomfort, or combinations thereof (Claims 11 and 12).
It is reiterated that the amount of psilocin exemplified in the oral film of Arnold is 1.3% by dry weight of the film formulation, which equates to a dose of 2 mg of psilocin ([0141] Example 8). Arnold teaches its inventive formulation, which includes a metered dose formulation for oral administration via sublingual film delivery, comprises an amount of anywhere between 3 micrograms to 1.3 g of one or more psychedelic compounds from a class of mushroom-related compounds (claim 1; claim 8). Arnold notes that each method of delivery/application requires a specific composition of dosage and amount of psychedelic compound ([0071]).
Arnold differs from the instantly claimed invention in that it fails to teach the oral film formulation comprises a penetration enhancer and acidifying agent, and that the surface pH of the film formulation is between 1.5 and 5, as recited in claims 1 and 22; thus, Arnold fails to claim the narrower ranges for surface pH recited in instant claim 2. Arnold also fails to exemplify that the penetration enhancer, specifically from the group of quaternary ammonium salts including benzalkonium chloride, is present in an amount of from 1% to 3%, or 0.5% to 5% by weight relative to the dry weight of the film formulation, as recited in instant claims. Arnold fails to teach the acidifying agent is selected from phosphoric acid, citric acid, tartaric acid, malic acid, acetic acid, succinic acid, maleic acid, hydrochloric acid, benzoic acid, fumaric acid, glucuronic acid, or lactic acid, as recited in instant claim 6. Arnold fails to exemplify the amount of active agent in the film is from about 2 to 25% by weight or 5 to 20% by weight, relative to the total dry weight of the oral film formulation, as recited in instant claim 8. Arnold also does not teach the formulation further comprises D-maltitol. Finally, Arnold fails to exemplify the method of buccal administration of the oral film, as recited in the methods of instant claims 20-21 and 23.
Shah teaches a pharmaceutical dosage form configured to disintegrate in saliva and maintain a pH of 4 or less within the saliva during the time the dosage form is dissolving therein, including a therapeutically effective amount of melatonin in a carrier matrix and a sufficient amount of acid to impart the pH to the saliva (Abstract). Shah teaches that the composition’s acidifying agent lowers the pH inside the mouth, which enhances the oral solubility of melatonin so the melatonin may more readily pass through the oral mucosa into the blood stream (Col. 1 lines 50-60). Shah teaches that the pH of the saliva has been reported to be about 6.4-6.6 and the pH of the tongue coating has been reported to be about 7.1-7.4; because melatonin is sparingly soluble at near neutral and basic pHs, the melatonin in an orally-releasing dosage form might not be soluble enough to be available for absorption via the oral mucosa, especially the sublingual or buccal mucosa (Col. 3-4 bridging para). Shah teaches the acidifying agent in its inventive dosage form lowers the pH inside the mouth to temporarily lower the local pH of the saliva and/or the tongue coating to maintain melatonin in a soluble form at the mucosa interfaces for absorption; in a particular example, the pH is maintained at 3.3 or below, which is below the pKa of melatonin (Col. 5 lines 37-48). Shah teaches the amount of acidifying agent used is effective to impart the pH discussed herein to the dosage form as well as the saliva in the vicinity of the dosage (Col. 7 lines 12-18). The Examiner notes that the pH of the entire dosage form inherently includes the pH on the surface of the dosage form, whether or not this is specifically addressed. Shah exemplifies the use of citric acid in a polymer strip formulation for rapid disintegration and absorption through oral mucosa; the citric acid controls the pH to allow for transdermal delivery and to stimulate saliva to help with dissolution and absorption (Col. 11 lines 37-42).
As evidenced by Migliaccio, psilocin has high lipid solubility, and has pKas of 8.47 and 11.33 (p. 208 Table II; R. Col. 2nd para).
Obeid teaches an orally administered dosage form that facilitates delivery of an agent locally in the buccal cavity for a sustained period of time including mucoadhesive particles that are made of at least a mucoadhesive material combined with the agent, and which are dispersed in a disintegrating film (Abstract). Obeid teaches polyalcohols and specifically maltitol can be incorporated into the disintegrating film to facilitate or enhance wettability and disintegration of the film (e.g. para 0029; 0031). As evidenced by Bedosky, Maltitol is also known as D-maltitol). Obeid also teaches adding penetration enhancer and specifically benzalkonium chloride. Obeid teaches penetration enhancer can increase buccal permeation of an active ingredient by enabling transcellular route for transportation of the drug through the buccal epithelium (e.g. para 0017, 0032).
Regarding the film formulation of instant claims 1 and 22, the pH ranges recited in instant claim 2, the limitations surrounding the acidifying agent and penetration enhancer in claims 5-7, and addition of D-maltitol recited in claim 17, it would have been prima facie obvious for a person having ordinary skill in the art to (1) add citric acid in an amount sufficient to impart a pH of 3.3 to the thin film dosage formulation of Arnold, akin to the pH imparted to the polymeric strip of Shah, and (2) add 1-3% by weight or 0.5-5% by weight of benzalkonium chloride relative to the dry weight of the thin film formulation of Arnold, and (3) add further include D-maltitol, and arrive at the instantly claimed invention.
The ordinarily skilled artisan would have performed modification (1) in order to use the technique taught by Shah (reducing an oral film’s pH to improve solubility of the active compound in the oral cavity) to improve the similar thin film formulation of Arnold in the same way (see MPEP 2143 I(C)). Arnold’s base film formulation contains the elements of the claimed oral film, except for the acidifying agent which imparts the claimed pH to the surface of the film. Shah teaches a comparable thin film for oral delivery of melatonin to the oral mucosa, which utilizes citric acid to impart a pH of 3.3 to the dosage form (i.e. the entire film, including the surface) in order to improve the solubility of the melatonin in the saliva during sublingual or buccal administration. The film of Shah has been improved in the same manner as the claimed oral film formulation. One of ordinary skill in the art would have applied the technique of adding citric acid to the formulation of Arnold in a sufficient amount to impart a pH of 3.3 to the dosage form, because the ordinarily skilled artisan would have recognized the benefit of doing so based on the fact that psilocin is lipid soluble, and thus may not be as soluble in oral saliva; furthermore, because the pKa of psilocin is 8.47, the ordinarily skilled artisan would recognize that a pH of 3.3 or less would improve the solubility of psilocin in saliva in the same way that a pH of 3.3 improved the solubility of melatonin in the oral saliva in Shah. Because the film of Shah is comparable to the film of Arnold, and is used in the same manner to deliver active agent for absorption by the oral mucosa, the addition of citric acid to the formulation of Arnold to generate a pH of 3.3 in the dosage form would predictably impart improved solubility of the psilocin in the oral mucosa.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further incorporate a penetration enhancer such as benzalkonium chloride in the formulation of Arnold based on the teachings of Obeid. One would have been motivated to do so because Obeid teaches adding penetration enhancer and specifically benzalkonium chloride, wherein such penetration enhancer can increase buccal permeation of an active ingredient by enabling transcellular route for transportation of the drug through the buccal epithelium. Based on this, one skilled in the art would have found it obvious to perform modification (2) and optimize the amount/concentration of the penetration enhancer and include an amount, such as the claimed amount/concentration, which would provide optimal penetration of the active ingredient. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further perform modification (3) and incorporate D-maltitol in the formulation of Arnold based on the teachings of Obeid. Obeid teaches an orally administered dosage form that facilitates delivery of an agent locally in the buccal cavity for a sustained period of time including mucoadhesive particles that are made of at least a mucoadhesive material combined with the agent, and which are dispersed in a disintegrating film. Obeid teaches polyalcohols and specifically maltitol can be incorporated into the disintegrating film to facilitate or enhance wettability and disintegration of the film. As discussed supra, Arnold teaches buccal administration of its sublingual thin film and one skilled in the art would have been motivated to include D-maltitol to enhance the wettability in the oral cavity and disintegration once the active drug has been released from the film formulation.
Regarding claim 8, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to perform routine optimization on the amount of psilocin present in the film of Arnold, in order to optimize the concentration of psychedelic compound present in the formulation for administration to improve the subject’s mental health condition. Arnold establishes that the amount of psychedelic in the formulation is a results-effective variable for treatment of a mental health condition. Arnold also establishes a finite range of concentrations (between 3 micrograms and 1.3 g) for the psychedelic compound within the sublingual film, with which the ordinarily skilled artisan can perform routine optimization on the amount of psilocin in the formulation with a reasonable expectation of success. The exemplified concentration for psilocin in Arnold’s film is 1.3% by dry weight of the formulation, which equates to 2 mg; thus, when performing routine optimization by incrementally increasing the amount of psilocin from the exemplified 2 mg to Arnold’s taught maximum of 1.3 g, the amount of psilocin will increase in % by dry weight of the formulation into a range which overlaps the range claimed in claim 8. In performing this routine optimization, the ordinarily skilled artisan would naturally happen upon concentrations for psilocin within the instantly claimed range for active agent recited in claim 8. In the case where the claimed ranges "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).
Regarding the methods recited in instant claims 20-21 and 23, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to buccally administer the resulting film rendered obvious by the combined teachings of Arnold and Shah, and arrive at the instantly claimed invention, because Arnold explicitly suggests buccal administration of its sublingual thin film for use in its method of administering the film to a patient to treat a mental health condition in the patient.
Claims 12 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021003467 A1 (Arnold, C. M. et al) published 01/07/2021 (cited in PTO-892) in view of US 10,500,280 B2 (Shah, S. M. et al) published 12/10/2019 (cited in PTO-892) and US 2018/0360736 A1 (Obeid, R.; Paiement, N.) published 08/03/2017 (cited in IDS 11/24/2023), as evidenced by “Trehalose.” (n.d.). Calorie Control Council, https://caloriecontrol.org/trehalose/#:~:text=Trehalose%20is%20a%20multi%2Dfunctional,as%20sucrose%20or%20table%20sugar (cited in PTO-892) and Migliaccio, G. P. et al. (1981). “Comparison of Solution Conformational Preferences for the Hallucinogens Bufotenin and Psilocin Using 360-MHz Proton NMR Spectroscopy.” J. Med. Chem. 24(2), 206-209 (cited in PTO-892) and Bedosky (https://www.everydayhealth.com/diet-nutrition/maltitol/guide/; 2024) as applied to claims 1-2, 5-11, 13-14, 17, 19-23 and further in view of US 2017/0216220 A1 (Bilal, M. et al) published 08/03/2017 (cited in IDS 11/24/2023).
The teachings of above cited references have been set forth above.
The collective teachings differ from the instantly claimed invention in that they fail to teach that the film further comprises an antioxidant, wherein the antioxidant is present in an amount of from about 0.01% to 5% or 0.1% to 1% by weight, relative to the total dry weight of the oral film formulation, as recited in instant claim 12.
Bilal teaches a film oral dosage form for oral transmucosal delivery of loxapine in a method of providing relief from agitation associated with schizophrenia or bipolar 1 disorder (Abstract). Bilal teaches loxapine film oral dosage forms advantageously employs an antioxidant or oxygen scavenger to prevent or reduce oxidative degradation of the loxapine salt, free base or prodrug prior to use; examples of antioxidant are sulfite salts such as sodium sulfite, sodium bisulfite, sodium metabisulfite and analogous salts of potassium and calcium ([0022]). A suitable amount of salt (e.g., sodium sulfite) is from about 0.01% to 5% or 0.1% to 1% of the weight of the film on a dry basis ([0023]).
The collective teachings of the above cited references also do not expressly teach the residence time of the formulation as recited in claim 26. The combination of Bilal and Obeid cure this deficiency.
Bilal teaches bulking agents or fillers may be added in the film oral dosage form as desired to increase or decrease the residence time (e.g. para 0029).
As discussed supra, Obeid also teaches an orally administered dosage form that facilitates delivery of an agent locally in the buccal cavity. Obeid teaches the formulation may be modulated for various residence times according to the desired treatment and the active agent effectiveness. The residence time in the oral cavity of the mucoadhesive particle will be modulated by various parameters such as size of the mucoadhesive. The mucoadhesive particles may have residence times lasting from about 5 min to a few days (e.g., 2 to 3 days). An extended release of the active agent is achieved via the longer residence time of the particles in the oral cavity. (para 0059, 0068, 0073-0074).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to add an antioxidant salt, such as sodium bisulfite, to the formulation of Arnold, at a concentration of from about 0.01% to 5% or 0.1% to 1% of the weight of the film on a dry basis, and arrive at the instantly claimed invention. Arnold’s base film formulation contains many of the elements of the claimed oral film, except for the antioxidant present in an amount of from about 0.01% to 5% or 0.1% to 1% by weight relative to the dry weight of the film. Bilal teaches a comparable film for oral delivery of an active agent (loxapine) which utilizes antioxidant (e.g. sodium sulfite) in order to prevent or reduce oxidative degradation of the pharmaceutical active. The film of Bilal has been improved in the same manner as the claimed oral film formulation. One of ordinary skill in the art would have applied the technique of adding antioxidant to the film formulation rendered obvious by the combined teachings of the above cited references in an amount of about 0.01% to 5% or 0.1% to 1% by weight relative to the dry weight of the film, because the ordinarily skilled artisan would have recognized the benefit of doing so based on the fact that Bilal improves its comparable oral film in this exact manner; thus, the addition of antioxidant in Bilal’s taught concentration range to the film formulation of Arnold would predictably prevent or reduce oxidative degradation of the psilocin.
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to modulate the residence time of Arnold’s formulation by adding bulking agent, fillers or by modifying size of the film formulation as taught by Bilal and Obeid and obtain a residence time (e.g. between 5 and 60 mins) which is desired. As mentioned above, Obeid teaches the formulation may be modulated for various residence times according to the desired treatment and the active agent effectiveness. The mucoadhesive particles may have residence times lasting from about 5 min to a few days (e.g., 2 to 3 days). An extended release of the active agent is achieved via the longer residence time of the particles in the oral cavity. Thus, depending on the type of release desired (e.g. extended or fast release), one skilled in the art would have found it obvious to modulate the residence time by modifying the parameters disclosed by Bilal and Obeid.
Claims 25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021003467 A1 (Arnold, C. M. et al) published 01/07/2021 (cited in PTO-892) in view of US 10,500,280 B2 (Shah, S. M. et al) published 12/10/2019 (cited in PTO-892) and US 2018/0360736 A1 (Obeid, R.; Paiement, N.) published 08/03/2017 (cited in IDS 11/24/2023), as evidenced by “Trehalose.” (n.d.). Calorie Control Council, https://caloriecontrol.org/trehalose/#:~:text=Trehalose%20is%20a%20multi%2Dfunctional,as%20sucrose%20or%20table%20sugar (cited in PTO-892) and Migliaccio, G. P. et al. (1981). “Comparison of Solution Conformational Preferences for the Hallucinogens Bufotenin and Psilocin Using 360-MHz Proton NMR Spectroscopy.” J. Med. Chem. 24(2), 206-209 (cited in PTO-892) and Bedosky (https://www.everydayhealth.com/diet-nutrition/maltitol/guide/; 2024) as applied to claims 1-2, 5-11, 13-14, 17, 19-23 and further in view of Stranska (WO2012097763A2).
The teachings of above cited references have been set forth above.
The collective teachings differ from the instantly claimed invention in that they fail to teach the limitations of claims 25 and 27. However, Stranska cures these deficiencies.
Stranska also teaches a carrier for oromucosal administration of physiologically active medicinal drug substances. Stranska in Fig. 2 discloses layer 1 of polymer nanofibres containing a drug and/or other physiologically active substances covered from one side with oromucosally non-adhesive covering layer 2 (i.e. the claimed second layer directed outwards from the mucosa and serving as protective barrier), while the free side of layer 1 of nanofibres is designated for contact with the sublingual mucosa or some other wall of the mouth cavity and enables penetration of the drug and/or other physiologically active substance into this wall. The covering layer 2 is usually impermeable for saliva and substances contained in the mouth cavity and prevents leaching of physiologically active substances from the carrier into the mouth cavity. That means that nearly all drugs and/or other physiologically active substances penetrate through the sublingual mucosa into the vascular system and into the human or animal organisms. Stranska in the examples teaches using polyurethane as non-biodegradable layer in covering layer. This also reads on claim 25 as the covering layer does not contain any buffers. (see e.g. Abstract; Claims; Figures; Principle of the Invention section; page 9, line 5-32; page 10, line 12 to page 11, line 2; page 11, line 20-33; page 12, line 15-20; page 13, line 23 to page 14, line 11; page 15, line 15-16 and line 31-33; Examples; Entire Document).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to further comprise a second layer directed outwards from the mucosa, wherein the second layer serves as a protective layer. As discussed supra, Stranska in Fig. 2 discloses layer 1 of polymer nanofibres containing a drug and/or other physiologically active substances covered from one side with oromucosally non-adhesive covering layer 2 (i.e. the claimed second layer directed outwards from the mucosa and serving as protective barrier), while the free side of layer 1 of nanofibres is designated for contact with the sublingual mucosa or some other wall of the mouth cavity and enables penetration of the drug and/or other physiologically active substance into this wall. Stranska provides the motivation to include a covering layer because the covering layer 2 is usually impermeable for saliva and substances contained in the mouth cavity and prevents leaching of physiologically active substances from the carrier into the mouth cavity. That means that nearly all drugs and/or other physiologically active substances penetrate through the sublingual mucosa into the vascular system and into the human or animal organisms. Stranska in the examples teaches using polyurethane as non-biodegradable layer in covering layer. This also reads on claim 25 as the covering layer does not contain any buffers.
From the combined teaching of the cited references, 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, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant argued that the cited prior art does not teach the limitations of claims as amended because Shah teaches 10% benzalkonium chloride as a surfactant, which is outside the claimed range of 0.5% to 5%.
In response, as discussed supra, Obeid teaches adding penetration enhancer and specifically benzalkonium chloride, wherein such penetration enhancer can increase buccal permeation of an active ingredient by enabling transcellular route for transportation of the drug through the buccal epithelium. Based on this, one skilled in the art would have found it obvious to include benzalkonium chloride as penetration enhancer and optimize the amount/concentration of the penetration enhancer and include an amount, such as the claimed amount/concentration, which would provide optimal penetration of the active ingredient. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Applicant argued that the examiner’s rationale for combining Arnold with Shah is based on the assertion that psilocin, like melatonin, is lipid soluble and would benefit from pH reduction. It was argued that Shah is directed to melatonin delivery and not psychedelic tryptamines and while both compounds may exhibit some degree of lipid solubility, the two compounds differ in their chemical structures, pKa values and pharmacokinetic profiles.
In response, as discussed supra, Shah teaches a comparable thin film for oral delivery of melatonin to the oral mucosa, which utilizes citric acid to impart a pH of 3.3 to the dosage form (i.e. the entire film, including the surface) in order to improve the solubility of the melatonin in the saliva during sublingual or buccal administration. The film of Shah has been improved in the same manner as the claimed oral film formulation. One of ordinary skill in the art would have applied the technique of adding citric acid to the formulation of Arnold in a sufficient amount to impart a pH of 3.3 to the dosage form, because the ordinarily skilled artisan would have recognized the benefit of doing so based on the fact that psilocin is lipid soluble, and thus may not be as soluble in oral saliva; furthermore, because the pKa of psilocin is 8.47, the ordinarily skilled artisan would recognize that a pH of 3.3 or less would improve the solubility of psilocin in saliva in the same way that a pH of 3.3 improved the solubility of melatonin in the oral saliva in Shah. Because the film of Shah is comparable to the film of Arnold, and is used in the same manner to deliver active agent for absorption by the oral mucosa, the addition of citric acid to the formulation of Arnold to generate a pH of 3.3 in the dosage form would predictably impart improved solubility of the psilocin in the oral mucosa. Thus, while the two compounds differ in their chemical structures, pKa values and pharmacokinetic profiles, the examiner has provided reasoning (discussed above) as to why one skilled in the art would have been motivated to add citric acid to the formulation of Arnold to generate a pH of 3.3.
Applicant also argued that the claimed oral film formulation requires the specific combination of (1) an active agent selected from psilocybin, psilocin, norpsilocin, bufotenin, bufotenidine, baeocystin, norbaeocystin, and aeruginascin, (2) a quaternary ammonium salt penetration enhancer at 0.5% to 5.0%, (3) an acidifying agent, and (4) a plasticizer, wherein the surface pH is between 1.5 and 5. This specific combination provides synergistic permeation enhancement that is not taught or suggested by the cited references.
In response, “The arguments of counsel cannot take the place of evidence in the record.” In re Schulze, 346 F.2d 600, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 40 USPQ 2d 1685 (Fed. Cir. 1996), In re De Blauwe et al., 222 USPQ 191, (Fed. Cir. 1984). Applicant has not provided any factual evidence establishing that the claimed combination provides synergistic permeation enhancement which would have been unexpected. While applicant make the argument of synergistic permeation enhancement, applicant have not provided any evidence and results which shows the claimed combination providing synergistic permeation enhancement over what is taught in the prior art. As discussed supra, Obeid teaches adding penetration enhancer and specifically benzalkonium chloride, wherein such penetration enhancer can increase buccal permeation of an active ingredient by enabling transcellular route for transportation of the drug through the buccal epithelium. Thus, addition of a penetration enhancer such as benzalkonium chloride was known to enhance permeation of the active agent and Applicant have not shown that the claimed combination enhances permeation significantly more than simply adding the penetration enhancer. Absence any evidence of synergistic effect, applicant’s argument are not found persuasive at this time.
Applicant argued that Arnold already teaches a functional sublingual film for psilocin delivery without the need for pH modification. Arnold's formulation achieves transmucosal delivery through its combination of hydrophilic polymers and optional surfactants.
In response, the examiner argues that Arnold teaching a functional sublingual film for psilocin delivery does not teach away from making any modifications to the formulation for improvement of the formulation and psilocin delivery as long as the combination of the references provide motivation or render obvious the modifications to the formulation. Thus, applicant’s argument that Arnold already teaches a functional sublingual film for psilocin delivery are not found persuasive at this time.
With respect to Applicant argument regarding newly added claims, Applicant’s attention is respectfully drawn to the new and modified rejections above which render obvious the limitations in the newly added claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-14, 17, 19-23, 25-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 7, 13-14 and 16 of U.S. copending patent application No. 17/842,372 in view of WO 2021003467 A1 (Arnold, C. M. et al) published 01/07/2021 (cited in PTO-892), US 10,500,280 B2 (Shah, S. M. et al) published 12/10/2019 (cited in PTO-892), US 2017/0216220 A1 (Bilal, M. et al) published 08/03/2017 (cited in IDS 11/24/2023) and US 2018/0360736 A1 (Obeid, R.; Paiement, N.) published 08/03/2017 (cited in IDS 11/24/2023) and Stranska (WO2012097763A2).
App’372 claims a method comprising orally administering to a subject an oral dissolvable film comprising: (i) a flowable water-soluble or water-swellable film-forming matrix that includes at least one polymer, (ii) psilocybin, psilocin, baeocystin, or a combination thereof; and (iii) a stabilizing inorganic acid; wherein, the psilocybin, psilocin, baeocystin, or combination thereof is present in a combined amount of 1 to 30 mg, wherein the ratio between psilocybin and psilocin to the inorqanic acid is 1:0.5 to 1:2 w/w and wherein the surface pH of the film is between 2 and 4.5 (Claim 1). App’372 claims the method wherein the inorganic acid is phosphoric acid. App’372 claims the administering is for improving creativity, boosting physical energy level, attaining emotional balance, increasing performance on problem-solving tasks, treating anxiety, treating depression, treating addiction, or any combination thereof (Claim 4). App’372 claims the administering is for treating at least one of obsessive-compulsive disorder (OCD), pain, irritability, fibromyalgia, post-traumatic stress disorder (PTSD), cluster headaches, paranoia, psychosis, anxiety, panic attacks, flashbacks, smoking addiction, alcohol addiction, and cocaine addiction (Claim 5). App’372 claims the oral dissolvable film is delivered enterally, sublingually, or transmucosally (Claim 7). App’372 claims the flowable water-soluble or water swellable film-forming matrix that includes a polymer comprises each of plasticizer, binder, preservative, and solvent. The active method step and treatments claimed by App’372 highly overlaps the methods of instant claims 20-21 and 23.
App’372 also claims an oral dissolvable film comprising: (a) a plasticizer selected from the group consisting of glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, and tributyl citrate, (b) solvent selected from the group consisting of water, ethanol, and combinations thereof, (c) sweetener, (d) flavoring agent, (e) binder selected from the group consisting of pectin, pullulan, starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols, (f) acidifying agent selected from the group consisting of inorganic acids, (g) psilocybin, psilocin, or combination thereof, wherein the ratio between psilocybin and psilocin to the inorqanic acid is 1:0.5 to 1:2 w/w, and wherein the surface pH of the film is between 2 and 4.5 (claims 13 and 16). App’372 claims the inorganic acid is phosphoric acid (claim 14). Sodium carboxymethylcellulose reads on both the mucoadhesive agent and film forming polymer of instant claims 9 and 13, respectively. The phosphoric acid reads on the acidifying agent of the instant claims 1 and 3. The sweetener reads on claim 19. The surface pH range overlaps or encompasses, and thus renders obvious, the pH ranges recited in instant claims 1-4.
App’372 differs from the instant invention in that it fails to claim that its method includes buccal administration of its film, as recited in instant claims 20-21 and 23. App’372 also fails to claim that its film includes a penetration enhancer in the claimed amount as recited in instant claims 1, 5, 7 and 22. App’372 fails to claim the amounts for each component relative to the dry weight of the oral film formulation, as recited in instant claims 8, 10-11, and 14. App’372 fails to claim inclusion of an antioxidant in the amount of instant claim 12. App’372 fails to claim inclusion of a miglitol pore former, as recited in instant claim 17.
The teachings of above cited references discussed supra are incorporated herein.
Arnold teaches preparation of a psilocin sublingual thin film comprising 0-15% hydroxypropyl methylcellulose on a dry weight basis, 0-15% Eudragit on a dry weight basis, 0-25% polyvinyl alcohol on a dry weight basis, 0-25% glycerol on a dry weight basis, 0-15% sodium alginate on a dry weight basis, 0-60% trehalose on a dry weight basis, and 1.3% psilocin on a dry weight basis; the thin film yields a dose of 2 mg of psilocin to the oral cavity of the subject for sublingual administration ([0141] Example 8). Arnold teaches its inventive formulation, which includes a metered dose formulation for oral administration via sublingual film delivery, comprises an amount of anywhere between 3 micrograms to 1.3 g of one or more psychedelic compounds from a class of mushroom-related compounds (claim 1; claim 8). Arnold notes that each method of delivery/application requires a specific composition of dosage and amount of psychedelic compound ([0071]).
Arnold teaches that its “sublingual film” refers to a substrate containing the psychedelic compounds and hydrophilic material that dissolves in the mouth for transmucosal, buccal or sublingual administration of a dose; the film combines the psychedelic compound, hydrophilic polymers, and optionally one or more of a surfactant such as benzalkonium chloride, and a sweetener ([0091]). As evidenced by the instant claims, benzalkonium chloride is a penetration enhancer (instant claim 5). Arnold teaches application of an amount of the formulation to a subject for treating or mitigating a neurological, physiological, or mental health condition, wherein said mental health condition comprises: anxiety, post-traumatic stress disorder, attention deficit disorders, depression, memory loss, dementia, cognitive dysfunction, hearing loss, vision loss, neurologic pain, insomnia, erectile dysfunction, physiological pain or discomfort, or combinations thereof (Claims 11 and 12).
Bilal teaches a film oral dosage form for oral transmucosal delivery of loxapine in a method of providing relief from agitation associated with schizophrenia or bipolar 1 disorder (Abstract). Bilal teaches loxapine film oral dosage forms advantageously employs an antioxidant or oxygen scavenger to prevent or reduce oxidative degradation of the loxapine salt, free base or prodrug prior to use; examples of antioxidant are sulfite salts such as sodium sulfite, sodium bisulfite, sodium metabisulfite and analogous salts of potassium and calcium ([0022]). A suitable amount of salt (e.g., sodium sulfite) is from about 0.01% to 5% or 0.1% to 1% of the weight of the film on a dry basis ([0023]).
Obeid teaches an orally administered dosage form that facilitates delivery of an agent locally in the buccal cavity for a sustained period of time including mucoadhesive particles that are made of at least a mucoadhesive material combined with the agent, and which are dispersed in a disintegrating film (Abstract). Obeid teaches the first step of production of the film oral dosage form includes combination of mucoadhesive particles, sweetener, flavor and a pore former; pore formers, such as maltodextrin, are a generally understood agent that aid, promote or speed up the disintegration time of the film in the oral cavity by quickly dissolving on the surface of the film, creating holes which allow water to enter the film and thus promote film dissolution and/or disintegration ([0090]).
Regarding the % weight amounts of each component in relation to the dry weight of the film recited in instant claims 8, 10-11, and 14, it would have been prima facie obvious for a person having ordinary skill in the art to perform routine optimization on the amount of plasticizer, active agent, and binder (which includes overlap between both the claimed mucoadhesive agent and film forming polymer) in the oral film of App’372, using the finite concentration ranges and specific amounts exemplified for each ingredient/component in the comparable film taught by Arnold, and arrive at the instantly claimed amounts for each in relation to the dry weight of the film formulation. Arnold teaches the use of the same plasticizer, active agent, and binder(s) including hydroxymethylcellulose and polyvinyl alcohol in its comparable psilocin oral film. Arnold also teaches finite concentration ranges within which the ordinarily skilled artisan can perform routine optimization with a reasonable expectation of success. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding instant claim 12, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to add an antioxidant salt, such as sodium bisulfite, to the formulation rendered obvious by the combined teachings of App’372 and the other references, at a concentration of from about 0.01% to 5% or 0.1% to 1% of the weight of the film on a dry basis, and arrive at the instantly claimed invention. App’372’s base film formulation contains many of the elements of the claimed oral film, except for the antioxidant present in an amount of from about 0.01% to 5% or 0.1% to 1% by weight relative to the dry weight of the film. Bilal teaches a comparable film for oral delivery of an active agent (loxapine) which utilizes antioxidant (e.g. sodium sulfite) in order to prevent or reduce oxidative degradation of the pharmaceutical active. The film of Bilal has been improved in the same manner as the claimed oral film formulation. One of ordinary skill in the art would have applied the technique of adding antioxidant to the film formulation rendered obvious by the combined teachings of App’372 and the other references in an amount of about 0.01% to 5% or 0.1% to 1% by weight relative to the dry weight of the film, because the ordinarily skilled artisan would have recognized the benefit of doing so based on the fact that Bilal improves its comparable oral film in this exact manner; thus, the addition of antioxidant in Bilal’s taught concentration range to the film formulation rendered obvious by App’372 and the other references would predictably prevent or reduce oxidative degradation of the psilocin.
Regarding the methods recited in instant claims 20-21 and 23, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to buccally administer the resulting film rendered obvious by the combined teachings of App’372 and the other references, and arrive at the instantly claimed invention, because Arnold suggests buccal administration of its comparable sublingual thin film for use in its method of administering the film to a patient to treat a mental health condition in the patient. This success of buccal administration of a comparable film provide a reasonable expectation of success to the ordinarily skilled artisan when using buccal administration of the film rendered obvious by the combined teachings of App’372 and the other references. Regarding the preambles/intended results of the method claimed in instant claims 20-21 and 23, please see the Claim Interpretation section supra.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further incorporate a penetration enhancer such as benzalkonium chloride in the formulation based on the teachings of Obeid. One would have been motivated to do so because Obeid teaches adding penetration enhancer and specifically benzalkonium chloride, wherein such penetration enhancer can increase buccal permeation of an active ingredient by enabling transcellular route for transportation of the drug through the buccal epithelium. Based on this, one skilled in the art would have found it obvious to optimize the amount/concentration of the penetration enhancer and include an amount, such as the claimed amount/concentration, which would provide optimal penetration of the active ingredient. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further incorporate D-maltitol in the formulation based on the teachings of Obeid. Obeid teaches an orally administered dosage form that facilitates delivery of an agent locally in the buccal cavity for a sustained period of time including mucoadhesive particles that are made of at least a mucoadhesive material combined with the agent, and which are dispersed in a disintegrating film. Obeid teaches polyalcohols and specifically maltitol can be incorporated into the disintegrating film to facilitate or enhance wettability and disintegration of the film. As discussed supra, ‘372 teaches oral dissolvable film and one skilled in the art would have been motivated to include D-maltitol to enhance the wettability in the oral cavity and disintegration once the active drug has been released from the film formulation.
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to modulate the residence time of the formulation by adding bulking agent, fillers or by modifying size of the film formulation as taught by Bilal and Obeid and obtain a residence time (e.g. between 5 and 60 mins) which is desired. As mentioned above, Obeid teaches the formulation may be modulated for various residence times according to the desired treatment and the active agent effectiveness. The mucoadhesive particles may have residence times lasting from about 5 min to a few days (e.g., 2 to 3 days). An extended release of the active agent is achieved via the longer residence time of the particles in the oral cavity. Thus, depending on the type of release desired (e.g. extended or fast release), one skilled in the art would have found it obvious to modulate the residence time by modifying the parameters disclosed by Bilal and Obeid.
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to further comprise a second layer directed outwards from the mucosa, wherein the second layer serves as a protective layer. As discussed supra, Stranska in Fig. 2 discloses layer 1 of polymer nanofibres containing a drug and/or other physiologically active substances covered from one side with oromucosally non-adhesive covering layer 2 (i.e. the claimed second layer directed outwards from the mucosa and serving as protective barrier), while the free side of layer 1 of nanofibres is designated for contact with the sublingual mucosa or some other wall of the mouth cavity and enables penetration of the drug and/or other physiologically active substance into this wall. Stranska provides the motivation to include a covering layer because the covering layer 2 is usually impermeable for saliva and substances contained in the mouth cavity and prevents leaching of physiologically active substances from the carrier into the mouth cavity. That means that nearly all drugs and/or other physiologically active substances penetrate through the sublingual mucosa into the vascular system and into the human or animal organisms. Stranska in the examples teaches using polyurethane as non-biodegradable layer in covering layer. This also reads on claim 25 as the covering layer does not contain any buffers.
This is a provisional non-statutory double patenting rejection.
Claims 1-2, 5-14, 17, 19-23, 25-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-17 of U.S. copending patent application No. 19/355,529 (US20260166007A1) in view of WO 2021003467 A1 (Arnold, C. M. et al) published 01/07/2021 (cited in PTO-892), US 10,500,280 B2 (Shah, S. M. et al) published 12/10/2019 (cited in PTO-892), US 2017/0216220 A1 (Bilal, M. et al) published 08/03/2017 (cited in IDS 11/24/2023) and US 2018/0360736 A1 (Obeid, R.; Paiement, N.) published 08/03/2017 (cited in IDS 11/24/2023) and Stranska (WO2012097763A2).
‘529 claims oral dissolvable film and bilayer film for oral transmucosal delivery. The film comprises tryptamine selected from psilocybin and psilocin, water-soluble polymer matrix and phosphoric acid, EDTA, BHT, propyl gallate, vitamin E (antioxidant), copper salts, sodium sulphite, and ascorbic acid. Water soluble polymer matrix comprises copovidone in amount of 30-55% and Hypromellose in amount of 12-25% by dry weight. Phosphoric acid is present in amount of 3-7%. Further comprises glycerin as a plasticizer in amount of 7-10% and D-maltitol as a pore former in amount of 4-10%. Film has a surface pH of 2 to 3.5.
‘529 does not teach the dissolvable film comprising penetration enhancer and amount thereof, amount of active agent, amount of antioxidant, a sweetener, method of treating a condition such as anxiety by administering through buccal route, and the limitations recited in claims 25-27. However, the references cited in the previous rejections above cure these deficiencies.
The teachings of the references cited in previous rejections above are incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to treat a condition such as anxiety by administering through buccal route because, as discussed supra, Arnold teaches oral film formulation for buccal route comprising the same active (psilocin) which is used to treat conditions such as anxiety. Thus, one skilled in the art would have been motivated to treat a condition such as anxiety through buccal administration because psilocin is taught in the prior art to treat this specific condition and administer the film formulation through buccal route. It would have been obvious to optimize the amount of the active agent based on parameters such as severity of disease, patient size, etc.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further incorporate a penetration enhancer such as benzalkonium chloride in the formulation based on the teachings of Obeid. One would have been motivated to do so because Obeid teaches adding penetration enhancer and specifically benzalkonium chloride, wherein such penetration enhancer can increase buccal permeation of an active ingredient by enabling transcellular route for transportation of the drug through the buccal epithelium. Based on this, one skilled in the art would have found it obvious to optimize the amount/concentration of the penetration enhancer and include an amount, such as the claimed amount/concentration, which would provide optimal penetration of the active ingredient. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Absence any evidence of unexpected effect, the amount of antioxidant would also have been obvious as Bilal teaches antioxidants with amounts that overlap the claimed amounts.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further incorporate a sweetener because ‘529 teaches an oral dissolvable film and addition of sweetener for better taste would have been obvious.
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to modulate the residence time of the formulation by adding bulking agent, fillers or by modifying size of the film formulation as taught by Bilal and Obeid and obtain a residence time (e.g. between 5 and 60 mins) which is desired. As mentioned above, Obeid teaches the formulation may be modulated for various residence times according to the desired treatment and the active agent effectiveness. The mucoadhesive particles may have residence times lasting from about 5 min to a few days (e.g., 2 to 3 days). An extended release of the active agent is achieved via the longer residence time of the particles in the oral cavity. Thus, depending on the type of release desired (e.g. extended or fast release), one skilled in the art would have found it obvious to modulate the residence time by modifying the parameters disclosed by Bilal and Obeid.
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to further comprise a second layer directed outwards from the mucosa, wherein the second layer serves as a protective layer. As discussed supra, Stranska in Fig. 2 discloses layer 1 of polymer nanofibres containing a drug and/or other physiologically active substances covered from one side with oromucosally non-adhesive covering layer 2 (i.e. the claimed second layer directed outwards from the mucosa and serving as protective barrier), while the free side of layer 1 of nanofibres is designated for contact with the sublingual mucosa or some other wall of the mouth cavity and enables penetration of the drug and/or other physiologically active substance into this wall. Stranska provides the motivation to include a covering layer because the covering layer 2 is usually impermeable for saliva and substances contained in the mouth cavity and prevents leaching of physiologically active substances from the carrier into the mouth cavity. That means that nearly all drugs and/or other physiologically active substances penetrate through the sublingual mucosa into the vascular system and into the human or animal organisms. Stranska in the examples teaches using polyurethane as non-biodegradable layer in covering layer. This also reads on claim 25 as the covering layer does not contain any buffers.
This is a provisional non-statutory double patenting rejection.
Response to Argument
Applicant argued that the claims of the instant application are patentably distinct from those of the copending application in view of the claim amendments submitted herewith, particularly the specific requirement for a quaternary ammonium salt penetration enhancer at 0.5% to 5.0% by weight.
In response, applicant’s attention is respectfully drawn to the new/modified claim rejections above which render obvious the claims as amended and specifically the requirement for a quaternary ammonium salt penetration enhancer at 0.5% to 5.0% by weight.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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