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 .
Withdrawn Objections/Rejections
The objections to claims 1, 7, and 16 are withdrawn in view of the claim amendments.
The rejections of claims 1-17 under 35 U.S.C. 112(b) are withdrawn in view of the claim amendments.
Claim Status
Applicant’s amendments and arguments filed 02/04/2026 have been fully considered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the
complete set presently being applied to the instant application.
Claims 17-30 are withdrawn.
Claims 1-16 are under current examination.
Information Disclosure Statement
The information disclosure statement (IDS) filed 10/08/2025 has been considered by the Examiner.
Objections Maintained
Claim 15 is objected to because of the following informalities: “tadafil” in line 2 is believed to be a typo of “tadalafil”.
New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 15 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 15 recites (emphasis added) “wherein the anhydrous suspension further comprises the tadafil”. Claims 1 and 10, from which claim 15 depend, require the inclusion of tadalafil or vardenafil. It is unclear if “further comprises” is intended to require that suspension comprises tadalafil in addition to vardenafil (that is, both are required) or intended to only require the inclusion of tadalafil. For purposes of examination and applying prior art, the Examiner interprets that claim 15 requires the presence of tadalafil, but does not require vardenafil.
Claim Interpretation
The instant specification does not set forth a definition of “configured to” nor define how the limitation “the anhydrous suspension is configured to self-emulsify when administered to an aqueous environment of the oral cavity of the subject to form a mixed micelle and liposome delivery system for transmucosal delivery of the tadalafil or vardenafil within the oral cavity” limits the structural components of the claimed topical composition. The specification suggests that a composition comprising an anhydrous base vehicle consistent with the anhydrous suspension of instant claim 1 is capable of such self-emulsification upon addition of water (see paragraphs [0075]-[0076] and [00112]).
Giving the claims their broadest reasonable interpretation in light of the specification, it is interpreted that a topical composition that meets the structural components of claim 1 (a topical composition comprising an anhydrous suspension comprising tadalafil or vardenafil, medium chain triglycerides, between 0.5% w/w and 10% w/w phosphatidylcholine, between 0.1 % w/w and 1 % w/w lysophosphatidylcholine, glyceryl distearate, and glyceryl monostearate) is capable of carrying out the function of self-emulsifying and forming a mixed micelle and liposome delivery system within an aqueous environment of an oral cavity, and thus meets the limitation of being “configured to” this function. Per MPEP 2111.04 (emphasis added) “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.”
Rejections Maintained, Slightly Modified to Address Claim Amendments
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.
Claims 1-2, 7, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Staniforth (US 2010/0159007 A1, published June 24, 2010; included on IDS submitted 07/15/2025) in view of Sams et al. (US 2015/0005307 A1, published January 1, 2015; of record), hereafter “Sams”, as evidenced by IOI Oleochemical (“MIGLYOL® 812 N & IMWITOR® 742 PRODUCT SPOTLIGHTS” https://www.ioioleo.de/wp-content/uploads/IOI_Spotlights_Pharma_WEB.pdf; of record), and further in view of Amano (US 11,571,385 B2, patented February 7, 2023; included on IDS submitted 07/15/2025).
Staniforth teaches compositions for transmucosal administration intended for buccal and/or sublingual delivery (abstract) that comprise submicron particles comprising an active agent (claim 1).
In an embodiment, the composition comprises one or more drugs including PDE5 inhibitors such as tadalafil and vardenafil; preferably the composition is for treating sexual dysfunction (paragraph [0094]). Active agents can be those that exhibit a high “first-pass” metabolism (claim 35), examples of which include tadalafil and vardenafil (paragraph [0065]). The compositions of Staniforth have the submicron particles dispersed within one or more inert materials which form a matrix (claim 23). The inert material is selected to dissolve or disperse rapidly and is selected from those including non-aqueous media, surfactants, self-emulsifying glyceryl monostearate, glyceryl distearate, and phospholipids, especially those that can aid adhesion to and/or spreading across mucosal surfaces such as phosphatidyl choline and lyso-phosphatidylcholine (paragraph [0040]). As the compositions of Staniforth are taught to have particles dispersed in non-aqueous media, they are interpreted as an anhydrous suspension.
Staniforth does not teach the inclusion of medium chain triglycerides (instant claim 1), or that the medium chain triglycerides comprise caprylic/capric triglycerides (instant claim 2). Staniforth further does not teach the inclusion of peppermint flavor, spearmint flavor, or both (instant claim 7) or that the tadalafil is present in an amount between 1 mg/mL and 5 mg/mL or the vardenafil is present in an amount between 5 mg/mL and 15 mg/mL (instant claim 10).
Sams teaches a pharmaceutical composition for the transmucosal delivery of a PDE5 inhibitor comprising a carrier in which the PDE5 inhibitor is soluble or forms a suspension or emulsion (abstract). Particularly, the PDE5 inhibitor can be successfully delivered by the sublingual transmucosal route, avoiding adverse gastrointestinal effects and providing a faster-acting product having particular benefits in the treatment of erectile dysfunction (paragraph [0006]). The PDE5 inhibitor is particularly taught to be vardenafil or tadalafil and the carrier comprises an oil that comprises a glyceride and the PDE5 inhibitor is suspended in the carrier (paragraph [0012]). Preferably, said oil comprises a medium chain triglyceride, preferably a miglyol, preferably miglyol 812 (paragraph [0013]). As evidenced by IOI Oleochemical, Miglyol 812 is a triglyceride ester of saturated caprylic and capric fatty acids. (“Description”, pg. 4)
Sams further teaches that in a preferred embodiment, the composition comprises a flavoring agent and/or a sweetener (paragraph [0015]). When the composition comprises an oil that comprises a glyceride, the composition preferably comprises a lipophilic flavoring agent, preferably peppermint oil or spearmint oil (paragraph [0017]).
Sams further teaches that the PDE5 inhibitor is present in the carrier at a concentration providing a required dose in a volume of no more than 1000 microliters, and in preferred embodiments, the PDE5 inhibitor is present at a concentration of at least 5 mg/mL (paragraph [0024]). Vardenafil is typically dosed orally at 10-20 mg, and it is preferred that the concentration of vardenafil is at least 5 mg/mL (paragraph [0030]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the compositions of Staniforth to include the medium-chain triglycerides of caprylic/capric triglycerides as suggested by Sams. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in order to incorporate a carrier known to form suspensions for the effective sublingual transmucosal delivery of the PDE5 inhibitors tadalafil and vardenafil which can avoid unwanted gastrointestinal effects and provide a faster-acting product, as suggested by Sams. There is a reasonable expectation of success as the compositions of Staniforth are for the sublingual administration of therapeutically active agents including tadalafil and vardenafil, and comprise an oil solvent (see Staniforth, claim 28).
It would further have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the composition of Staniforth to include the peppermint or spearmint oil flavoring agent taught by Sams. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to incorporate a lipophilic flavoring agent that improves the taste of a sublingual transmucosal formulation for the delivery of tadalafil or vardenafil, as suggested by Sams. There is a reasonable expectation of success as such the compositions of Staniforth are used for transmucosal administration (via buccal and/or sublingual delivery) and comprise tadalafil or vardenafil.
It would further have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the amount of tadalafil or vardenafil in the composition Staniforth to be at least 5 mg/mL (overlapping the claimed range), as suggested by Sams. This could be achieved by routine optimization in order to achieve a required dose of active agent for the treatment of erectile dysfunction that can be delivered in a desired volume of composition, as suggested by Sams. There is a reasonable expectation of success as the composition of Staniforth is preferably for treating sexual dysfunction (Staniforth, paragraph [0094]). Per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and per MPEP 2144.05 II. A., “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).”
Staniforth does not teach that the phosphatidylcholine is present between 0.5% w/w and 10% w/w or that the lysophosphatidylcholine is present between 0.1 and 1% w/w.
Amano teaches a self-emulsifiable composition including a monoacyl phospholipid, a diacyl phospholipid, oils and fats, and a polyhydric alcohol, wherein the content ratio between the monoacyl phospholipid and the diacyl phospholipid is in the range of 1:9 to 9:1 as a mass ratio (abstract). The monoacyl phospholipid is preferably lysophosphatidylcholine (column 5, lines 1-7), and examples of the diacyl phospholipid include phosphatidylcholine (column 5, lines 32-36). The composition can be used as a pharmaceutical product when the water content is less than 5% by mass and a substantially non-water-based composition is obtained (column 8, lines 51-55). A nanoemulsion forms when the self-emulsifiable composition is mixed with an aqueous solution (column 10, line 65-column 11, line 3). Amano further teaches that the total content of the monoacyl phospholipid and the diacyl phospholipid is not particularly limited; however, for example, the total content may be from 0.1 % by mass to 70% by mass based on the total amount of the composition; in this range, a self-emulsifiable composition that can produce a nanoemulsion by a simple operation such as addition of an aqueous solution can be suitably obtained (column 6, lines 1-16). Thus, Amano suggests amounts of lysophosphatidylcholine and phosphatidylcholine overlapping those of the instant claims; as just one example, the ranges of Amano are inclusive of lysophosphatidylcholine present at 0.1% w/w and a weight ratio of 1:9 with phosphatidylcholine, or 0.9% w/w of phosphatidylcholine. Amano further suggests that these amounts can be adjusted to provide the desired self-emulsification properties of a non-water based pharmaceutical composition upon addition of an aqueous solution.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the compositions comprising phosphatidylcholine and lysophosphatidylcholine of Staniforth with the amounts overlapping the claimed ranges suggested by Amano. One of ordinary skill in the art would have been motivated to do so in order to use amounts of lysophosphatidylcholine and phosphatidylcholine which allow a pharmaceutical non-water based self-emulsifiable composition to form a nanoemulsion upon addition of water. There is a reasonable expectation of success as the compositions of Staniforth are taught to be non-aqueous and comprise self-emulsifying components; further, the compositions of Staniforth are intended for buccal and/or sublingual delivery (abstract), the mouth being an aqueous environment (paragraph [0024]). Further, per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and per MPEP 2144.05 II. A., “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).”
The limitation of instant claim 1 that the topical composition is “for administration to an oral cavity of a subject and oral absorption therein to treat erectile disfunction” recites the intended use of the claimed topical composition and does not structurally limit the composition. The combination of Staniforth in view of Sams and Amano renders obvious the claimed composition, and arrives at a composition for transmucosal administration (via buccal and/or sublingual delivery) comprising tadalafil or vardenafil and self-emulsifying components that can be used to treat sexual dysfunction. Thus, the compositions of the modified Staniforth are capable of performing the intended use as claimed.
As set forth above, it is interpreted that a topical composition that meets the structural components of claim 1 (a topical composition comprising an anhydrous suspension comprising tadalafil or vardenafil, medium chain triglycerides, between 0.5% w/w and 10% w/w phosphatidylcholine, between 0.1 % w/w and 1 % w/w lysophosphatidylcholine, glyceryl distearate, and glyceryl monostearate) is capable of carrying out the function of self-emulsifying and forming a mixed micelle and liposome delivery system within an aqueous environment of an oral cavity, and thus meets the limitation of being “configured to” this function. The combination of Staniforth in view of Sams and Amano renders obvious the structural components of claimed composition, and arrives at a composition for transmucosal administration (via buccal and/or sublingual delivery) comprising self-emulsifying components. Thus, the compositions of the modified Staniforth are interpreted to meet the limitation of being “configured to self-emulsify when administered to an aqueous environment of the oral cavity of the subject to form a mixed micelle and liposome delivery system for transmucosal delivery of the tadalafil or vardenafil within the oral cavity”.
Claims 3-4 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, and Amano as applied to claims 1-2, 7, and 10 above, and further in view of Dhingra et al. (US 2013/0303495 A1, published November 14th, 2013; included on IDS submitted 07/15/2025), hereafter “Dhingra”.
The teachings of the modified Staniforth are described above. Regarding instant claim 12, Staniforth further teaches the inclusion of magnesium stearate in the inert material of the compositions for transmucosal administration of tadalafil or vardenafil (paragraph [0040]).
The combination of Staniforth, Sams, and Amano do not teach that the caprylic/capric triglycerides are present in an amount between 60% and 95% w/w (instant claim 3) or an amount between 50% and 81% w/w (instant claim 4). It further does not teach the limitation of instant claim 12 that the anhydrous suspension comprises microcrystalline cellulose.
Dhingra teaches a self-emulsified drug delivery system formulation for drug delivery of a lipophilic therapeutic agent (abstract) such as anti-erectile dysfunction agents (paragraph [0073]). The compositions can be used in treating a subject in need of treatment for erectile dysfunction comprising administering an androgen and PDE V inhibitor such as tadalafil or vardenafil (paragraph [0276]). Formulations can be for sublingual and/or buccal administration of the therapeutic agent (paragraph [0071]) and can be provided as a lipid suspension (paragraph [0242]).The formulations include a solubilizer (abstract) which allow a significant fraction of the therapeutic agent to be solubilized in the composition and is capable of providing an immediate and therapeutically effective amount of the therapeutic agent to a patient in a readily absorbable form upon administration (paragraph [0198]). Examples of solubilizers include propylene glycol dicaprylate/caprate, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride, e.g. synthetic medium chain triglycerides having C8-12 fatty acid chains or other derivatized (synthetic) triglycerides of the type known and commercially available under Miglyol 810, 812, 818, 829 and 840 (paragraph [0199]). The amount of solubilizer in not particularly limited, but is preferably between 12.5% to 85% by weight; the amount is limited to a bio-acceptable amount when administered to a subject, which can be readily determined by routine experimentation (paragraph [0232]). Dhingra further teaches the inclusion of fillers (paragraph [0245]); the fillers are pharmacologically inert and optionally nutritionally beneficial to humans and animals, and examples include microcrystalline cellulose (paragraph [0245]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to adjust the amount of caprylic/capric triglycerides in the composition of the modified Staniforth to be within the range of 12.5% to 85% by weight, overlapping the claimed ranges of instant claims 3 and 4, as suggested by Dhingra.
One of ordinary skill in the art would be motivated to do so to achieve a composition for the buccal and/or sublingual administration of anti-erectile dysfunction agents such as tadalafil and vardenafil that allows a significant fraction of the therapeutic agent to be solubilized in the composition and is capable of providing an immediate and therapeutically effective amount of the therapeutic agent to a patient, as suggested by Dhingra. One of ordinary skill in the art would further be motivated to optimize the amount of caprylic/capric triglycerides within the range of Dhingra to achieve an amount of solvent that is bio-acceptable (Dhingra, paragraph [0232]). Per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and per MPEP 2144.05 II. A., “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 before the effective filing date to incorporate the microcrystalline cellulose taught by Dhingra in the composition of the modified Staniforth. One of ordinary skill in the art would have been motivated to do so to use a pharmacologically inert and nutritionally beneficial filler known to be used in sublingual and or/buccal self-emulsified drug delivery systems for the delivery of anti-erectile dysfunction agents including tadalafil and vardenafil. There is a reasonable expectation of success as the formulations of Staniforth are taught to include inert materials which form a matrix, and are similarly taught to be used for buccal and/or sublingual delivery of tadalafil and vardenafil and comprise self-emulsifying components.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, and Amano as applied to claims 1-2, 7, and 10 above, and further in view of Pauletti et al. (US 2003/0219472 A1, published November 27th, 2003; included on IDS submitted 07/15/2025), hereafter “Pauletti”.
The teachings of the modified Staniforth are described above.
The combination of Staniforth, Sams, and Amano does not teach the limitation of instant claim 5 that the anhydrous suspension further comprises polycarbophil in an amount between 0.2% and 2% w/w or of instant claim 6 that the anhydrous suspension further comprises polycarbophil in an amount between 0.17% and 2% w/w.
Pauletti teaches compositions for buccal transmucosal delivery of drugs (abstract) which assert a therapeutic effect when delivered to the systemic circulation through the vaginal, nasal, or buccal mucosa (paragraphs [0081]). The compositions can be formulated as a suspension for buccal delivery (paragraph [0096]). The compositions may comprise a mucoadhesive agent to bring the drug into prolonged, close contact with the mucosal surface, and examples of mucoadhesive agents include polycarbophil (paragraph [0066]). The mucoadhesive agent is present between about 0.05-25% by weight, and more preferably about 0.02-7.5% for buccal delivery (paragraph [0071]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to include a polycarbophil mucoadhesive agent in an amount overlapping the claimed range, as suggested by Pauletti, in the composition of the modified Staniforth.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to bring the drug into prolonged, close contact with the buccal mucosa, as suggested by Pauletti. There is a reasonable expectation of success as and the compositions of the modified Staniforth are used for transmucosal administration (via buccal and/or sublingual delivery) of active agents. Staniforth further teaches that promotion or enhancement of mucosal adhesion can improve transmucosal delivery of an active agent (paragraph [0014]), and the inclusion of macromolecules to aid adhesion to mucosal surfaces (paragraph [0040]). Further, per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, and Amano as applied to claims 1-2, 7, and 10 above, and further in view of Murty et al. (US 2007/0104741 A1, published May 10, 2007; included on IDS submitted 07/15/2025), hereafter “Murty”.
The teachings of the modified Staniforth are described above. Sams further teaches that vardenafil and tadalafil are lipophilic PDE5 inhibitors (paragraph [0012]).
The combination of Staniforth, Sams, and Amano do not teach that the glyceryl distearate and glyceryl monostearate are each present in an amount between 0.5% and 5% w/w.
Murty teaches a self-emulsifying drug-delivery system comprising an oily medium (e.g. triglycerides and/or mixed glycerides and/or free fatty acids containing medium and/or long chain saturated, mono-unsaturated, and/or polyunsaturated free fatty acids) together with at least one surfactant (abstract). The compositions are useful to improve the dissolution, bioavailability, and stability of lipophilic drugs having poor aqueous solubility (paragraph [0094]). The oily medium is selected from the group including glyceryl esters of saturated fatty acids and glyceryl distearate, and mixtures thereof (claim 4). The oily medium comprises from about 5-90 wt% (claim 10). Murty therefore suggests the inclusion glyceryl esters of saturated fatty acids (consistent with the glyceryl stearate of the modified Staniforth) and glyceryl distearate in an amount of about 5% for use in self-emulsifying compositions for the delivery of lipophilic drugs.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the compositions comprising glyceryl monostearate and glyceryl distearate of Staniforth in view of Sams and Amato with the amounts overlapping the claimed ranges suggested by Murty. One of ordinary skill in the art would have been motivated to do so in order to use amounts of glyceryl monostearate and glyceryl distearate known in the art for use as an oily medium for the delivery of poorly water soluble drugs in a self-emulsifying system. There is a reasonable expectation of success as the compositions of the modified Staniforth comprise self-emulsifying components and are used for administration of lipophilic drugs. Further, per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, and Amano as applied to claims 1-2, 7, and 10 above, and further in view of Dhingra et al. (US 2013/0303495 A1, published November 14th, 2013; included on IDS submitted 07/15/2025), hereafter “Dhingra” and Murty et al. (US 2007/0104741 A1, published May 10, 2007; included on IDS submitted 07/15/2025), hereafter “Murty”.
The teachings of the modified Staniforth are described above. Regarding instant claim 11, as set forth above, the combined teachings of Staniforth, Sams, and Amano arrive at concentrations of phosphatidylcholine and lysophosphatidylcholine overlapping the claimed ranges. Particularly, Amano suggests amounts of lysophosphatidylcholine and phosphatidylcholine overlapping those of the instant claims; as just one example, the ranges of Amano are inclusive of lysophosphatidylcholine present at 0.3% w/w and a weight ratio of 1:9 with phosphatidylcholine, or 2.7% w/w of phosphatidylcholine. Amano further suggests that these amounts can be adjusted to provide the desired self-emulsification properties of a composition. Per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
The combination of Staniforth, Sams, and Amano do not teach the limitations of instant claim 11 that the caprylic/capric triglycerides are present in an amount between 60% and 95% w/w or that the glyceryl distearate and glyceryl monostearate are each present in an amount between 0.5% and 5% w/w.
Dhingra teaches a self-emulsified drug delivery system formulation for drug delivery of a lipophilic therapeutic agent (abstract) such as anti-erectile dysfunction agents (paragraph [0073]). The compositions can be used in treating a subject in need of treatment for erectile dysfunction comprising administering an androgen and PDE V inhibitor such as tadalafil or vardenafil (paragraph [0276]). Formulations can be for sublingual and/or buccal administration of the therapeutic agent (paragraph [0071]) and can be provided as a lipid suspension (paragraph [0242]).The formulations include a solubilizer (abstract) which allow a significant fraction of the therapeutic agent to be solubilized in the composition and is capable of providing an immediate and therapeutically effective amount of the therapeutic agent to a patient in a readily absorbable form upon administration (paragraph [0198]). Examples of solubilizers include propylene glycol dicaprylate/caprate, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride, e.g. synthetic medium chain triglycerides having C8-12 fatty acid chains or other derivatized (synthetic) triglycerides of the type known and commercially available under Miglyol 810, 812, 818, 829 and 840 (paragraph [0199]). The amount of solubilizer in not particularly limited, but is preferably between 12.5% to 85% by weight; the amount is limited to a bio-acceptable amount when administered to a subject, which can be readily determined by routine experimentation (paragraph [0232]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to adjust the amount of caprylic/capric triglycerides in the composition of the modified Staniforth to be within the range of 12.5% to 85% by weight, overlapping the claimed range of instant claim 11, as suggested by Dhingra.
One of ordinary skill in the art would be motivated to do so to achieve a composition for the buccal and/or sublingual administration of anti-erectile dysfunction agents such as tadalafil and vardenafil that that allow a significant fraction of the therapeutic agent to be solubilized in the composition and is capable of providing an immediate and therapeutically effective amount of the therapeutic agent to a patient, as suggested by Dhingra. One of ordinary skill in the art would further be motivated to optimize the amount of caprylic/capric triglycerides within the range of Dhingra to achieve an amount of solvent that is bio-acceptable (Dhingra, paragraph [0232]). Per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and per MPEP 2144.05 II. A., “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).”
Murty teaches a self-emulsifying drug-delivery system comprising an oily medium (e.g. triglycerides and/or mixed glycerides and/or free fatty acids containing medium and/or long chain saturated, mono-unsaturated, and/or polyunsaturated free fatty acids) together with at least one surfactant (abstract). The compositions are useful to improve the dissolution, bioavailability, and stability of lipophilic drugs having poor aqueous solubility (paragraph [0094]). The oily medium is selected from the group including glyceryl esters of saturated fatty acids and glyceryl distearate, and mixtures thereof (claim 4). The oily medium comprises from about 5-90 wt% (claim 10). Murty therefore suggests the inclusion glyceryl esters of saturated fatty acids (consistent with the glyceryl stearate of the modified Staniforth) and glyceryl distearate in an amount of about 5% for use in self-emulsifying compositions for the delivery of lipophilic drugs.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the compositions comprising glyceryl monostearate and glyceryl distearate of Staniforth in view of Sams and Amato with the amounts overlapping the claimed ranges suggested by Murty. One of ordinary skill in the art would have been motivated to do so in order to use amounts of glyceryl monostearate and glyceryl distearate known in the art for use as an oily medium for the delivery of poorly water soluble drugs in a self-emulsifying system. There is a reasonable expectation of success as the compositions of the modified Staniforth comprise self-emulsifying components and are used for administration of lipophilic drugs. Further, per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, Amano, and Dhingra as applied to claim 12 above, and further in view of Ulbrich et al. (US 2009/0186896 A1, published July 23, 2009; of record), hereafter “Ulbrich” .
The teachings of the modified Staniforth are described above. Regarding instant claim 13, Staniforth further teaches that it may be desirable to include components in the composition to ensure rapid disintegration, that such disintegrants are known, and include cross-linked PVP (crospovidone) (paragraph [0051]).
The combination of Staniforth, Sams, Amano, and Dhingra do not teach the limitation of instant claim 13 that the anhydrous suspension further comprises colloidal silicon dioxide.
Ulbrich teaches pharmacological compositions comprising PDE-5 inhibitors selected from the group including vardenafil and tadalafil for the treatment of urological disorders including erectile dysfunction (abstract, claim 7). The composition can be formulated for oral administration (e.g., buccal, sublingual, oral mucosal and peroral administration) (paragraph [0018]). Oral compositions generally include functional excipients (paragraph [0023]) and examples include disintegrants such a crospovidone and glidants such as colloidal silicon dioxide (paragraph [0024]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to incorporate colloidal silicon dioxide in the compositions of the modified Staniforth, as suggested by Ulbrich. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to incorporate a functional excipient to compositions for oral mucosal delivery of the PDE-5 inhibitors vardenafil and tadalafil that achieves a glidant effect, as suggested by Ulbrich. There is a reasonable expectation of success as the compositions of the modified Staniforth are used for oral transmucosal administration (via buccal and/or sublingual delivery) of vardenafil and tadalafil.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, Amano, Dhingra, and Ulbrich as applied to claim 13 above, and further in view of Drai et al. (US 2009/0118211 A1, published May 7, 2009; of record), hereafter “Drai”.
The teachings of the modified Staniforth are described above.
The combination of Staniforth, Sams, Amano, Dhingra, and Ulbrich do not teach the limitation of instant claim 14 that the anhydrous suspension further comprises lactose monohydrate.
Drai teaches compositions for treating sexual dysfunction comprising a PDE5 inhibitor as an erection enhancing agent (abstract, claims 49 and 53); the PDE5 inhibitor is taught to be tadalafil or vardenafil (claims 59 and 62). Pharmaceutical compositions may be manufactured by processes well known in the art; suitable routes of administration include transmucosal and oral administration (paragraphs [0189]-[0190]). For oral administration, the active ingredients can be formulated into suspensions and can be made using a solid excipient including fillers or diluents (paragraph [0192]-[0193]); lactose monohydrate is provided as an example of a suitable filler or diluent (paragraph [0194]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to incorporate the lactose monohydrate, suggested by Drai, into the composition of the modified Staniforth. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to incorporate an excipient filler/diluent known to be useful in oral suspensions for the delivery of tadalafil or vardenafil. There is a reasonable expectation of success as the compositions of Staniforth are used for oral transmucosal administration of vardenafil and tadalafil, and Staniforth further teaches the inclusion of inert materials (paragraph [0040]) and that diluents can be included, especially where the amount of active agent to be administered is small (paragraph [0045]).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, and Amano as applied to claims 1-2, 7, and 10 above, and further in view of Choung et al. (WO 2025/104674 A1, international filing date November 14, 2024; of record), hereafter “Choung”.
The teachings of the modified Staniforth are described above. Regarding instant claim 15, as set forth above, the composition of the modified Staniforth comprises tadalafil. Further, tadalafil is a PDE5 inhibitor (see Sams, paragraph [0022]) and PDE5 inhibitors are used to treat erectile dysfunction (see Sams, paragraph [0004]).
The combination of Staniforth, Sams, and Amano do not teach that the anhydrous suspension further comprises semaglutide and is configured for a combination treatment of erectile disfunction and one or more of type-2 diabetes, chronic weight maintenance, or overindulgence.
Choung teaches a pharmaceutical composition for the prevention or treatment of neurodegenerative disorders comprises a phosphodiesterase 5 inhibitor selected from the group including tadalafil and a glucagon-like peptide 1 (GLP-1) receptor agonist selected from the group including semaglutide (abstract; claims 3, 6-7, and 9). The neurodegenerative disorder is selected from those including Type 2 diabetes mellitus (claim 12). The compositions of Choung are taught to target multiple pathways involved in the disease process and may provide a multi-targeted approach to addressing the complex pathophysiology of neurodegenerative disorders (paragraphs [0073]-[0075]). The combinations can be provided as a pharmaceutical composition suitable for administration via the sublingual or buccal mucosal route (paragraph [0109]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to include semaglutide in the composition of the modified Staniforth, as suggested by Choung. As the PDE5 inhibitor of tadalafil is known to treat erectile dysfunction and the combination of tadalafil and semaglutide is taught by Choung to treat type-2 diabetes, it is interpreted that this modification results in a composition that is configured for a combination treatment of erectile disfunction and type-2 diabetes.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order achieve a combination pharmaceutical composition capable of targeting multiple pathways involved in the complex pathophysiology of neurodegenerative disorders such as type-2 diabetes, as suggested by Choung. There is a reasonable expectation of success as the compositions of the modified Staniforth comprise tadalafil and can incorporate drugs for treating neurodegenerative diseases (see Staniforth, paragraph [0085]).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Staniforth in view of Sams, as evidenced by IOI Oleochemical, Amano, and Choung as applied to claim 15 above, and further in view of Werle et al. (US 2021/0087250 A1, published March 25, 2021; included on IDS submitted 04/28/2025), hereafter “Werle”.
The teachings of the modified Staniforth are described above. Regarding instant claim 16, Staniforth further teaches the inclusion of magnesium stearate in the inert material of the compositions for transmucosal administration of tadalafil or vardenafil (paragraph [0040]).
The combination of Staniforth, Sams, Amano, and Choung do not teach the limitations of instant claim 16 that the anhydrous suspension further comprises microcrystalline cellulose, povidone, and salcaprozate sodium.
Werle teaches a pharmaceutical composition for transmucosal administration comprising a peptide or protein drug (abstract, claim 1) with the peptide or protein drug selected from the group including semaglutide, a GLP-1 agonist (claims 9-11). The pharmaceutical composition is particularly taught for use in treating or preventing diabetes, obesity, or non-alcoholic fatty liver disease (claim 21), and type 2 diabetes mellitus is provided as an example of diabetes (paragraph [0033]). The pharmaceutical composition is preferably formulated for oral administration, oromucosal administration, or nasal administration (paragraph [0063]), with oromucosal administration referring to the deposition or application of the pharmaceutical composition onto a mucosal epithelium in the oral cavity of a subject/patient (paragraph [0069]).The pharmaceutical composition of Werle is taught to be a solid or liquid composition, either of which can be free of water (anhydrous), and the liquid composition may be, e.g., a solution, a suspension, or an emulsion (paragraph [0049]). The composition of Werle further comprises a permeation enhancer (claim 12) and particularly preferred permeation enhancers include SNAC (synonym for salcaprozate sodium) when the peptide or protein drug is a GLP-1 agonist (paragraph [0048]). The pharmaceutical composition of Werle can comprise one or more additives such as carriers, diluents, and fillers, in particular, microcrystalline cellulose (paragraph [0058]). Werle further teaches that the pharmaceutical composition may comprise one or more solubility enhancers such as polyvinylpyrrolidone (synonym for povidone) (paragraph [0059]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to incorporate the salcaprozate sodium, microcrystalline cellulose, and povidone, suggested by Werle, into the composition of the modified Staniforth. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to improve the permeation and solubility of semaglutide in an oromucosal formulation and to incorporate a diluent/filler known to be preferred in oral suspensions for the delivery of semaglutide. There is a reasonable expectation of success as the compositions of the modified Staniforth are used for oral transmucosal administration of tadalafil in combination with semaglutide.
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 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 19/067,153 in view of Staniforth (US 2010/0159007 A1, published June 24, 2010; included on IDS submitted 07/15/2025 and Drai et al. (US 2009/0118211 A1, published May 7, 2009; of record), hereafter “Drai”.
Both the instant claims and those of copending Application No. 19/067,153 recite a topical composition for administration to an oral cavity of a subject and oral absorption therein comprising an anhydrous suspension comprising an active ingredient, medium chain triglycerides comprising caprylic/capric triglycerides, phosphatidylcholine, lysophosphatidylcholine, glyceryl distearate, glyceryl monostearate, polycarbophil, peppermint flavor, spearmint flavor, or both, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide. Both sets of claims recite that the anhydrous suspension is configured to self-emulsify in an aqueous environment of the oral cavity of the subject to form a mixed micelle and liposome delivery system for transmucosal delivery. Both sets of claims recite overlapping amounts of active ingredient, caprylic/capric triglycerides, phosphatidylcholine, lysophosphatidylcholine, glyceryl distearate, glyceryl monostearate and polycarbophil.
The claims of copending Application No. 19/067,153 differ from those of the instant claims in that the anhydrous suspension requires the active ingredient of naltrexone, while the anhydrous suspension of the instant claims requires tadalafil or vardenafil. The claims of copending Application No. 19/067,153 further do not require that the anhydrous suspension comprises crospovidone, as required by instant claim 13 or lactose monohydrate, as required by instant claim 14.
Staniforth teaches compositions for transmucosal administration intended for buccal and/or sublingual delivery (abstract) that comprise submicron particles comprising an active agent (claim 1). In an embodiment, the composition comprises one or more drugs including PDE5 inhibitors such as tadalafil and vardenafil (paragraph [0094]) and can comprise one or more drugs for treating drug dependency including naltrexone (paragraph [0093]). The compositions of Staniforth have the submicron particles dispersed within one or more inert materials which form a matrix (claim 23). The inert material is selected to dissolve or disperse rapidly and is selected from those including non-aqueous media, surfactants, self-emulsifying glyceryl monostearate, glyceryl distearate, and phospholipids, especially those that can aid adhesion to and/or spreading across mucosal surfaces such as phosphatidyl choline, lyso-phosphatidylcholine (paragraph [0040]). As the compositions of Staniforth are taught to have particles dispersed in non-aqueous media, they are interpreted as an anhydrous suspension. Staniforth further teaches that it may be desirable to include components in the composition to ensure rapid disintegration, that such disintegrants are known, and include cross-linked PVP (crospovidone) (paragraph [0051]). Staniforth further teaches that diluents can be included, especially where the amount of active agent to be administered is small (paragraph [0045]).
Drai teaches compositions for treating sexual dysfunction comprising a PDE5 inhibitor as an erection enhancing agent (abstract, claims 49 and 53); the PDE5 inhibitor is taught to be tadalafil or vardenafil (claims 59 and 62). Pharmaceutical compositions may be manufactured by processes well known in the art suitable routes of administration include transmucosal and oral administration (paragraphs [0189]-[0190]). For oral administration, the active ingredients can be formulated into suspensions and can be made using a solid excipient including fillers or diluents (paragraph [0192]-[019]); lactose monohydrate is provided as an example of a suitable filler or diluent (paragraph [0194]).
It would have been prima facie obvious to one of ordinary skill in the art to substitute the naltrexone recited in the claims of copending Application No. 19/067,153 with the tadalafil or vardenafil taught by Staniforth. Simple substitution of one active agent known for delivery via transmucosal administration in an inert material comprising non-aqueous media, surfactants, self-emulsifying glyceryl monostearate, glyceryl distearate, phosphatidylcholine and lysophosphatidylcholine for another such agent is within the purview of the skilled artisan and would yield predictable results (see MPEP 2143 B). It would further have been prima facie obvious to one of ordinary skill in the art to include the crospovidone taught by Staniforth in order to ensure rapid disintegration of the active ingredient.
It would have been prima facie obvious to one of ordinary skill in the art to incorporate the lactose monohydrate, suggested by Drai, into the composition of copending Application No. 19/067,153. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to incorporate an excipient filler/diluent known to be useful in oral suspensions for the delivery of active pharmaceutical ingredients.
This is a provisional nonstatutory double patenting rejection.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 19/067,176 in view of Staniforth (US 2010/0159007 A1, published June 24, 2010; included on IDS submitted 07/15/2025 and Ulbrich et al. (US 2009/0186896 A1, published July 23, 2009; of record), hereafter “Ulbrich”.
Both the instant claims and those of copending Application No. 19/067,176 recite a topical composition for administration to an oral cavity of a subject and oral absorption therein comprising an anhydrous suspension comprising an active ingredient, medium chain triglycerides comprising caprylic/capric triglycerides, phosphatidylcholine, lysophosphatidylcholine, glyceryl distearate, glyceryl monostearate, polycarbophil, peppermint flavor, spearmint flavor, or both, magnesium stearate, microcrystalline cellulose, and lactose monohydrate. Both sets of claims recite that the anhydrous suspension is configured to self-emulsify in an aqueous environment of the oral cavity of the subject to form a mixed micelle and liposome delivery system for transmucosal delivery. Both sets of claims recite overlapping amounts of active ingredient, caprylic/capric triglycerides, phosphatidylcholine, lysophosphatidylcholine, glyceryl distearate, glyceryl monostearate and polycarbophil.
The claims of copending Application No. 19/067,176 differ from those of the instant claims in that the anhydrous suspension requires the active ingredient of sumatriptan, while the anhydrous suspension of the instant claims requires tadalafil or vardenafil. The claims of copending Application No. 19/067,176 further do not require that the anhydrous suspension comprises crospovidone and colloidal silicon dioxide, as required by instant claim 13.
Staniforth teaches compositions for transmucosal administration intended for buccal and/or sublingual delivery (abstract) that comprise submicron particles comprising an active agent (claim 1). In an embodiment, the composition comprises one or more drugs including PDE5 inhibitors such as tadalafil and vardenafil (paragraph [0094]) and can comprise sumatriptan (claim 42, paragraph [0087]). The compositions of Staniforth have the submicron particles dispersed within one or more inert materials which form a matrix (claim 23). The inert material is selected to dissolve or disperse rapidly and is selected from those including non-aqueous media, surfactants, self-emulsifying glyceryl monostearate, glyceryl distearate, and phospholipids, especially those that can aid adhesion to and/or spreading across mucosal surfaces such as phosphatidyl choline and lyso-phosphatidylcholine (paragraph [0040]). As the compositions of Staniforth are taught to have particles dispersed in non-aqueous media, they are interpreted as an anhydrous suspension. Staniforth further teaches that it may be desirable to include components in the composition to ensure rapid disintegration, that such disintegrants are known, and include cross-linked PVP (crospovidone) (paragraph [0051]). Staniforth further teaches that diluents can be included, especially where the amount of active agent to be administered is small (paragraph [0045]).
Ulbrich teaches pharmacological compositions comprising PDE-5 inhibitors selected from the group including vardenafil and tadalafil for the treatment of urological disorders including erectile dysfunction (abstract, claim 7). The composition can be formulated for oral administration (e.g., buccal, sublingual, oral mucosal and peroral administration) (paragraph [0018]). Oral compositions generally include functional excipients (paragraph [0023]) and examples include disintegrants such a crospovidone and glidants such as colloidal silicon dioxide (paragraph [0024]).
It would have been prima facie obvious to one of ordinary skill in the art to substitute the sumatriptan recited in the claims of copending Application No. 19/067,176 with the tadalafil or vardenafil taught by Staniforth. Simple substitution of one active agent known for delivery via transmucosal administration in an inert material comprising non-aqueous media, surfactants, self-emulsifying glyceryl monostearate, glyceryl distearate, phosphatidylcholine and lysophosphatidylcholine for another such agent is within the purview of the skilled artisan and would yield predictable results (see MPEP 2143 B). It would further have been prima facie obvious to one of ordinary skill in the art to include the crospovidone taught by Staniforth in order to ensure rapid disintegration of the active ingredient.
It would have been prima facie obvious to one of ordinary skill in the art to incorporate the colloidal silicon dioxide, suggested by Ulbrich, into the composition of copending Application No. 19/067,176. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to incorporate an excipient that achieves a glidant effect to compositions for oral mucosal delivery of active pharmaceutical ingredients.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5-7, 10, 12, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 12,589,135 B2 (previously Application No. 18/236,300) in view of Choung et al. (WO 2025/104674 A1, international filing date November 14, 2024; of record), hereafter “Choung”, Sams et al. (US 2015/0005307 A1, published January 1, 2015; of record), hereafter “Sams”, Amano (US 11,571,385 B2, patented February 7, 2023; included on IDS submitted 07/15/2025), and Pauletti et al. (US 2003/0219472 A1, published November 27th, 2003; included on IDS submitted 07/15/2025), hereafter “Pauletti”.
The claims of U.S. Patent No. 12,589,135 B2 recite administration of a topical composition to an oral cavity of a subject and oral absorption therein for the treatment of type-2 diabetes. Similar to the instant claims, the topical composition recited in U.S. Patent No. 12,589,135 B2 comprises an anhydrous suspension comprising semaglutide, caprylic/capric triglycerides (medium chain triglycerides), phosphatidylcholine, lysophosphatidylcholine, glyceryl distearate, glyceryl monostearate, polycarbophil, magnesium stearate, microcrystalline cellulose, povidone, and salcaprozate sodium. The claims further recite that the anhydrous suspension self-emulsifies in an aqueous environment of the oral cavity to form mixed micelles and liposomes.
The claims of U.S. Patent No. 12,589,135 B2 do not recite that the topical composition comprises tadalafil in an amount between 1 mg/mL and 5 mg/mL or the inclusion of peppermint flavor, spearmint flavor, or both.
Choung teaches a pharmaceutical composition for the prevention or treatment of neurodegenerative disorders comprises a phosphodiesterase 5 inhibitor selected from the group including tadalafil and a glucagon-like peptide 1 (GLP-1) receptor agonist selected from the group including semaglutide (abstract; claims 3, 6-7, and 9). The neurodegenerative disorder is selected from those including Type 2 diabetes mellitus (claim 12). The compositions of Choung are taught to target multiple pathways involved in the disease process and may provide a multi-targeted approach to addressing the complex pathophysiology of neurodegenerative disorders (paragraphs [0073]-[0075]). The combinations can be provided as a pharmaceutical composition suitable for administration via the sublingual or buccal mucosal route (paragraph [0109]).
Sams teaches a pharmaceutical composition for the transmucosal delivery of a PDE5 inhibitor comprising a carrier in which the PDE5 inhibitor is soluble or forms a suspension or emulsion (abstract). Particularly, the PDE5 inhibitor can be successfully delivered by the sublingual transmucosal route, avoiding adverse gastrointestinal effects and providing a faster-acting product having particular benefits in the treatment of erectile dysfunction (paragraph [0006]). The PDE5 inhibitor is particularly taught to be vardenafil or tadalafil and the carrier comprises an oil that comprises a glyceride and the PDE5 inhibitor is suspended in the carrier (paragraph [00012]). Sams further teaches that the PDE5 inhibitor is present in the carrier at a concentration providing a required dose in a volume of no more than 1000 microliters, and in preferred embodiments, the PDE5 inhibitor is present at a concentration of at least 5 mg/mL (paragraph [0024]). Sams further teaches that in a preferred embodiment, the composition comprises a flavoring agent and/or a sweetener (paragraph [0015]). When the composition comprises an oil that comprises a glyceride, the composition preferably comprises a lipophilic flavoring agent, preferably peppermint oil or spearmint oil (paragraph [0017]).
It would have been prima facie obvious to one of ordinary skill in the art to include tadalafil in an amount overlapping the range of instant claim 10 in the composition of U.S. Patent No. 12,589,135 B2, as suggested by Choung and Sams. One of ordinary skill in the art would have been motivated to do so in order achieve a combination pharmaceutical composition capable of targeting multiple pathways involved in the complex pathophysiology of neurodegenerative disorders such as type-2 diabetes, as suggested by Choung, and to achieve a required dose of tadalafil that can be delivered in a desired volume of composition, as suggested by Sams. Per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and per MPEP 2144.05 II. A., “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 further have been prima facie obvious to one of ordinary skill in the art to modify the composition of U.S. Patent No. 12,589,135 B2 to include the peppermint or spearmint oil flavoring agent taught by Sams. One of ordinary skill in the art would have been motivated to do so in order to incorporate a lipophilic flavoring agent that improves the taste of a sublingual transmucosal formulation for the delivery of active ingredients.
The claims of U.S. Patent No. 12,589,135 B2 do not recite the claimed amounts of phosphatidylcholine and lysophosphatidylcholine.
Amano teaches a self-emulsifiable composition including a monoacyl phospholipid, a diacyl phospholipid, oils and fats, and a polyhydric alcohol, wherein the content ratio between the monoacyl phospholipid and the diacyl phospholipid is in the range of 1:9 to 9:1 as a mass ratio (abstract). The monoacyl phospholipid is preferably lysophosphatidylcholine (column 5, lines 1-7), and examples of the diacyl phospholipid include phosphatidylcholine (column 5, lines 32-36). The composition can be used as a pharmaceutical product when the water content is less than 5% by mass and a substantially non-water-based composition is obtained (column 8, lines 51-55). A nanoemulsion forms when the self-emulsifiable composition is mixed with an aqueous solution (column 10, line 65-column 11, line 3). Amano further teaches that the total content of the monoacyl phospholipid and the diacyl phospholipid is not particularly limited; however, for example, the total content may be from 0.1 % by mass to 70% by mass based on the total amount of the composition; in this range, a self-emulsifiable composition that can produce a nanoemulsion by a simple operation such as addition of an aqueous solution can be suitably obtained (column 6, lines 1-16). Thus, Amano suggests amounts of lysophosphatidylcholine and phosphatidylcholine overlapping those of the instant claims; as just one example, the ranges of Amano are inclusive of lysophosphatidylcholine present at 0.1% w/w and a weight ratio of 1:9 with phosphatidylcholine, or 0.9% w/w of phosphatidylcholine. Amano further suggests that these amounts can be adjusted to provide the desired self-emulsification properties of a non-water based pharmaceutical composition upon addition of an aqueous solution.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the compositions comprising phosphatidylcholine and lysophosphatidylcholine of U.S. Patent No. 12,589,135 B2 with the amounts overlapping the claimed ranges suggested by Amano. One of ordinary skill in the art would have been motivated to do so in order to use amounts of lysophosphatidylcholine and phosphatidylcholine which allow a pharmaceutical non-water based self-emulsifiable composition to form a nanoemulsion upon addition of water. Further, per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and per MPEP 2144.05 II. A., “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).”
The claims of U.S. Patent No. 12,589,135 B2 do not recite the claimed amounts of polycarbophil.
Pauletti teaches compositions for buccal transmucosal delivery of drugs (abstract) which assert a therapeutic effect when delivered to the systemic circulation through the vaginal, nasal, or buccal mucosa (paragraphs [0081]). The compositions can be formulated as a suspension for buccal delivery (paragraph [0096]). The compositions may comprise a mucoadhesive agent to bring the drug into prolonged, close contact with the mucosal surface, and examples of mucoadhesive agents include polycarbophil (paragraph [0066]). The mucoadhesive agent is present between about 0.05-25% by weight, and more preferably about 0.02-7.5% for buccal delivery (paragraph [0071]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to adjust the amount of polycarbophil in the composition of U.S. Patent No. 12,589,135 B2 to be in an amount overlapping the claimed range, as suggested by Pauletti.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to use an amount of polycarbophil capable of bringing a drug into prolonged, close contact with the buccal mucosa, as suggested by Pauletti. Further, per MPEP 2144.05 I., “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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Response to Arguments
Applicant’s arguments filed 02/04/2026 have been fully considered.
Regarding the rejections under 35 U.S.C. § 103, Applicant argues that the combination of Staniforth, Sams, and Amano fails to teach the composition of claim 1 at least because the references teach fundamentally incompatible approaches to transmucosal drug delivery that one skill in the art would not combine as alleged. Particularly, Applicant argues that Staniforth relies on submicron particles that are “sticky” and that remain in an undissolved state until positioned in the micro-environment adjacent to the mucosal membrane. Applicant argues that Amano is in direct contrast to Staniforth in teaching a liquid self-emulsifying composition that spontaneously disperses into the aqueous solution that are mobile in the aqueous phase and do not exhibit the adhesive “stickiness” central to Staniforth’s delivery mechanism; one of ordinary skill would recognize that combining Amano’s self-emulsifying system with Staniforth would defeat Staniforth’s purpose of adhering to oral mucosa. Applicant further argues that Amano does not contemplate self-emulsification in saliva, but rather greater volumes of aqueous solution; Amano’s only discussion of oral administration relates to either pre-formed nanoemulsion or adding aqueous solution at the time of use.
These arguments are unpersuasive. The Examiner first respectfully maintains that Staniforth reasonably suggests the inclusion of phosphatidylcholine, lysophosphatidylcholine, and self-emulsifying components in compositions for the transmucosal (buccal and/or sublingual) administration of tadalafil or vardenafil, as set forth above. While Staniforth does not teach the amounts of phosphatidylcholine and lysophosphatidylcholine of instant independent claim 1, per MPEP 2144.05 II. A., differences in concentration will generally not support patentability unless there is evidence that such concentration is critical. The Examiner finds no evidence of record that the claimed amounts of lysophosphatidylcholine and phosphatidylcholine are critical.
However, the Examiner notes that, per MPEP 2144.05 III. A., “Applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” Applicant is encouraged to provide or point to evidence on the record demonstrating the criticality of the claimed range.
Further, the Examiner respectfully disagrees that the self-emulsification approach of Amano is incompatible with that of Staniforth. By teaching the inclusion of self-emulsifying components, Staniforth reasonably suggests to one of ordinary skill in the art that self-emulsification is compatible with their transmucosal delivery approach. Further, while Amano does not exemplify emulsification in saliva, the Examiner notes that the test for obviousness is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Here, Amano reasonably suggests the use of the self-emulsifying composition as a substantially non-water-based pharmaceutical product (column 8, lines 51-55) and formation of a nanoemulsion when a self-emulsifiable composition is mixed with an aqueous solution (column 10, line 65-column 11, line 3). Staniforth explicitly recognizes the mouth as an aqueous environment (paragraph [0024]), and teaches inclusion of the same phospholipids used in the self-emulsifying compositions of Amano, suggesting that the approaches can be combined with a reasonable expectation of success.
Applicant further argues that Sams is incompatible with Staniforth as Staniforth teaches compositions preferably provided as a solid dosage form while Sams teaches liquid compositions delivered as a spray. Applicant argues that Staniforth states that in oral liquids for transmucosal administration there is a likelihood of swallowing much of the active agent, and disparages spray compositions (paragraphs [0011] and [0013]). Applicant argues that suspending the drug of Staniforth in an oil carrier as Sams teaches would defeat the “sticky” mechanism of Staniforth, and one of ordinary skill would not have been motivated to combine Sams with Staniforth nor have a reasonable expectation of success in doing so.
These arguments are unpersuasive. While Staniforth exemplifies solid dosage forms, Staniforth explicitly contemplates compositions comprising an oil solvent (claim 28). Per MPEP 2123 I., “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989).” Sams provides motivation to the skilled artisan to select the particular solvent of medium-chain triglycerides of caprylic/capric triglycerides as a known carrier for the effective sublingual transmucosal delivery of tadalafil and vardenafil which can avoid unwanted gastrointestinal effects and provide a faster-acting product. In the paragraphs cited in Applicant’s arguments, Staniforth is providing background information on limitations of previously known formulations for transmucosal delivery via the sublingual or buccal mucosa. Staniforth highlights limitations in many types of known delivery systems, including solid formulations (see paragraphs [0011]-[0013]). Staniforth suggests that their invention improves on these known issues by providing compositions which provide effects such as improved transmucosal absorption upon administration by promoting or enhancing mucosal adhesion, persistence at the mucosa, enhancement of transmucosal flux, etc. (paragraph [0014]).
In view of the foregoing, and as further detailed in the above rejections, the Examiner maintains that the instant claims are prima facie obvious over the teachings of the modified Staniforth.
Regarding the nonstatutory double patenting rejections over the claims of co-pending Applications 19/067,153 and 19/067,176, Applicant requests that the provisional rejections be held in abeyance until the subject matter that will mature into a patent is known.
In response, the Examiner notes that a request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see MPEP 37 CFR 1.111(b) and 714.02). Thus, the double patenting rejections set forth above have been maintained as no action regarding these rejections has been taken by Applicant at this time.
Regarding the nonstatutory double patenting rejections over the claims of co-pending Application No. 18/236,300 (now U.S. Patent No. 12,589,135 B2), Applicant argues that they have filed a terminal disclaimer with respect to the application, rendering the double patenting rejection moot.
In response, the Examiner notes that no terminal disclaimer is found on the record. Thus, the double patenting rejections set forth above have been maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached at (571)272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
Prosecution Insights