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 .
DETAILED ACTION
This office action is response to communication filed on 01/15/2026.
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 01/15/2026, wherein claim 1 and 41-44 are amended, claims 4 and 25 are cancelled.
Election/Restrictions
Applicant elected without traverse, Group I, a formulation comprising vardenafil, and PEG400 (a polyethylene glycol) as the solvent species, in the reply filed 09/02/2025.
Status of Claims
Claims 1, 6-9, 16-17, 19-22, 27-30, and 39-46 are pending in instant application.
Claims 16-17, 19-22, 27-30, and 46 remain withdrawn being directed to non-elected inventions, there being no allowable generic or linking claim.
Claims 1, 6-9 and 39-45 are currently under examination in this office action.
Priority
This application 17/999,826 filed on 12/01/2022 is a 371 of PCT/US2021/061488 filed 12/01/2021, and a CIP of PCT/US21/34334 filed 05/26/2021, which claims US provisional application No. 63/029,881 filed on 05/26/2020.
Claim Interpretation
Instant claims recite “organic-aqueous solvent” which is considered as water-soluble or miscible organic solvent that could dissolve/mix with water to form organic-aqueous solution.
Instant claims recite “for enhancing permeation of vardenafil across a nasal mucosal membrane” and “wherein the organic-aqueous solvent enhances solubility of the vardenafil relative to solubility of the vardenafil in water” (claim 1), “wherein the formulation has a steady state flux (Jss) equal to or greater than that obtained in aqueous formulation with solubility of 20mg/ml or more at pH 3.5 or higher” (claim 41). Instant claims are product claims. The recited “for enhancing permeation of vardenafil across a nasal mucosal membrane ” and “wherein the organic-aqueous solvent enhances solubility of the vardenafil relative to solubility of the vardenafil in water” (claim 1), “wherein the formulation has a steady state flux (Jss) equal to or greater than that obtained in aqueous formulation” are constructed as intended use/function of organic-aqueous solvent which do NOT necessarily contribute to the structural limitation of formulation comprising vardenafil. If the prior art structure is capable of performing the intended use/function, then it meets the limitation.
Action Summary/Response to Arguments
Applicant's remarks filed 01/15/2026 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks. The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office action.
Declaration by inventor Moses Chow under 37 CFR 1.130 (a) filed on 01/15/2026 is persuasive. Claims 1, 6-8 and 45 rejected under 35 U.S.C. § 103 as being unpatentable over Park is withdrawn.
As necessitated by amendment, claims 1, 6-8 and 45 rejections as being anticipated by Serno’950 (US 8613950B2) under 35 USC§ 102 is withdrawn. Claims 1, 6-8 and 45 are now rejected as being unpatentable over Serno’950 under 35 USC§ 103.
The following rejections are either newly reapplied or maintained/reiterated necessitated by amendment. They constitute the complete set presently being applied to the instant application and made Final.
Claim Rejections - 35 USC§ 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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, 6-8 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Serno’950 (US 8613950B2) (newly reapplied as necessitated by amendment).
Serno’950 teaches formulations of vardenafil comprising sugar alcohols that dissolves rapidly in the mouth with increased bioavailability that might be used for transmucosal delivery via mouth mucosa (See abstract, Col. 2, lines 4-40). Serno’950 teaches vardenafil or salt thereof may be dissolved or suspended in an organic solvent or aqueous solvent with polymers or surfactant (See Col. 3, lines 25-31). Serno’950 teaches embodiments comprising vardenafil, ethanol, propylene glycol, etc. for sublingually administration (See Col. 4, lines 1-5). Serno’950 also teaches embodiments comprising vardenafil hydrochloride trihydrate, Macrogol 400(i.e. PEG 400), crosslinked polyvinylpyrrolidone, etc. (See Examples 7 and 8).
Regarding the amended concentration of vardenafil and ethanol, Serno’950 teaches embodiments comprising vardenafil and ethanol, wherein vardenafil is calculated to be 2 mg/ml and ethanol is calculated to be about 25% (See Comparative example 2, Col.4, lines1-8).
Serno’950 collectively teaches formulation comprising vardenafil or salt thereof and organic-aqueous solvent (e.g. ethanol, Macrogol 400/PEG 400, propylene glycol, etc.). Serno’950 is silent about organic-aqueous solvent (PEG 400, propylene glycol, etc.) enhances solubility of the vardenafil relative to solubility of the vardenafil in water and enhancing permeation of vardenafil across a nasal mucosal membrane. However, the functional effects of the solvent would be intrinsic property of polyethylene glycol. Based upon the fact that prior formulation contains the instantly claimed ingredients as in instant application, the reference composition should be capable of performing the claimed intended function/effect if applicant’s invention functions as claimed.
It would have been obvious to a person of ordinary skilled in the art, before the effective filing date of instant invention to explore different solvent and mixture thereof for optimal solubility of vardenafil based on the collective teachings of Serno’950 and general knowledge of organic solvent for pharmaceutical formulation. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with further exploration/optimization based on general knowledge of PDE5 inhibitors and formulation (e. g. nasal/mucosal delivery). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues “none of tablet that as disclosed in Examples 6-8 of Serno'950, which demonstrated increase bioavailability, contains ethanol. Therefore, a person of ordinary skilled in the art would not have been motivated to adjust the inventive tablet formulation in Serno'950 to that of the pending claims for enhancing permeation of vardenafil across a nasal mucosal membrane”.
RESPONSE: Applicant’s argument is NOT persuasive. Please note the intended use/function of organic-aqueous solvent for enhancing solubility of the vardenafil relative to solubility of the vardenafil in water, and permeation of vardenafil across a nasal mucosal membrane do NOT necessarily contribute to the structural limitation of formulation product comprising vardenafil and ethanol. Exploring different solvent mixture and concentration thereof for optimal solubility of active ingredient in liquid formulation and pharmacokinetic profile thereof is within the general knowledge of POSA. Serno'950 teaches further exploration of more embodiments comprising vardenafil. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further optimize combination of inactive ingredients (e.g. solvent, penetration enhancer, pH adjuster) and concentration thereof for desired pharmacokinetic profile of vardenafil formulation.
Claims 1, 6-7 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Lipp (US 2017/0014417 A1) (maintained/ reiterated as necessitated by amendment).
Lipp teaches pharmaceutical composition comprising PDE inhibitor (e.g. vardenafil) or pharmaceutical salt thereof and pharmaceutical carriers, e.g. solvent/cosolvent, penetration enhancer, etc. as liquid formulation or spray for transdermal delivery (See abstract, [0024], Examples 3, 6 and 10, claims 1-3, 5-6 and 23-24) (newly reapplied as necessitated by amendment).
Regarding instantly claimed ethanol and polyethene glycol, Lipp teaches solvent and co-solvents may form a solvent system, e.g. water-soluble alcohols, polyols, and mixtures thereof. The water-soluble alcohols may include ethanol, propanol, isopropanol, and mixtures thereof and the polyols may be 1,2-propane diol, polyethylene glycol, glycerol, and mixtures thereof (See [0036], [0043]).
Regarding the amended concentration of vardenafil and ethanol, Lipp teaches embodiments comprising vardenafil and ethanol (See Formulation 3, 6 and 10). The concentration of ethanol in Formulation 3 is calculated to be about 66.5%. As stated in MPEP 2144.05, 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."
Regarding claim 44, Lipp teaches embodiments comprising penetration enhancer, e.g. pyrrolidone, preferably N-methyl-2-pyrrolidone (See [0035]), wherein the penetration enhancer may be 0.1-25% by weight (See 0033]) (which overlaps with the range of claim 44).
Lipp is silent about polyethylene glycol (organic-aqueous solvent) enhances solubility of the vardenafil relative to solubility of the vardenafil in water and enhancing permeation of vardenafil across a nasal mucosal membrane. However, the functional effects of the solvent would be intrinsic property of polyethylene glycol. Based upon the fact that prior formulation contains the instantly claimed ingredients as in instant application, the reference composition should be capable of performing the claimed intended function/effect if applicant’s invention functions as claimed.
It would have been obvious to a person of ordinary skilled in the art, before the effective filing date of instant invention to explore different solvent and mixture thereof for optimal solubility of vardenafil based on the collective teachings of Lipp and general knowledge of organic solvent for formulation. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with further exploration/optimization based on general knowledge of PDE5 inhibitors and formulation (e. g. nasal/mucosal delivery). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues “Lipp only teaches a vardenafil formulation comprising 95% ethanol/water (70% v/v), which is equivalent to about 66.5% of ethanol in the formulation... Lipp provides no motivation to modify its formulation to arrive at the claimed formulation”.
RESPONSE: Applicant’s argument is NOT persuasive. As stated in MPEP 2144.05, Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Instant amended vardenafil and ethanol concentration are considered as routine experimentation /optimization based on the combined teachings of prior art and general knowledge of organic solvent for formulation. Exploring different solvent mixture and concentration thereof for optimal solubility of active ingredient in liquid formulation and pharmacokinetic profile thereof is common practice and within knowledge of an ordinary skilled in the art of pharmaceutical formulation as demonstrated in Lipp.
Claims 1, 6-9 and 39-45 are rejected under 35 U.S.C. 103 as being unpatentable over Serno et al. (US 6,740,306 B2, hereafter “Serno’306”, Applicant’s IDS dated 12/10/2024), in view of Lipp (US 2017/0014417 A1) (maintained/ reiterated as necessitated by amendment).
Regarding the active ingredient, Serno’306 disclosed a composition comprising imidazotriazinone cGMP PDE inhibitor (e.g. vardenafil) or pharmaceutical salt thereof and organo-aqueous solvent for nasal administration for treating disease (e.g. male erectile dysfunction) (See abstract, Col. 4, lines 1-4; Examples 1-5; claims 1, 10-31). Serno explicitly teaches embodiments comprising vardenafil or pharmaceutical salt thereof (See Col. 4, lines 1-4; Col. 5, line 30; Examples 1-5). Serno’306 teaches advantage of nasal administration of an active ingredient, such as achieve a faster rise in the level of active ingredient in the blood stream, accelerated onset of action, etc. and nasally administration of cGMP PDE5 inhibitors (e.g. sildenafil mesylate in water) for treating male erectile dysfunction (Col. 1, lines 30-59).
Regarding the solvent limitation of claims 1, 6-7 and 45, Serno’306 disclosed solvent in the liquid formulation could be water, glycerol, polyethylene glycol, propylene glycol, medium-chain triglycerides, etc. (See Col. 9. lines 18-20) (which read on organic-aqueous solvent, elected polyethylene glycol PEG). Serno’306 teaches compositions may contain one or more surfactants and/or solubilizers (e.g. polyethylene glycol, polyoxyl or polyoxyethylene derivative, Tween 80, etc.) to increase the solubility of cGMP PDE inhibitor (See Col.9, lines 53-67). Serno’306 teaches the solubilizer at various concentration, e.g. from 0.001% (m/v) to about 5% (m/v) (See Col. 10, lines 1-5) (which overlaps with instantly claimed range 5% to 45% of claim 4, and 1% to 40% of claim 9). Serno’306 explicitly disclosed embodiments comprising vardenafil hydrochloride trihydrate in organic-aqueous solvent (e.g. glycerol), wherein the organic solubilizer (e.g. glycerol) is present at about 1-2% (See Examples 1-5 and Comparative Examples 1-2).
Regarding the pH recited in instant claim 39 and weak salt limitation of instant claims 42-43, Serno’306 teaches weak acid salt, e.g. lactic acid (lactate), acetate, phosphate or citrate buffers were used to adjust pH of the composition, preferable from 3 to 8, in order to avoid irritation in the nose and optimize the absorption of the cGMP PDE inhibitors (See Col. 9, lines 21). Serno’306 explicitly teaches embodiments comprising vardenafil salt and lactic acid at about 0.8 % m/v at pH 3.7 (See Example 1).
Regarding claim 40, Serno’306 teaches embodiments comprising vardenafil or salt thereof at concentration of 20mg/ml at pH 3.7 (i.e. 2g/100ml, 1mg/50uL) (See Examples 2-3 and 5).
Regarding claim 41, Serno’306 teaches pharmacokinetics of composition comprising vardenafil hydrochloride trihydrate (15mg/ml, i.e. 3mg/ 200uL) in organic-aqueous system (See Table 1).
Serno’306 collectively teaches formulation comprising vardenafil or salt thereof and organic-aqueous solvent system comprising alcohol (e.g. glycerol, polyethylene glycol, propylene glycol, etc.) and water for nasal administration, wherein the organic-aqueous solvent enhances the solubility of vardenafil or salt thereof.
Serno’306 is silent about ethanol and N-methyl- 2-pyrrolidone/ NMP. As disclosed by instant specification (See [0056]), ethanol and glycerol are considered as equivalent alcohol solvent to increase solubility/permeability/bioavailability of the phosphodiesterase PDE inhibitor in water. Exploring different solvent and mixture thereof for optimal solubility of active ingredient is common practice and within knowledge of an ordinary skilled in the art of pharmaceutical formulation.
The collective teachings of Lipp is elaborated in preceding 103 rejection and applied as before.
Lipp teaches pharmaceutical composition comprising PDE inhibitor (e.g. vardenafil) or pharmaceutical salt thereof and pharmaceutical carriers, e.g. solvent/cosolvent, penetration enhancer, etc. as liquid formulation, wherein the solvent system comprise water-soluble alcohols, polyols, e.g. ethanol, propanol, isopropanol, polyols polyethylene glycol, glycerol, and mixtures thereof. Lipp explicitly teaches embodiments comprising vardenafil and ethanol. Lipp also teaches embodiments comprising penetration enhancer, e.g. pyrrolidone, preferably N-methyl-2-pyrrolidone (See [0035]), wherein the penetration enhancer may be 0.1-25% by weight (See 0033])
It would have been obvious to a person of ordinary skilled in the art, before the effective filing date of instant invention to further explore/optimize nasal formulation comprising vardenafil or pharmaceutical salt thereof and organic-aqueous solvent taught by Serno’306 , with the teachings of the solvent system (e.g. ethanol, polyethylene glycols, propylene glycol) and penetration enhancer N-methyl-2-pyrrolidone, etc. ) for vardenafil taught by Lipp, together with experimentation/optimization based on general knowledge of PDE5 inhibitors and formulation for nasal/mucosal delivery, and arrive at instantly claimed invention with reasonable expectation of success. At the time instant claimed invention was made, it was already known a formulation comprising vardenafil or pharmaceutical salt thereof in organo-aqueous solvent (e.g. glycerol, PEG, propylene glycol, etc.) for nasal administration could be made as taught by Serno’306. It was also known ethanol, polyethylene glycols, propylene glycol, N-methyl-2-pyrrolidone are solvent /solubilizing agent/ penetration enhancer for vardenafil in liquid formulation as taught by Lipp.
A skilled artisan would be motivated to explore/optimize Serno’306 ’s formulation comprising vardenafil or salt thereof and organic-aqueous solvent system with beneficial teachings of Lipp since all references are directed to formulation for vardenafil. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further optimize combination of inactive ingredients (e.g. solvent, penetration enhancer, pH adjuster) and concentration thereof for desired pharmacokinetic profile. Exploring different solvent and mixture thereof for optimal solubility of active ingredient in liquid formulation and pharmacokinetic profile thereof is common practice and within knowledge of an ordinary skilled in the art of pharmaceutical formulation as demonstrated in Serno’306 and Lipp. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05. The combined teachings of prior art, together with experimentation/optimization based on general knowledge of PDE inhibitors and formulation for nasal/mucosal delivery would provide a formulation comprising vardenafil or salt thereof in organic-aqueous solvent mixtures with desirable solubility/ pharmacokinetic profile for nasal/ mucosal delivery of vardenafil or salt thereof with benefit of accelerated onset of therapeutic action, higher bioavailability, etc.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with further exploration/optimization based on general knowledge of PDE5 inhibitors and formulation (e. g. nasal/mucosal delivery). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s argument about Lipp is similar as above: “Lipp only teaches a vardenafil formulation comprising 95% ethanol/water (70% v/v), which is equivalent to about 66.5% of ethanol in the formulation... the combination of Serno and Lipp does not teach or reasonably suggest the formulation as recited in the amended claims”.
RESPONSE: Applicant’s argument is NOT persuasive Instant amended vardenafil and ethanol concentration are considered as routine experimentation /optimization based on the combined teachings of prior art and general knowledge of organic solvent for formulation. Serno’306 teaches embodiments comprising vardenafil or salt thereof at concentration of 20mg/ml and solubilizer at various concentration which overlaps with instantly claimed range. Exploring different solvent mixture and concentration thereof for optimal solubility of active ingredient in liquid formulation and pharmacokinetic profile thereof is common practice and within knowledge of an ordinary skilled in the art of pharmaceutical formulation as demonstrated in Serno’306 and Lipp.
Claims 1, 6-9 and 39-45 are rejected under 35 U.S.C. 103 as being unpatentable over Serno et al. (US 6,740,306 B2, hereafter “Serno’306”, Applicant’s IDS dated 12/10/2024), in view of Vallabhaneni et al. (WO 01/35926 A2, Applicant’s IDS dated 09/02/2025) (maintained/ reiterated as necessitated by amendment).
The collective teachings of Serno are elaborated in preceding 103 rejection and applied as before.
Serno’306 collectively teaches formulation comprising vardenafil or salt thereof and organic-aqueous solvent system comprising alcohol (e.g. glycerol, polyethylene glycol, propylene glycol, etc.) and water for nasal administration, wherein the organic-aqueous solvent enhances the solubility of vardenafil or salt thereof.
Serno’306 is silent about ethanol and N-methyl- 2-pyrrolidone/ NMP. As disclosed by instant specification (See [0056]), ethanol and glycerol are considered as equivalent alcohol solvent to increase solubility/permeability/bioavailability of the phosphodiesterase PDE inhibitor in water. Exploring different solvent and mixture thereof for optimal solubility of active ingredient is common practice and within knowledge of an ordinary skilled in the art of pharmaceutical formulation.
Vallabhaneni teaches pharmaceutical composition comprising sildenafil or salt thereof in organic-aqueous solvent/vehicle comprising of a solvent, cosolvent and / or solubilizing agent, penetration enhancer, stabilizing agent, buffering agent, and a tonicity agent for nasal administration for the treatment of male erectile dysfunction (See abstract, page 1, para 1-4; page 5, para 4;
Examples 1-8; claims 1-10).
Vallabhaneni teaches protogenic solvent ( e.g. lactic acid, citric acid, etc.) dissolved in water, mixed with cosolvent /solubilizers and penetration enhancers ( e.g. polyethylene glycol, propylene glycol, glycerol, ethyl alcohol, diethylene glycol monoethyl ether, propyleneglycol monolaurate, etc.) or combination thereof, wherein pH is adjusted 3.0 to 8.0 with citrate, acetate or phosphate buffer for synergistically promoting rapid absorption and rapid onset of action of sildenafil for nasal administration (See page 1, para 4; claim 1; Examples 1-8).
Vallabhaneni teaches the co-solvents may be selected from a group of "amphiprotic" solvents, which act as both proton acceptors and proton donors such as the alcohols e.g. ethyl alcohol, propylene glycol, glycerol and polyethylene glycols having a nominal molecular weight of 200 - 600 or N-methyl-
2-pyrrolidone, which enhances the solubility of sildenafil or its salts by formation of complex, wherein the co-solvents is present from 1.0 to 50.0% v/v preferably 15.0 to 30.0% v/v (See page 6, para 2) (which falls within the range of instant claims 4, 9 and 44).
Vallabhaneni teaches solubilising agents may be selected from diethylene glycol monoethyl ether, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, etc. or combination thereof at concentration/amount ranging from 0.01 to 30.0% w/v, preferably 5.0 to 15.0% w/v (See page 6, para 3).
Vallabhaneni also teaches ethyl alcohol, propylene glycol, N-methyl-2-pyrrolidone, propyleneglycol monolaurate, diethylene glycol monoethyl ether are commonly known penetration enhancers in the art for intranasal application, that may be present at range from 0.1 to 30.0 %v/v or w/v,
preferably 5.0 to 25.0%v/v or w/v. (See page 6, para 4). Vallabhaneni explicitly teaches embodiments comprising ethyl alcohol and polyethylene glycol (See Examples 3-4 ) and N-methyl-2-pyrrolidone (See Example 2).
Vallabhaneni collectively teaches organic-aqueous solvent/vehicle comprising cosolvent /solubilizing agent/ penetration enhancer, e.g. ethyl alcohol, polyethylene glycols, propylene glycol, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether, etc. and weak acid or salt thereof (citrate, lactate etc.) for nasal administration of PDE inhibitor (sildenafil).
It would have been obvious to a person of ordinary skilled in the art, before the effective filing date of instant invention to further explore/optimize nasal formulation comprising vardenafil or pharmaceutical salt thereof and organic-aqueous solvent taught by Serno’306 , with the teachings of nasal delivery vehicle comprising cosolvent /solubilizing agent/ penetration enhancer (e.g. ethyl alcohol, polyethylene glycols, propylene glycol, N-methyl-2-pyrrolidone, etc. ) for sildenafil taught by Vallabhaneni, together with experimentation/optimization based on general knowledge of PDE5 inhibitors and formulation for nasal/mucosal delivery, and arrive at instantly claimed invention with reasonable expectation of success. At the time instant claimed invention was made, it was already known a formulation comprising vardenafil or pharmaceutical salt thereof in organo-aqueous solvent (e.g. glycerol, PEG, propylene glycol, etc.) for nasal administration could be made as taught by Serno’306. It was also known ethyl alcohol, polyethylene glycols, propylene glycol, N-methyl-2-pyrrolidone are cosolvent /solubilizing agent/ penetration enhancer for nasal/mucosal delivery of PDE inhibitor (sildenafil) as taught by Vallabhaneni, Vallabhaneni also teaches NMP forms complex with sildenafil.
A skilled artisan would be motivated to explore/optimize Serno’306 ’s formulation comprising vardenafil or salt thereof and organic-aqueous solvent system with beneficial teachings of Vallabhaneni since all references are directed to formulation for nasal/mucosal administration of PDE5 inhibitors. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further optimize combination of inactive ingredients (e.g. solvent, penetration enhancer, pH adjuster) and concentration thereof for desired pharmacokinetic profile. Exploring different solvent and mixture thereof for optimal solubility of active ingredient in liquid formulation and pharmacokinetic profile thereof is common practice and within knowledge of an ordinary skilled in the art of pharmaceutical formulation as demonstrated in Serno’306 and Vallabhaneni. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05. The combined teachings of prior art, together with experimentation/optimization based on general knowledge of PDE inhibitors (e.g. vardenafil, sildenafil, tadalafil, etc.) and formulation for nasal/mucosal delivery would provide a formulation comprising vardenafil or salt thereof in organic-aqueous solvent mixtures with desirable solubility/ pharmacokinetic profile for nasal/ mucosal delivery of vardenafil or salt thereof with benefit of accelerated onset of therapeutic action, higher bioavailability, etc.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with further exploration/optimization based on general knowledge of PDE5 inhibitors and formulation (e. g. nasal/mucosal delivery). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues Vallabhaneni only teaches solvents for the API sildenafil... While both sildenafil and vardenafil have similar in vivo mechanisms of action, they differ in many chemical properties, including lipid and water solubility, permeability, and overall potency per unit of molecule. Given those differing properties, one skilled in the art has no reasonable expectation of success that one of the solvents used to enhance the solubility of sildenafil in Vallabhaneni would work on vardenafil, especially when Serno'306 does not suggest using alcohol as a solvent for vardenafil.
RESPONSE: Applicant’s argument is NOT persuasive. Instant amended vardenafil and ethanol concentration are considered as routine experimentation /optimization based on the combined teachings of prior art and general knowledge of organic solvent for formulation. Please note the intended use/function of organic-aqueous solvent for enhancing solubility of the vardenafil relative to solubility of the vardenafil in water, and permeation of vardenafil across a nasal mucosal membrane do NOT necessarily contribute to the structural limitation of formulation product comprising vardenafil. Serno’306 teaches embodiments comprising vardenafil or salt thereof at concentration of 20mg/ml and solubilizer at various concentration which overlaps with instantly claimed range. Vallabhaneni explicitly teaches embodiments comprising ethyl alcohol and polyethylene glycol (See Examples 3-4 ) and N-methyl-2-pyrrolidone (See Example 2). Although sildenafil and vardenafil might have different chemical/physical properties, in searching for formulation for treating erectile dysfunction with PDE5 inhibitors, one skilled in the art would refer to sildenafil formulation as taught by Vallabhaneni for the inactive ingredient for further exploration and reasonably expect formulation comprising vardenafil, ethanol and NMP would achieve efficacy for treating erectile dysfunction in absence of evidence to the contrary.
Claims 1, 4, 6-9 and 39-45 are rejected under 35 U.S.C. 103 as being unpatentable over Serno et al. (US 6,740,306 B2, hereafter “Serno’306”, Applicant’s IDS dated 12/10/2024), in view of Elshafeey et al. (AAPS PharmSciTech, Vol. 10, No. 2, June 2009, DOI: 10.1208/s12249-009-9213-6, Intranasal Microemulsion of Sildenafil Citrate: In Vitro Evaluation and In Vivo Pharmacokinetic Study in Rabbits) and Hubinette et al (WO2019122245A1, Applicant’s IDS dated 12/10/2024) (maintained/ reiterated as necessitated by amendment).
The collective teachings of Serno’306 is elaborated in preceding 103 rejection and applied as before. Serno’306 collectively teaches formulation comprising vardenafil or salt thereof and organic-aqueous solvent system (e.g. glycerol, polyethylene glycol, propylene glycol and water) for nasal administration, wherein the organic-aqueous solvent enhances the solubility of vardenafil or salt thereof.
Serno’306 is silent about ethanol and N-methyl- 2-pyrrolidone/ NMP.
Elshafeey teaches intranasal formulation of sildenafil citrate comprising organic-aqueous solvent and bioavailability after nasal administration in rabbits to attain rapid onset of action with good efficacy at lower doses (See whole article). Elshafeey teaches various organic-aqueous solvent system comprising different solvent, co-solvent (e.g. ethanol, PEG 400, propylene glycol, transcutol, etc.) at various ratio and saturated solubility of sildenafil citrate in these solvent or mixtures thereof (See page 362, right column; page 364, left column; Table I and III). Elshafeey teaches pharmacokinetic parameters of sildenafil citrate after nasal administration (See Table VI), wherein the plasma time profile showed nearly two folds higher serum drug levels were achieved in nasal microemulsion with significantly higher Cmax and shorter tmax, with relative bioavailability 112.89% (See page 366, right column).
Hubinette teaches a liquid formulation comprising vardenafil or salt thereof in liquid carrier (e.g. NMP, C3-C12 polyol, etc) at pH 3.4 to 4.0 which could be further formulated as mucoadhesive film for delivering vardenafil across mucosal membrane (See abstract, page 6, lines 20, 23; page 13, lines 21-24; page 14, lines 20-24; Table 8 on page 29; claim 1 and 4). Hubinette explicitly teaches NMP act as cosolvents for vardenafil in the liquid formulation and possibly also as a mucosal permeation enhancer for the vardenafil (See page 7, lines13-14). Hubinette teaches embodiments comprising various concentration/amount of NMP (e.g. from 2% to 10%) in combination with vardenafil (See Table 8 on page 29; Table 13 on page 34; page 7, line 8 -9; page 20, lines 29-31, etc.).
It would have been obvious to a person of ordinary skilled in the art, before the effective filing date of instant invention to further explore/optimize nasal formulation comprising vardenafil or pharmaceutical salt thereof and organic-aqueous solvent taught by Serno’306 , with the teachings of nasal delivery system comprising ethanol and polyols (e.g. PEG, propylene glycol) taught by Elshafeey, NMP as cosolvent for vardenafil as taught by Hubinette, together with experimentation/optimization based on general knowledge of PDE5 inhibitors and formulation for nasal/mucosal delivery, and arrive at instantly claimed invention with reasonable expectation of success. At the time instant claimed invention was made, it was already known a formulation comprising vardenafil or pharmaceutical salt thereof in organo-aqueous solvent (e.g. glycerol, PEG, propylene glycol, etc.) for nasal administration could be made as taught by Serno’306. It was also known ethanol, PEG-400 and propylene glycol, etc. are commonly-known solvent in formulation for nasal/mucosal delivery of PDE5 inhibitor as taught by Elshafeey. Elshafeey also teaches optimization of solvent for saturated solubility and optimal pharmacokinetic profile for nasal delivery of sildenafil (Viagra®). Hubinette explicitly teaches NMP as cosolvents for vardenafil in the liquid formulation and possibly also as a mucosal permeation enhancer for the vardenafil.
A skilled artisan would be motivated to explore/optimize Serno’306 ’s formulation comprising vardenafil or salt thereof and organic-aqueous solvent system with beneficial teachings of Elshafeey and Hubinette since all references are directed to formulation for nasal/mucosal administration and Serno’306 and Elshafeey teaches advantage of nasal administration of PDE5 inhibitor for treating male erectile dysfunction, such as rapid absorption, accelerated onset of therapeutic action, higher bioavailability with lower doses, avoidance of liver or gastrointestinal metabolism, avoidance of irritation of the gastrointestinal membrane, reduced risk of overdose, non-invasive administration, etc. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further optimize combination of inactive ingredients(e.g. solvent, pH adjuster ) and ratio thereof for desired pharmacokinetic profile. Exploring different solvent and mixture thereof for optimal solubility of active ingredient in liquid formulation and pharmacokinetic profile thereof is common practice and within knowledge of an ordinary skilled in the art of pharmaceutical formulation as demonstrated in Elshafeey. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05. The combined teachings of prior art, together with experimentation/optimization based on general knowledge of PDE inhibitors (e.g. vardenafil, sildenafil, tadalafil, etc.) and formulation for nasal/mucosal delivery would provide a formulation comprising vardenafil or salt thereof in organic-aqueous solvent mixtures with desirable solubility/ pharmacokinetic profile for nasal/ mucosal delivery of vardenafil or salt thereof with benefit of accelerated onset of therapeutic action, higher bioavailability at lower doses, etc.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with further exploration/optimization based on general knowledge of PDE5 inhibitors and formulation (e. g. nasal/mucosal delivery). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues Elshafeey only teaches solutions comprising sildenafil citrate and similar argument about the difference of sildenafil and vardenafil.
RESPONSE: Applicant’s argument is NOT persuasive. As elaborated above, the intended use/function of organic-aqueous solvent for enhancing solubility of the vardenafil relative to solubility of the vardenafil in water, and permeation of vardenafil across a nasal mucosal membrane do NOT necessarily contribute to the structural limitation of formulation product comprising vardenafil. Serno’306 eaches embodiments comprising vardenafil or salt thereof at concentration of 20mg/ml and solubilizer at various concentration which overlaps with instantly claimed range. Elshafeey explicitly teaches sildenafil formulation comprising various amount of ethanol and PEG400. Although sildenafil and vardenafil might have different chemical/physical properties, in searching for formulation for treating erectile dysfunction with PDE5 inhibitors, one skilled in the art would refer to sildenafil formulation as taught by Elshafeey for the inactive ingredient for further exploration and reasonably expect formulation comprising vardenafil and ethanol would achieve efficacy for treating erectile dysfunction in absence of evidence to the contrary.
Conclusion
No claims are allowed
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/LIYUAN MOU/
Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628