IP Library › Granted Patent US 12,697,329
Granted Patent B2
US 12,697,329 · App. 18/745,005 · Granted Aug 4, 2026

Method for reducing side effects from administration of phosphodiesterase-4 inhibitors

Inventor: David W. Osborne (Fort Collins, CO)
Assignee: ARCUTIS BIOTHERAPEUTICS, INC.
A61K31/44A61K9/0014A61K9/06A61K9/122A61K47/10A61K47/24A61P19/02A61K45/06
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Quick Facts
Patent No.
US 12,697,329
App. No.
18/745,005
Filed
Jun 17, 2024
Granted
Aug 4, 2026
Kind
B2
Art Unit
1615
USPC
424/400
Abstract

A method for altering the PK profile of a pharmaceutical formulation containing a PDE-4 inhibitor, such as roflumilast, to reduce the spike in Cmax. The spike in Cmax is reduced by topically administering the PDE-4 inhibitor in combination with one or more phosphate ester surfactants. Reducing the spike in Cmax will reduce gastrointestinal side effects and result in better patient compliance.

Claims (42)

1 . A pharmaceutical composition for topical administration comprising:

(i) roflumilast, wherein the roflumilast is in an amount of 0.05-1% (w/w);

(ii) a phosphate ester surfactant blend comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate;

(iii) a solvent; and

(iv) water;

wherein said surfactant is in an amount sufficient to produce a stable emulsion, and

wherein said roflumilast composition has a roflumilast absorption profile that produces in a patient following administration a plasma concentration time curve with a peak to trough ratio less than 2 at steady state.

2 . The composition of claim 1 , wherein said solvent is selected from the group consisting of acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methyl pyrrolidinone, polyethylene glycol, glycerol, propylene glycol, specially denatured alcohol, and combinations thereof.

3 . The composition of claim 2 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

4 . The composition of claim 2 , wherein said composition comprises a polymer or thickener selected from the group consisting of acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, methylcellulose, and combinations thereof.

5 . The composition of claim 4 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

6 . The composition of claim 2 , wherein the composition further comprises a surfactant selected from the group consisting of alkyl aryl sodium sulfonate, a multisterol extract of lanolin alcohols in petrolatum, ammonium lauryl sulfate, apricot kernel oil, polyethylene glycol (PEG)-6 esters, [(2R)-2-[(3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl](Z)-octadec-9-enoate, benzalkonium chloride, ceteareth-6, ceteareth-12, ceteareth-15, ceteareth-30, cetearyl alcohol, cetearyl ethylhexanoate, ceteth-10, ceteth-10 phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide ether sulfate, cocamine oxide, coco betaine, coco diethanolamide, coco monoethanolamide, coco-caprylate/caprate, disodium cocoampho-diacetate, dicetyl phosphate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamido monoethanolamine sulfosuccinate, docusate sodium, laureth-2, laureth-23, laureth-4, lauric diethanolamide, lecithin, methoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2, oleth-20, PEG 6-32 stearate, PEG-100 stearate, PEG-12 glyceryl laurate, PEG-120 methyl glucose dioleate, PEG-15 cocamine, PEG-150 distearate, PEG-2 stearate, PEG-20 methyl glucose sesquistearate, PEG-22 methyl ether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate, PEG-45/dodecyl glycol copolymer, PEG-5 oleate, PEG-50 Stearate, PEG-54 hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castor oil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate, pegoxol 7 stearate, pentaerythritol cocoate, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, polyglyceryl-3 oleate, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl 6, polyoxyl 32, polyoxyl glyceryl stearate, polyoxyl stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate, propylene glycol diacetate, propylene glycol dicaprylate, propylene glycol monostearate, sodium xylene sulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2, steareth-20, steareth-21, steareth-40, tallow glycerides, emulsifying wax, and combinations thereof.

7 . The composition of claim 6 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

8 . The composition of claim 6 , wherein said composition comprises a polymer or thickener selected from the group consisting of acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, methylcellulose, and combinations thereof.

9 . The composition of claim 8 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

10 . The composition of claim 1 , wherein said composition further comprises a carrier or humectant selected from the group consisting of glycerin, sorbitol, hexylene glycol, propylene glycol, and combinations thereof.

11 . The composition of claim 1 , wherein said roflumilast is in an amount of 0.3% (w/w).

12 . The composition of claim 1 , wherein said roflumilast is in an amount of 0.15% (w/w).

13 . The composition of claim 1 , wherein said roflumilast is in an amount of 0.05% (w/w).

14 . The composition of claim 1 , wherein said phosphate ester surfactant blend is in an amount sufficient to decrease a slope of the plasma concentration curve of the roflumilast between administration of said composition and Cmax.

15 . The composition of claim 1 , wherein the plasma concentration curve of the roflumilast has no spike at Cmax.

16 . The composition of claim 1 , wherein said phosphate ester surfactant blend is in an amount of 5% to 15% (w/w).

17 . The composition of claim 16 , wherein said phosphate ester surfactant blend is in an amount of about 10% (w/w).

18 . The composition of claim 1 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

19 . The composition of claim 1 , wherein said composition comprises a polymer or thickener selected from the group consisting of acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, methylcellulose, and combinations thereof.

20 . The composition of claim 19 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

21 . The composition of claim 1 , wherein said composition is a foam.

22 . The composition of claim 1 , wherein said composition is a cream.

23 . A pharmaceutical composition for topical administration comprising:

(i) roflumilast, wherein the roflumilast is in an amount of 0.05-1% (w/w);

(ii) a phosphate ester surfactant selected from the group consisting of potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3 phosphate, oleyl ethyl phosphate, oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10-phosphate, DEA-oleth-3 phosphate, DEA C8-18 perfluoroalkylethyl phosphate, dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl phosphate, tristearyl phosphate, or a combination thereof;

(iii) a solvent; and

(iv) water;

wherein said surfactant is in an amount sufficient to produce a stable emulsion, and

wherein said roflumilast composition has a roflumilast absorption profile that produces in a patient following administration a plasma concentration time curve with a peak to trough ratio less than 2 at steady state.

24 . The composition of claim 23 , wherein said solvent is selected from the group consisting of acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methyl pyrrolidinone, polyethylene glycol, glycerol, propylene glycol, specially denatured alcohol, or a combination thereof.

25 . The composition of claim 24 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

26 . The composition of claim 24 , wherein said composition comprises a polymer or thickener selected from the group consisting of acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, methylcellulose, and combinations thereof.

27 . The composition of claim 26 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

28 . The composition of claim 23 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

29 . The composition of claim 23 , wherein said composition comprises a polymer or thickener selected from the group consisting of acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, methylcellulose, and combinations thereof.

30 . The composition of claim 29 , wherein said composition comprises a moisturizer selected from the group consisting of 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, hydrocarbon gel 50W, stearyl alcohol, and combinations thereof.

Assignments (2)
SECURITY INTEREST Recorded Aug 9, 2024
From: ARCUTIS BIOTHERAPEUTICS, INC.
To: SLR INVESTMENT CORP.
Reel/Frame 068236/0418 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2024
From: OSBORNE, DAVID W.
To: ARCUTIS BIOTHERAPEUTICS, INC.
Reel/Frame 067957/0906 →
Continuity (6)
Continuation 18670960 · May 22, 2024
Continuation 18353870 · Jul 17, 2023
Continuation 17327236 · May 21, 2021
Continuation 16563435 · Sep 6, 2019
Provisional Application 62768314 · Nov 16, 2018
Related Publication 20250049771A1 · Feb 13, 2025
References Cited (212)
US 4482537A · El-Menshawy et al. · 1984 [cited by applicant]
US 5374661A · Betlach, II · 1994 [cited by applicant]
US 5712298A · Amschler · 1998 [cited by applicant]
US 5863560A · Osborne · 1999 [cited by applicant]
US 6056955A · Fischetti et al. · 2000 [cited by applicant]
US 6060085A · Osborne · 2000 [cited by applicant]
US 6106848A · Preuilh et al. · 2000 [cited by applicant]
US 6117915A · Pereira et al. · 2000 [cited by applicant]
US 6214322B1 · Castro et al. · 2001 [cited by applicant]
US 7470791B2 · Kohl et al. · 2008 [cited by applicant]
US 7951398B2 · Dietrich et al. · 2011 [cited by applicant]
US 8293288B2 · Ma · 2012 [cited by applicant]
US 8338648B2 · Stock et al. · 2012 [cited by applicant]
US 8536206B2 · Kohl et al. · 2013 [cited by applicant]
US 8618142B2 · Kohl et al. · 2013 [cited by applicant]
US 9205044B2 · Linder · 2015 [cited by applicant]
US 9649302B2 · Vakkalanka · 2017 [cited by applicant]
US 9884050B1 · Osborne · 2018 [cited by applicant]
US 9895359B1 · Osborne · 2018 [cited by applicant]
US 9907788B1 · Osborne · 2018 [cited by applicant]
US 10092588B2 · Tamarkin · 2018 [cited by applicant]
US 10105354B1 · Osborne · 2018 [cited by applicant]
US 10172841B2 · Osborne · 2019 [cited by applicant]
US 10940142B2 · Osborne · 2021 [cited by applicant]
US 10987290B2 · Wei · 2021 [cited by applicant]
US 11129818B2 · Osborne et al. · 2021 [cited by applicant]
US 11534493B2 · Osborne · 2022 [cited by applicant]
US 11707454B2 · Berk · 2023 [cited by applicant]
US 11793796B2 · Osborne · 2023 [cited by applicant]
US 11819496B2 · Osborne · 2023 [cited by applicant]
US 20050112162A1 · Drader · 2005 [cited by applicant]
US 20050244339A1 · Jauernig et al. · 2005 [cited by applicant]
US 20060084684A1 · Bolle · 2006 [cited by applicant]
US 20060153905A1 · Carrara · 2006 [cited by applicant]
US 20060204452A1 · Lathrop et al. · 2006 [cited by applicant]
US 20060204526A1 · Lathrop · 2006 [cited by applicant]
US 20060234006A1 · Terra · 2006 [cited by applicant]
US 20070048241A1 · Obukowho et al. · 2007 [cited by applicant]
US 20070207107A1 · Winckle et al. · 2007 [cited by applicant]
US 20070259009A1 · Linder · 2007 [cited by applicant]
US 20070287689A1 · Harada · 2007 [cited by applicant]
US 20080039405A1 · Langley · 2008 [cited by applicant]
US 20080045572A1 · Linder · 2008 [cited by applicant]
US 20080280958A1 · Bolle et al. · 2008 [cited by applicant]
US 20090104132A1 · Segura-Orsoni · 2009 [cited by applicant]
US 20090111780A1 · Giordano · 2009 [cited by applicant]
US 20090214628A1 · De Rijk · 2009 [cited by applicant]
US 20090215836A1 · Beume · 2009 [cited by applicant]
US 20090220583A1 · Pereswetoff-Morath et al. · 2009 [cited by applicant]
US 20110117182A1 · Ahluwalia et al. · 2011 [cited by applicant]
US 20110212157A1 · Edelson et al. · 2011 [cited by applicant]
US 20120252793A1 · Bream et al. · 2012 [cited by applicant]
US 20130005816A1 · Chen · 2013 [cited by applicant]
US 20130017282A1 · Ma · 2013 [cited by applicant]
US 20130018104A1 · Lathrop et al. · 2013 [cited by applicant]
US 20130217742A1 · Yang · 2013 [cited by applicant]
US 20140112991A1 · Johnson et al. · 2014 [cited by applicant]
US 20140275184A1 · Jones et al. · 2014 [cited by applicant]
US 20140275265A1 · Mattison · 2014 [cited by applicant]
US 20140296191A1 · Patel et al. · 2014 [cited by applicant]
US 20140303215A1 · Bolle et al. · 2014 [cited by applicant]
US 20150099752A9 · Bernal Anchuela et al. · 2015 [cited by applicant]
US 20150297601A1 · Henkin · 2015 [cited by applicant]
US 20160030435A1 · Henkin · 2016 [cited by applicant]
US 20170152273A1 · Merchant · 2017 [cited by applicant]
US 20170266289A1 · Kipari · 2017 [cited by applicant]
US 20180353490A1 · Osborne · 2018 [cited by applicant]
US 20190091333A1 · Osborne · 2019 [cited by applicant]
US 20190175491A1 · Abraham et al. · 2019 [cited by applicant]
US 20190365642A1 · Osborne · 2019 [cited by applicant]
US 20200155524A1 · Welgus et al. · 2020 [cited by applicant]
US 20210161870A1 · Welgus et al. · 2021 [cited by applicant]
US 20210275509A1 · Welgus et al. · 2021 [cited by applicant]
US 20210386719A1 · Osborne et al. · 2021 [cited by applicant]
US 20220211730A1 · Osborne et al. · 2022 [cited by applicant]
US 20230091358A1 · Osborne et al. · 2023 [cited by applicant]
US 20230201177A1 · Osborne · 2023 [cited by applicant]
US 20230285319A1 · Osborne et al. · 2023 [cited by applicant]
US 20230310345A1 · Osborne et al. · 2023 [cited by applicant]
CN 1655782 · 2005 [cited by applicant]
EP 1511516 · 2005 [cited by applicant]
JP 2005529930A · 2005 [cited by applicant]
JP 2007533606A · 2007 [cited by applicant]
JP 2011219364A · 2011 [cited by applicant]
WO 9501338 · 1995 [cited by applicant]
WO 9810768 · 1998 [cited by applicant]
WO 2003099334 · 2003 [cited by applicant]
WO WO2005016296A1 · 2005 [cited by applicant]
WO 2005115322 · 2005 [cited by applicant]
WO 2006073559A1 · 2006 [cited by applicant]
WO 2008009616A2 · 2008 [cited by applicant]
WO 2009069006A2 · 2009 [cited by applicant]
WO 2013030789 · 2013 [cited by applicant]
WO 2013081565 · 2013 [cited by applicant]
WO 2014055801 · 2014 [cited by applicant]
WO 2014130922 · 2014 [cited by applicant]
WO 2014201541 · 2014 [cited by applicant]
WO 2015132708 · 2015 [cited by applicant]
WO 2016033308 · 2016 [cited by applicant]
WO 2017216738 · 2017 [cited by applicant]
WO 2018226584 · 2018 [cited by applicant]
WO 2019060379 · 2019 [cited by applicant]
WO 2021045804 · 2021 [cited by applicant]
Akhtar et al., “Exploring preclinical and clinical effectiveness of nanoformulations in the treatment of atopic dermatitis: Safety aspects and patent reviews,” Bulletin of Faculty of Pharmacy, Cairo University 55 (2017)… [cited by applicant]
Bardin P et al. “Roflumilast for asthma: Efficacy findings in mechanism of action studies.” Pulmonary Pharmacology & Therapeutics, vol. 35, Aug. 19, 2015, S4-S10. [cited by applicant]
Brown, “Treating COPD with PDE 4 inhibitors”, International Journal of COPD 2007: 2(4) 517-533. [cited by applicant]
Examination Report cited in India Application No. 20194705011 dated Jul. 9, 2021. 6 pages. [cited by applicant]
Examination Report cited in India Application No. 202047016247 dated Jun. 28, 2021. 4 pages. [cited by applicant]
Final Office Action issued in U.S. Appl. No. 15/712,900 dated May 23, 2022. 14 pages. [cited by applicant]
Huang, J. et al., “Pharmacokinetics of single- and multiple-dose roflumilast: an open-label, three-way crossover study in healthy Chinese volunteers.” Drug Design, Development and Therapy, 2018(12). pp. 4047-4057. [cited by applicant]
International Search Report and Written Opinion cited in PCT/US2018/051691 dated Nov. 22, 2018, 11 pages. [cited by applicant]
International Preliminary Report on Patentability and Written Opinion cited PCT/US2018/051691 dated Mar. 24, 2020. 6 pages. [cited by applicant]
International Preliminary Report on Patentability and Written Opinion cited I PCT/US2018/051691 dated Apr. 2, 2020. 8 pages. [cited by applicant]
International Search Report issued in PCT/US2021/031144 dated Sep. 21, 2021. 12 pages. [cited by applicant]
Ip.com translation KR1999-0015251 A, printed 2022 (year2022), 1 page. [cited by applicant]
Julian N. Mayba et al. Review of Atopic Dermatitis and Topical Therapies:, Journal of Cutaneous Medicine and Surgery, BC Decker Inc. CA. vol. 21 No. 3 Dec. 27, 2016, pp. 227-236. [cited by applicant]
Karande et al., “Enhancement of transdermal drug delivery via synergistic action of chemicals”, Biochimica Et Biophysica Acta, 1788 (2009), pp. 2632-2373. [cited by applicant]
Kawamatawong, “Roles of roflumilast, a selective phosphodiesterase 4 inhibitor in airway diseases,” J. Thorac Dis 2017. 9(4). 1144-1154. [cited by applicant]
Kircik, L et al., “Rational Vehicle Design Ensures Targeted Cutaneous Steroid Delivery.” Journal of Clinical and Aesthetic Dermatology 10(2). Feb. 2017. pp. 12-19. [cited by applicant]
Lorimer, “Thermodynamics of solubility in mixed solvent systems”, Pure & Appl. Chem., 1993, vol. 65, 2, pp. 183-191. [cited by applicant]
Minghetti et al., “Ex Vivo Study of Transdermal Permeation of Four Diclofenac Salts from Different Vehicles”, Journal of Pharmaceutical Sciences, vo. 96, No. 4, Apr. 2007, pp. 814-823. [cited by applicant]
Nair et al., “Basic considerations in the dermatokinetics of topical formulations”, Brazilian Journal of Pharmaceutical Sciences, vol. 43, No. 3, Jul./Sep. 2013, pp. 423-434. [cited by applicant]
Notification of Transmittal of the International Search Report and The Written Opinion of the International Searching Authority cited in PCT/US2020/29008 dated Jul. 6, 2020. 13 pages. [cited by applicant]
Notification of Transmittal of the International Search Report and Written Opinion cited in PCT/US2019/034640 dated Dec. 4, 2019, 10 pages. [cited by applicant]
Notification of Transmittal of the International Search Report and The Written Opinion of the International Searching Authority cited in PCT/US2021/015740 dated Apr. 23, 2021. 17 pages. [cited by applicant]
Notification of Transmittal of the International Search Report and Written Opinion of the International Searching Authority issued in PCT/US2022/013344 dated Jun. 9, 2022, 16 pages. [cited by applicant]
Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority issued in PCT/US2021/061871, dated Apr. 5, 2022. 12 pages. [cited by applicant]
Notification of Transmittal of the International Search Report and Written Opinion cited in PCT/US2019/034640, dated Dec. 4, 2019, 14 pages. [cited by applicant]
Office Action issued in MX/a/2019/014741 dated Nov. 4, 2022 (7 pages). [cited by applicant]
Osborne, “Diethylene glycol monoethyl ether: an emerging solvent in topical dermatology products”, J. Cosmet Dermatol, Dec. 2011, 10(4), pp. 324-329. [cited by applicant]
Pathan et al., “Chemical Penetration Enhancers for Transdermal Drug Delivery Systems”, Tropical Journal of Pharmaceutical Research, Apr. 2009, 8(2), pp. 173-179. [cited by applicant]
Patzelt et al., “Hair follicles, their disorders and their opportunities”, Drug Discovery Today: Disease Mechanisms, vol. 5, Issue 2, Summer 2008, pp. e-173-e-181. [cited by applicant]
PCT International Search Report and Written Opinion issued in PCT/US2018/0358584 on Aug. 17, 2018, 12 pages. [cited by applicant]
Pudipeddi et al., “Trends in Solubility of Polymorphs”, Journal of Pharmaceutical Sciences, May 2005, vol. 94, Issue 5, pp. 929-939, Abstract only. [cited by applicant]
Shakeel et al. “Solubilization behavior of paracetamol in Transcutol—water mixtures at (298.15 to 333.15) K,” Journal of Chemical & Engineering Data 58:3551-3556, 2013. [cited by applicant]
Sikarra et al., “Techniques for Solubility Enhancement of Poorly Soluble Drugs: An Overview”, Journal of Medical Pharmaceutical and Allied Sciences, (2012), 01; pp. 1-22. [cited by applicant]
Snape et al., “A phase I randomized trial to assess the effect on skin infiltrate thickness and tolerability of topical phosphodiesterase inhibitors in the treatment of psoriasis vulgaris using a modified psoriasis plaq… [cited by applicant]
Special Chem “Ethoxydiglycol,” printed 2019; https://cosmetics.specialchem.com/inci/ethoxydiglycol. [cited by applicant]
Tradename (roflumilast) Tablets NDA 22-522, Summary of Basis for the Recommended Action from Chemistry, Manufacturing, and Controls, Forest Research Institute, Inc., Reference ID 2901509, Jul. 2009, 3 pages. [cited by applicant]
Translation Abstract. of Office Action for Chinese Patent Application No. 201810581282.7 dated Oct. 22, 2019; 13 pages. [cited by applicant]
Wikipedia “Corticosteroid,” last edited Nov. 15, 2019; https://en.wikipedia.org/wiki/Corticosteroid. [cited by applicant]
Wittmann et al. “Phosphodiesterase 4 Inhibition in the Treatment of Psoriasis, Psoratic Arthritis and Other Chronic Inflammatory Diseases”. Dermatol Ther(Heidelb) (2013) 3:1-15. [cited by applicant]
E P Bezuglaya et al., “Water-Hexylene Glycol System as A Potential Medicinal Base”, Pharmaceutical Chemistry, vol. 47, pp. 281-286. 2013. [cited by applicant]
Pre-grant Opposition documents filed for Indian Application No. 201947050111, Apr. 5, 2023, 38 pages. [cited by applicant]
T. Gao, et al., “Sunscreen Formulas with Multilayer Lamella Structure,” Cosmetics & Toiletries, vol. 118, pp. 41-52 (Oct. 2003). [cited by applicant]
D.Y.M. Leung, et al., “New Insights into Atopic Dermatitis,” J. Clin. Invest., vol. 113, pp. 651-657 (2004). [cited by applicant]
L. Kircik, “Topical Treatment Adherence for Psoriasis,” Skin Therapy Letter—Family Practice Edition, vol. 4, No. 2, pp. 4 & 5 (2008). [cited by applicant]
S.R. Feldman, et al., “Psoriasis: Improving Adherence to Topical Therapy,” J. Am. Acad. Dermatol., vol. 59, pp. 1009-1016 (2008). [cited by applicant]
S.M. Ali, et al., “Skin pH: From Basic Science to Basic Skin Care,” Acta Derm. Venereal., vol. 93, pp. 261-267 (1-9), Tb1. SI (2013). [cited by applicant]
Study NCT01856764, “Topical Roflumilast in Adults with Atopic Dermatitis,” sponsored by Takeda, available at https://clinicaltrials.gov/ (Jul. 2015). [cited by applicant]
Y. Javadzadeh, et al., “Transcutol® (Diethylene Glycol Monoethyl Ether): A Potential Penetration Enhancer,” Ch. 12, pp. 195-205, in N. Dragicevic, et al., eds., Percutaneous Penetration Enhancers Chemical Methods in Pen… [cited by applicant]
D.W. Osborne, et al., “Skin Penetration and Permeation Properties of Transcutol®—Neat or Diluted Mixtures,” AAPS PharmSciTech, vol. 19, pp. 3512-3533 (2018). [cited by applicant]
FDA, Inactive Ingredient Guide (Jan. 1996). [cited by applicant]
M.J. O'Neil, et al., eds., The Merck Index, pp. 2822, 8379 (15th ed., 2013). [cited by applicant]
Labeling for ELOCON® (mometasone furoate) Cream (2013). [cited by applicant]
Labeling for DALIRESP® (roflumilast) Tablets (2013). [cited by applicant]
Physicians' Desk Reference, pp. 305, 748-52, 1432-35 (67th/2013 ed., 2012). [cited by applicant]
I.M. Rosenstock, “Understanding and Enhancing Patient Compliance with Diabetic Regimens,” Diabetes Care, vol. 8, pp. 610-616 (1985). [cited by applicant]
J. Urquhart, “The Electronic Medication Event Monitor: Lessons for Pharmacotherapy,” Clin. Pharmacokinet., vol. 32, pp. 345-356 (1997). [cited by applicant]
S.S. Zaghloul, et al., “Objective Assessment of Compliance with Psoriasis Treatment,” Arch. Dermatol., vol. 140, pp. 408-414 (2004). [cited by applicant]
P. Assawasuwannakit, et al., “Quantification of the Forgiveness of Drugs to Imperfect Adherence,” CPT Pharmacometrics Syst. Pharmacol., vol. 4, e4, pp. 1-8 (2015). [cited by applicant]
Office Action issued in U.S. Appl. No. 18/453,674 dated Oct. 27, 2023 (13 pages). [cited by applicant]
Office Action issued in U.S. Appl. No. 17/155,679 dated Feb. 5, 2024 (9 pages). [cited by applicant]
Office Action issued in U.S. Appl. No. 18/345,692 dated Oct. 26, 2023 (68 pages). [cited by applicant]
Office Action issued in U.S. Appl. No. 18/345,732 dated Jan. 24, 2024 (12 pages). [cited by applicant]
Office Action issued in U.S. Appl. No. 18/345,760 dated Oct. 26, 2023 (19 pages). [cited by applicant]
Office Action issued in U.S. Appl. No. 18/353,870 dated Jan. 12, 2024 (10 pages). [cited by applicant]
Office Action issued in U.S. Appl. No. 18/353,869 dated Sep. 18, 2023 (7 pages). [cited by applicant]
Notification of Certification of Invalidity, Unenforceability, and/or Noninfringement for U.S. Pat. No. 9,884,050; U.S. Pat. No. 9,907,788; U.S. Pat. No. 10,940,142; U.S. Pat. No. 11,129,818; U.S. Pat. No. 11,793,796; a… [cited by applicant]
Notice of Panel Decision from Pre-Appeal Brief Review issued in U.S. Appl. No. 18/057,777 dated May 31, 2024 (2 pages). [cited by applicant]
Office Action issued for U.S. Appl. No. 17/821,051 on Jan. 29, 2025, 13 pages. [cited by applicant]
Office Action issued for U.S. Appl. No. 18/345,760 on Dec. 19, 2024, 43 pages. [cited by applicant]
Office Action issued for U.S. Appl. No. 17/887,798 on Dec. 19, 2024, 91 pages. [cited by applicant]
Office Action issued for U.S. Appl. No. 18/670,960 on Feb. 24, 2025, 11 pages. [cited by applicant]
Notification of Certification of Invalidity, Unenforceability, and/or Non-Infringement for U.S. Pat. No. 11,992,480; U.S. Pat. No. 12,005,051; U.S. Pat. No. 12,005,052; U.S. Pat. No. 12,011,437; And U.S. Pat. No. 12,016… [cited by applicant]
Bethke et al. (2007) “Dose-Proportional Intraindividual Single and Repeated-Dose Pharmacokinetics of Roflumilast, an Oral, Once-Daily Phosphodiesterase 4 Inhibitor” [cited by applicant]
Heo et al. (2010) “Topical effects of roflumilast on 1-chloro-2,4-dinitrobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice” [cited by applicant]
Jin et al. (2012) “Phosphodiesterase 4 and Its Inhibitors in Inflammatory Diseases” [cited by applicant]
Pleasants (2018) “Clinical Pharmacology of Oral Maintenance Therapies for Obstructive Lung Diseases” [cited by applicant]
Rabe (2011) “Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease” [cited by applicant]
Notification of Certification of Invalidity, Unenforceability, and/or Non-Infringement for U.S. Pat. No. 12,042,487 Pursuant to § 505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act, Sep. 12, 2024, 107 pages. [cited by applicant]
Communication of a Notice of Opposition Against European Patent No. 3 634 380, Sep. 26, 2024, 22 pages. [cited by applicant]
Felton “Remington: Essentials of Pharmaceutics” London: Pharmaceutical Press (2012), 54 pages. [cited by applicant]
“Hexylene Glycol GPS Safety Summary,” Arkema, Apr. 30, 2012, 5 pages. [cited by applicant]
Article 94(3) communication in EP 20861685.4 issued Oct. 8, 2024, 5 pages. [cited by applicant]
Communication of a Notice of Opposition Against European Patent No. 3 684 334, Aug. 20, 2024, 26 pages. [cited by applicant]
Gattefosse (2015) “Efficient Skin Delivery: No Compromise With Transcutol®” https://api.semanticscholar.org/CorpusID:203610770, 17 pages. [cited by applicant]
Fenton (2012) “Handbook of Pharmaceutical Excipients” [cited by applicant]
Osborne (2008) “Review of Changes in Topical Drug Product Classification” [cited by applicant]
Aulton (2013) “Aulton's Pharmaceutics” Elsevier Ltd (4th Ed.), 20 pages. [cited by applicant]
Office Action issued Jun. 26, 2024 in CN 202080075942.X, 15 pages. [cited by applicant]
Non-Final Office Action issued for U.S. Appl. No. 18/345,760 on May 8, 2025, 23 pages. [cited by applicant]
Gattefossé Pharmaceuticals, “Pharmaceuticals for oral, topical, rectal and vaginal delivery”, Mar. 2017, (34 pages). [cited by applicant]
Gattefossé Pharmaceuticals, “Selecting the best excipients”, Jan. 2025, pp. 1-16. [cited by applicant]
Declaration of Prof. Narasimha Murthy, Ph.D. Oct. 1, 2025, pp. 1-3 (25 pages). [cited by applicant]
Murgia et al. (2013) “Characterization of the Solutol® HS15/water phase diagram and the impact of the D9-tetrahydrocannabinol solubilization” Journal of Colloid and Interface Science 390:129-36. [cited by applicant]
Liu et al. (2016) “Kolliphor® HS 15 Micelles for the Delivery of Coenzyme Q10: Preparation, Characterization, and Stability” AAPS PharmSciTech 17(3):757-66. [cited by applicant]
Franzé et al. (2019) “Drug-in-micelles-liposomes (DiMiL) systems as a novel approach to prevent drug leakage from deformable liposomes” European Journal of Pharmaceutical Sciences 130:27-35. [cited by applicant]
Scientific Committee on Consumer Safety (SCCS), “Opinion On Diethylene Glycol Monoethyl Ether (Degee)”, European Union, Feb. 26, 2013, pp. 1-53. [cited by applicant]
Reply in Response to the New Summons to attend oral proceedings pursuant to Rule 115(1) EPC dated May 16, 2025 against European Patent No. 3 684 334, Oct. 2, 2025, pp. 1-19. [cited by applicant]
Opponent's reply to patentee's observations, European Patent No. 3 684 334, Feb. 14, 2025, (13 pages). [cited by applicant]
Summons to attend oral proceedings pursuant to Rule 115(1) EPC, European Patent No. 3 684 334, Apr. 23, 2025, pp. 1-27 (32 pages). [cited by applicant]
Summons to attend oral proceedings pursuant to Rule 115(1) EPC, European Patent No. 3 684 334, May 16, 2025 (32 pages). [cited by applicant]
Oct. 2, 2025 Brief Communication in European Patent No. 3 684 334 regarding Opponent's further submissions (Rule 116 EPC) dated Sep. 25, 2025 (8 pages). [cited by applicant]
Opponent's reply to patentee's further submissions, European Patent No. 3 684 334, Nov. 24, 2025 (12 pages). [cited by applicant]
Reply in Response to the Opponent's letter dated Nov. 24, 2025 against European Patent No. 3 684 334, Nov. 28, 2025 (29 pages). [cited by applicant]
Reply to Letter from the Opponent dated Feb. 14, 2025 against European Patent No. 3 684 334, Apr. 16, 2025 (12 pages). [cited by applicant]
Oct. 2, 2025 Reply in Response to the New Summons to attend oral proceedings pursuant to Rule 115(1) EPC dated May 16, 2025, European Patent No. 3 684 334 (19 pages). [cited by applicant]
Chang et al. (2013) “Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products”, The AAPS Journal, vol. 15(1):41-52. [cited by applicant]
Non-Final Office Action issued for U.S. Appl. No. 18/345,760 on Dec. 10, 2025 (25 pages). [cited by applicant]
Kouchak et al. (2014) “Effects of Various Penetration Enhancers on Penetration of Aminophylline Through Shed Snake Skin,” Jundishapur J Nat Pharm Prod. 9(1):24-29. [cited by applicant]
Office Action for corresponding Canadian Patent Application No. 3,150,222, mailed May 5, 2026, 4 pages. [cited by applicant]