DETAILED ACTION
This office action is in response to applicant’s filing dated March 16, 2026.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 16, 2026 has been entered.
Status of Claims
Claims 18-27 and 31-36 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed August 19, 2025. Acknowledgement is made of Applicant's amendment of claims 18-24, 32, 33, and 35; cancelation of claims 28 and 29; and addition of new claim 36. Claims 1-17 and 30 were previously canceled.
Applicants elected without traverse Group I, drawn to a pharmaceutical composition suitable for topical administration, comprising apremilast, or a pharmaceutically acceptable salt thereof, wherein said apremilast is present in the range of 0.01% to 20% by weight as the elected invention and a formulation species comprising
Permeation enhancers: isopropyl myristate, dimethyl sulfoxide, diethylene glycol monoethyl ether and polyethylene glycol, or combinations thereof;
Emulsifiers: sodium lauryl sulphates, polyoxylglycerides and polyols, or combinations thereof;
Solvents / Carriers: polysorbates, oils, fatty esters and triglycerides, or combinations thereof; and
corticosteroid
in the reply filed on July 6, 2020 and November 23, 2020. The requirement is still deemed proper. Claim 35 remains withdrawn.
The Examiner notes that the election contains the phrase “or combinations thereof.” This has been construed as the election containing alternative embodiments. The Examiner notes that the instant election does not appear to be fully responsive to the election requirement set forth on May 5, 2020. However, in the interest of compact prosecution, and for the purposes of applying art, by broadest reasonable interpretation in view of the alternative language, the election has been construed as the presence of any one of the cited permeation enhancers, emulsifiers, and solvents/carriers reads on the elected formulation.
Claims 18-29 and 31-34 are presently under examination as they relate to the elected species:
Permeation enhancers: isopropyl myristate, dimethyl sulfoxide, diethylene glycol monoethyl ether and polyethylene glycol, or combinations thereof;
Emulsifiers: sodium lauryl sulphates, polyoxylglycerides and polyols, or combinations thereof;
Solvents / Carriers: polysorbates, oils, fatty esters and triglycerides, or combinations thereof; and
Corticosteroid.
Priority
The present application is a 371 of PCT/IN2018/050038 filed on January 24, 2018, which claims benefit of foreign priority to INDIA 20171003041 filed on January 27, 2017. The effective filing date of the instant application is January 27, 2017.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
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 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 18-27, 31, 32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Zeldis et al (US 2007/0155791 A1, cited in a previous Office Action) in view of Sloth Weidner (WO 2015/062611 A1) and Chang et al (The AAPS Journal, 2012; 15(1):41-52, cited in a previous Office Action).
Regarding claims 18, 20, 23, 24, 27, 31, 32, and 34, Zeldis teaches Compound 1 is (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione ([0056] and claim 1):
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wherein the compound is administered topically in a dosage form of ointment, cream, gel, paste, dusting powder, lotion, spray, liniment, poultice, aerosol, solution, emulsion or suspension (claim 21). Zeldis further teaches a paste for topical use can be prepared comprising:
10 g active ingredient
2.0 g carboxylmethyl cellulose
25.0 glycerin
2.8 g cetanol
9.3 g glyceryl monostearate
2.0 g Tween 80
1.0 g glucuronic acid
20.0 g 0.4 mol/L citrate buffer
to 100 g distilled water ([0170], Example 12).
Glycerin is equivalent to glycerol. Thus, glycerin reads on an emollient as evidenced by instant claim 18. The composition of Zeldis further comprises glyceryl monostearate (instant claim 20). Glyceryl monostearate is equivalent to glyceryl stearate. Tween 80 reads on a nonionic emulsifying agent.
Zeldis teaches additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention; penetration enhancers can be used to assist in delivering the active ingredients to the tissue; suitable penetration enhancers include dimethyl sulfoxide [0144]. Moreover, Zeldis teaches suitable excipients (e.g., carriers and diluents) can be used to provide transdermal and topical dosage forms and include water to form lotions, tinctures, creams, emulsions, gels or ointments [0139].
Zeldis does not explicitly teach topical compositions comprise cetostearyl alcohol and/or a preservative or that the preservative is those listed in instant claims 18 or 23.
However, the composition taught by Zeldis comprises cetanol. Moreover, Zeldis does teach the use of preservatives in formulating the disclosed compositions [0119].
Moreover, Sloth Weidner teaches a composition comprising a mixture of comprising a) Water; b) An emollient; c) A water soluble emulsifier; d) A anionic water soluble emulsifier; and e) A lipid soluble emulsifier (claim 34); wherein the composition is for topical use (claim 37); wherein the composition further comprises an active pharmaceutical ingredient (claim 38), wherein said pharmaceutical ingredient includes apremilast (claim 40). Sloth Weidner teaches according to an embodiment, the invention concerns the composition, comprising:
a) 15% - 65% water;
b) 10% - 60% of a branched or unbranched alkane of C12-C40;
c) 5% - 20% of at least one branched or unbranched alkanol of C14-C30;
d) 0.5% - 2% of at least one unbranched alkylsulfate of C12-C20 or a salt thereof;
e) 0.2% - 2.0% of glyceryl monocaprylate; and optionally
f) an antimicrobial preservative. (page 6, lines 3-9);
wherein said at least one branched or unbranched alkanol of C14-C30 is cetostearyl alcohol; suitable water soluble emulsifiers may comprise, but are not limited to, cetyl alcohol, stearyl alcohol, myristyl alcohol, and mixtures of aforementioned (page 6, lines 22-25); further comprising a humectant, preferably glycerol and/or propylene glycol (page 6, lines 26-27). Thus, Sloth Weidner establishes that cetostearyl alcohol and cetyl alcohol, also known as cetanol, can be alternatively used as a water soluble emulsifier in topical compositions comprising apremilast. Sloth Weidner further teaches the use of an antimicrobial preservative in such compositions.
Moreover, Chang teaches most topical preparations, especially those with emulsion formulations have a potential for contamination by various bacteria; hence, antimicrobial preservatives are used to inhibit the growth of bacteria, fungi, and mold; a combination of methylparaben and propylparaben is the most commonly used preservative at levels typically ranging from 0.01% to 0.3% (page 45, left, 3rd paragraph).
It would have been prima facie obvious before the effective filing date of the invention to substitute cetostearyl alcohol for cetanol or combine cetostearyl and cetanol for use in the composition taught by Zeldis with a reasonable expectation of success, since the prior art teaches that cetanol and cetostearyl alcohol are useful as emulsifiers in topical compositions comprising an active ingredient including apremilast. Moreover, it would have been to include a preservative in the topical composition taught by Zeldis and to utilize a combination of methylparaben and propylparaben as the preservative as taught by Chang with a reasonable expectation of success, since the prior art teaches most topical emulsion compositions have potential for contamination and a combination of methylparaben and propylparaben is the most commonly used preservative at levels.
A composition comprising 10g active ingredient, Compound 1 in a composition total weight 100g would comprise 10% Compound 1/apremilast. A composition comprising 25.0 g glycerin in a composition total weight 100g would comprise 25% emollient. A composition comprising 2.0 g tween 80 in a composition total weight 100g would comprise 2% emulsifier. A composition comprising 2.8 g cetostearyl alcohol and/or cetanol/cetyl alcohol in a composition total weight 100g would comprise 2.8% carrier.
Regarding the amounts of emollient, emulsifier, and pharmaceutically acceptable carrier, MPEP 2144.05 states: 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). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). In the instant case, Zeldis teaches a topical composition comprising 10% w/w apremilast, which is slightly greater than the instantly claimed range. However, the amounts disclosed by Zeldis are sufficiently close that prima facie one skilled in the art would have expected them to have the same properties.
Moreover, Zeldis teaches various dosage forms of the invention are discussed in section 5.5; typical dosage forms of the invention comprise (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione (apremilast), in an amount from about 0.10 to about 1000 mg, from about 0.10 to about 800 mg, from about 0.10 to about 600 mg, from about 0.10 to about 500 mg, from about 0.10 to about 400 mg, from about 0.10 to about 300 mg, from about 0.10 to about 200 mg, or from about 0.10 to about 100 mg. In one embodiment, typical dosage forms comprise the compound in an amount of about 1, 2, 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg [0106]. It would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of apremilast taught by Zeldis as a starting point for optimizing the amount of apremilast utilized to formulate a topical composition comprising apremilast.
Regarding the amount of dimethylsulfoxide of instant claim 18, Zeldis teaches Tween 80 and dimethyl sulfoxide are alternatively useful as penetration enhancers in the claimed compositions. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to utilize the amount of Tween 80 taught by Zeldis (2% as a starting point for optimizing the amount of dimethylsulfoxide utilized as a permeation enhancer to formulate a topical composition comprising apremilast and a permeation enhancer.
Regarding the amount of methylparaben and propylparaben of instant claim 18, Chang teaches a combination of methylparaben and propylparaben is the most commonly used preservative at levels typically ranging from 0.01% to 0.3% (page 45, left, 2nd paragraph). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to utilize the amount of a combination of methylparaben and propylparaben taught by Chang as a starting point for optimizing the amount of methylparaben and propylparaben utilized as a preservative to formulate a topical composition comprising apremilast and a preservative.
Moreover, dosage amount is a result-effective variable, i.e., a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding claim 21, Zeldis teaches compounds such as metal stearates (e.g., calcium stearate, zinc stearate, magnesium stearate, sodium stearate, lithium stearate, potassium stearate, etc.) can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery; in this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant and as a delivery-enhancing or penetration-enhancing agent [0145]. Sodium stearate and potassium stearate read on wherein the emulsifier is anionic as evidenced by the instant specification which teaches emulsifying agents include soaps (e.g., alkali metal salts and sodium or potassium salts) of fatty acids (see paragraph [0035].
Regarding claim 22, glucuronic acid reads on an organic acid.
Regarding claim 25, Zeldis teaches humectants can also be added to pharmaceutical compositions and dosage forms [0139].
Regarding claim 26, the methods further comprise the administration of a therapeutically effective amount of at least a second active agent which may be an anti-inflammatory such as corticosteroids (e.g., dexamethasone) [0020].
Regarding claim 27, Zeldis teaches transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, sprays, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art [0138].
Taken together, all this would result in the composition of claims 18, 20-27, 31, and 32 with a reasonable expectation of success.
Regarding claim 19, Zeldis does not explicitly teach the emollient comprises a mixture of coconut oil and glycerol. However, as set forth above, Zeldis does teach topical compositions comprising apremilast and glycerol. Zeldis further teaches the use of emollients in topical dosage forms ([0139] and [0142]). Moreover, Sloth Weidner teaches a composition comprising a mixture of comprising a) Water; b) An emollient; c) A water soluble emulsifier; d) A anionic water soluble emulsifier; and e) A lipid soluble emulsifier (claim 34); wherein the composition is for topical use (claim 37); wherein the composition further comprises an active pharmaceutical ingredient (claim 38), wherein said pharmaceutical ingredient includes apremilast (claim 40). Sloth Weidner teaches according to an embodiment, the invention concerns the composition, comprising:
a) 15% - 65% water;
b) 10% - 60% of a branched or unbranched alkane of C12-C40;
c) 5% - 20% of at least one branched or unbranched alkanol of C14-C30;
d) 0.5% - 2% of at least one unbranched alkylsulfate of C12-C20 or a salt thereof;
e) 0.2% - 2.0% of glyceryl monocaprylate; and optionally
f) an antimicrobial preservative. (page 6, lines 3-9);
wherein said branched C12-C40 include coconut oil (page 6, lines 16-18), wherein said at least one branched or unbranched alkanol of C14-C30 is cetostearyl alcohol; suitable water soluble emulsifiers may comprise, but are not limited to, cetyl alcohol, stearyl alcohol, myristyl alcohol, and mixtures of aforementioned (page 6, lines 22-25); further comprising a humectant, preferably glycerol and/or propylene glycol (page 6, lines 26-27). Thus, Sloth Weidner establishes that coconut oil can be used as an emollient in topical compositions comprising apremilast.
It would have been prima facie obvious before the effective filing date of the invention to utilize modify the composition taught by Zeldis to further comprise coconut oil as an emollient as taught by Sloth Weidner with a reasonable expectation of success, since the prior art teaches that coconut oil is useful as an emollient in topical compositions comprising an active ingredient including apremilast, cetostearyl alcohol and/or cetyl alcohol, glycerol, a preservative and water.
Taken together, all this would result in the composition of claim 19 with a reasonable expectation of success.
Regarding claim 34, Zeldis teaches suitable excipients (e.g., carriers and diluents) that can be used to provide transdermal or topical dosage forms are well known to those skilled in the pharmaceutical arts; typical excipients include water, ethanol, propylene glycol, isopropyl myristate and mixtures thereof [0139]. Zeldis teaches penetration enhancers can be used to assist in delivering the active ingredients to the tissue; suitable penetration enhancers include; polyethylene glycol and Tween 80 (polysorbate 80) [0144]. Thus, Zeldis teaches the use of water, ethanol, propylene glycol, isopropyl myristate, and polyethylene glycol and mixtures thereof as carriers. Moreover, Zeldis teaches ethanol; polyethylene glycol; Tween 80 (polysorbate 80) are useful as penetration enhancers. It would have been prima facie obvious to one of ordinary skill in the art to modify the topical composition comprising carboxylmethyl cellulose, glycerin, cetanol, glyceryl monostearate, Tween 80, glucuronic acid, citrate buffer, and water to comprise ethanol, propylene glycol, isopropyl myristate, and polyethylene glycol since Zeldis teaches these and mixtures thereof are suitable carriers. It would have been prima facie obvious to utilize the amount of the carrier, water and glycerin, taught by Zeldis as a starting point for optimizing the amounts of ethanol, propylene glycol, isopropyl myristate, and polyethylene glycol utilized as a carrier with a reasonable expectation of success, since Zeldis teaches these as alternatively useful and useful in combination as a carrier for a topical composition comprising apremilast. Similarly, it would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of Tween 80 (polysorbate 80) as a starting point to optimize the amount of ethanol and polyethylene glycol, since Zeldis teaches these as alternatively useful as a penetration enhancer for a topical composition comprising apremilast
Taken together, all this would result in the composition of claim 34 with a reasonable expectation of success.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Zeldis et al (US 2007/0155791 A1, cited in a previous Office Action) in view of Sloth Weidner (WO 2015/062611 A1) and Chang et al (The AAPS Journal, 2012; 15(1):41-52, cited in a previous Office Action) as applied to claims 18-27, 31, 32, and 34 above, and further in view of De Villiers (Surfactants and emulsifying agents. A Practical Guide to Contemporary Pharmacy Practice; Thompson, JE, Ed.; Lippincott Williams and Wilkins, 2009, pages 251-256, cited in a previous Office Action).
Regarding claim 33, Zeldis teaches all the limitations of claim 33 (see above 103), except wherein the emulsifier is sodium lauryl sulfate. However, Zeldis does teach that sodium lauryl sulfate is a suitable excipient for apremilast ([0127] and [0163]). Moreover, Zeldis teaches suitable excipients for topical dosage forms include moisturizers such as emollients [0139] and emollients when combined with an emulsifier, they may help hold oil and water in the stratum corneum [0142].
Moreover, De Villiers teaches surfactants can function as emulsifying agents (page 251, Definitions A. 2.); the emulsifier must produce a stable film at the interface; some surface-active agents are capable of producing emulsions, but the emulsions separate on standing or storage because the surfactant is incapable of producing stable, strong barriers to prevent the coalescence of the dispersed droplets; agents such as these may be useful if combined with a second substance that acts as a stabilizer; the surfactant is then referred to as the primary emulsifying agent and the stabilizer as the secondary or auxiliary emulsifier; an example of such a system is the use of the primary emulsifier sodium lauryl sulfate with the auxiliary emulsifier stearyl alcohol in Hydrophilic Ointment USP (page 252, B). De Villiers establishes that it was known in the art to utilize sodium lauryl sulfate as an emulsifier in topical formulations.
It would have been prima facie obvious before the effective filing date of the invention to utilize sodium lauryl sulfate as the emulsifier in the topical composition comprising apremilast taught by Zeldis with a reasonable expectation of success, since the prior art teaches sodium lauryl sulfate is a suitable excipient for apremilast and it was known in the art to utilize sodium lauryl sulfate as an emulsifier in topical formulations.
Taken together, all this would result in the composition of claim 33 with a reasonable expectation of success.
New Objections and/or Rejections
Necessitated by Claim Amendment
Claim Rejections - 35 USC § 103
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Zeldis et al (US 2007/0155791 A1, cited in a previous Office Action) in view of Sloth Weidner (WO 2015/062611 A1) and Chang et al (The AAPS Journal, 2012; 15(1):41-52, cited in a previous Office Action) as applied to claims 18-27, 31, 32, and 34 above, and further in view of Om et al (Inventi Rapid Pharm Tech, 2016; 1:1-8).
As set forth above, Zeldis, Sloth Weidner, and Chang suggest a topical composition comprising Apremilast, coconut oil, glycerol, cetostearyl alcohol, a nonionic emulsifying agent (Tween 80), dimethylsulfoxide, methyl paraben, propyl paraben, and water. Moreover, Zeldis teaches the pharmaceutical compositions comprise one or more compounds that reduce the rate by which an active ingredient will decompose including pH buffers [0116]. Sloth Weidner teaches additives to the topical compositions include buffering agents and pH-adjusting agents (page 12, lines 14-15). Chang teaches acidifying/alkalizing/buffering agent to maintain a proper pH for the dosage form (Table II). Thus, Zeldis, Sloth Weidner, and Chang suggest a topical composition comprising Apremilast, coconut oil, glycerol, cetostearyl alcohol, a nonionic emulsifying agent (Tween 80), dimethylsulfoxide, methyl paraben, propyl paraben, water, and a pH-adjusting agent. As set forth above, the cited art renders the claimed amount of Apremilast, glycerol, cetostearyl alcohol, a nonionic emulsifying agent (Tween 80), dimethylsulfoxide, methyl paraben, propyl paraben. It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the invention to utilize the amounts of glycerol and emollient taught by the cited art as a starting point for optimizing the amount of glycerol and coconut oil utilized to formulate a composition comprising Apremilast, coconut oil, glycerol, cetostearyl alcohol, a nonionic emulsifying agent (Tween 80), dimethylsulfoxide, methyl paraben, propyl paraben, water and a pH-adjusting agent.
The cited art does not teach the composition comprises a carrier comprising carbomer.
However, Om teaches carbomers are polymerized form of acrylic acid monomers, widely used in pharmaceutical industry, used as gelling agents or viscosity modifier in semisolid dosage form or liquid dosage forms (abstract). Om teaches carbomers are used in liquid or semisolid pharmaceutical formulations as rheology modifiers; formulations include creams, gels, lotions and ointments for use in topical preparations; carbomers the most widely used excipient for thickening lotions creams and gels; carbomers polymers have enabled the formulation of topical pharmaceutical products for fifty years and are widely used on a global basis (page 3, right, 2nd-3rd paragraph). Moreover, Om teaches Benefits of Carbomers Topical Formulations include:
Long history of safe and effective use in semi-solid formulations.
Demonstrated to have low irritancy and non-sensitizing properties with repeated usage.
Compatibility with most acidic, basic and neutral drugs.
Applications across a broad pH range (4.5 - 10.0)
Excellent thickening and suspending agents in aqueous, anhydrous and hydroalcoholic systems. (Typical use levels in aqueous systems: 0.1 - 1.0% wt.)
Consistent and reproducible properties due to their synthetic nature.
Do not support microbial growth.
Chemically stable and maintain formulation stability.
Excellent dispersions can be formed without alternate heating and cooling cycles.
No heat sensitivity compared to other thickening agents.
Formulations can be sterilized by autoclaving or gamma radiation.
Provide a non-greasy formulation, with no irritation.
Function as primary emulsifiers (Pemulen™ polymers) or emulsification stabilizers (Carbopol® polymers).
Possess shear thinning properties to facilitate extrusion from product packaging.
Can increase bioavailability of the active pharmaceutical ingredient due to their bioadhesive properties.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate the composition comprising Apremilast, coconut oil, glycerol, cetostearyl alcohol, a nonionic emulsifying agent (Tween 80), dimethylsulfoxide, methyl paraben, propyl paraben, water and a pH-adjusting agent suggested by the cited art to further comprise carbomer in view of the teachings of Om. The skilled artisan would have been motived to include carbomer since it is known to the be most widely used excipient for thickening lotions creams and gels and has excellent benefits including low irritancy properties with repeated use, consistent and reproducible properties, do not support microbial growth, chemically stable and maintain formulation stability and increase the bioavailability of the active ingredient due to their bioadhesive properties. Moreover, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to utilize the typical use amounts taught by Om (0.1 – 1.0 % wt) and the amount of cetostearyl alcohol taught by Zeldis and Sloth Weidner as a starting point for optimizing the amounts of cetostearyl alcohol and carbomer utilized in a composition comprising Apremilast, coconut oil, glycerol, cetostearyl alcohol, carbomer, a nonionic emulsifying agent (Tween 80), dimethylsulfoxide, methyl paraben, propyl paraben, water and a pH-adjusting agent.
Taken together, all this would result in the composition of claims 36 with a reasonable expectation of success.
Response to Arguments
Applicant argues:
Zeldis fails to teach or suggest a topical pharmaceutical composition comprising the specific components and amounts as presently claimed. The Office Action does not identify any disclosure in Zeldis, Weidner, or Chang that teaches or suggests the specific ranges in combination within a single topical composition.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicants are reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As set forth above, Zeldis teaches a paste for topical use can be prepared comprising:
10% active ingredient, including apremilast; 25.% glycerin/glycerol; 2.8% cetanol/cetyl alcohol; and 2% nonionic emulsifying agent, Tween 80, and one embodiment, typical dosage forms comprise the compound (apremilast) in an amount of about 1, 2, 5, and 10 mg. As set forth above, Sloth Weidner teaches according to an embodiment, the invention concerns the composition, comprising: a) 15% - 65% water; b) 10% - 60% of a branched or unbranched alkane of C12-C40, including coconut oil; c) 5% - 20% of at least one branched or unbranched alkanol of C14-C30, including cetostearyl alcohol and cetyl alcohol and mixtures thereof; e) 0.2% - 2.0% of glyceryl monocaprylate; and f) an antimicrobial preservative. As set forth above, Chang teaches a combination of methylparaben and propylparaben is the most commonly used preservative at levels typically ranging from 0.01% to 0.3%. As set forth above, Om teaches carbomers are commonly used in pharmaceutical compositions including topical, and typical amounts are 0.1 - 1.0% wt. As set forth above, it would have been prima facie obvious to one of ordinary skill in the art to utilize the amounts of apremilast and formulation components taught by the cited art as a starting point for optimizing the amounts utilized to formulate a composition comprising Apremilast, coconut oil, glycerol, cetostearyl alcohol, carbomer, a nonionic emulsifying agent (Tween 80), dimethylsulfoxide, methyl paraben, propyl paraben, water and a pH-adjusting agent with a reasonable expectation of success since the prior art teaches the use of these agents to formulate topical formulations comprising apremilast. Moreover, dosage amount is a result-effective variable, i.e., a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Applicant argues:
Topical pharmaceutical formulation is a highly unpredictable field in which small changes in excipients and excipient concentration can affect drug solubility, stability, and skin penetration. The rationale presented in the Office Action appears to rely on knowledge of Applicant's disclosure to reconstruct the claimed invention from the cited references. Specifically, the rejection proceeds by selecting a paste formulation example from Zeldis, modifying the emulsifier system based on Weidner, and importing preservative teachings from Chang. The cited references themselves do not suggest this sequence of modifications, nor do they provide guidance that would lead a person of ordinary skill in the art to construct the claimed composition.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 2145. X. A. states, "Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Applicants may also argue that the combination of two or more references is “hindsight” because “express” motivation to combine the references is lacking. However, there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). See MPEP § 2141 and § 2143 for guidance regarding establishment of a prima facie case of obviousness.” In the instant case, the obviousness rejection is based on the combined teachings of Zeldis, Sloth Weidner, and Chang. The Examiner acknowledges that Zeldis teaches the cited topical composition, which was cited to establish that topical formulations comprising apremilast were known in the art. Zeldis further teaches utilizing preservatives for compositions comprising apremilast. Sloth Weidner further establishes topical compositions comprising apremilast and that preservatives are optionally included. Moreover, Chang establishes that methyl paraben and propyl paraben are commonly utilized preservatives utilized in topical compositions. Moreover, Zeldis clearly teaches topical dosage forms include emulsions [0138]; and emollients combined with an emulsifier help hold oil and water in the stratum corneum in topical formulations [0142]. Thus, Zeldis clearly contemplates inclusion of emulsifiers in the disclosed topical formulations. Therefore, the instant obviousness rejection is based on teachings known in the art at the time of the instant invention and not solely on the applicant's disclosure.
Conclusion
Claims 18-27, 31-34, and 36 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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