DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application, filed on 01/11/2021, claims priority from international Applications PCT/GB2018/052191 filed on 07/31/2018.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 01/11/2021, 06/23/2021, 01/12/2022, 04/06/2022, 05/30/2023, 06/23/2023, 11/21/2023 and 01/24/2025 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/26/2025 has been entered.
DETAILED ACTION
The Amendments and Applicant’s argument submitted on 12/11/2025 have been received and have been carefully considered.
Claim 20 was added, and claims 2, 6, 8, and 19 were previously cancelled. Claims 1, 3-5, 7, 9-18 and 20 are pending.
Rejection Maintained
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.
§ 103 Rejection over Akama, Lopes, Safety Assessment of Triglycerides and Kim
Claims 1, 3-5, 9-17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over T. Akama et al. (US PG-PUB 2009/0291917A1, 11/26/2009, “Akama” cited in the previous PTO-892 dated 08/23/2023) in view of C. Kim et al. (EP 0410348 A1, 1991, “Kim” cited in the PTO-892 dated 10/11/2024), L. Lopes, Journal of Pharmaceutical Sciences, 2010, VL 99, IS 3, P. 1346-1357, “Lopes” cited in the PTO-892), and Safety Assessment of Triglycerides, 02/14/2018, retrieved from Internet Archive, website: https://www.cir-safety.org/sites/default/files/trygly122017FAR.pdf, cited in the PTO-892).
Akama teaches a topical composition for the treatment of inflammatory-related diseases comprising compound C17, wherein the topical composition contains an oil phase and an aqueous phase, [Akama, pg. 66, 0434]:
PNG
media_image1.png
200
400
media_image1.png
Greyscale
[Akama, pg. 79, 0596].
Compound C17 is defined by instant specification as Crisaborole.
Akama teaches that the Pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions and water-in-oil emulsions. [Pg. 64, [0415]]. Creams containing the active agent for delivery are viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is generally comprised of petrolatum or a fatty alcohol, such as cetyl- or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. [0434]. A lotion or cream may include a relatively large aqueous phase and a relatively small oil phase. Furthermore, the lotions and creams of the invention may include the active compound “all-in-solution” in the oil phase so that substantially none of the active compound crystallizes out at room temperature. [Pg. 66, [0435]].
Akama teaches that the topical composition contains at least one emulsifying agent including surfactants, preferably cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate, each emulsifying agent is present in amount from about 0.5 to about 2.5 wt. %, preferably 0.5 to 2.0%, more preferably 1.0% or 1.8%. [Pg. 67, [0444] and [0446]].
Akama discloses a topical composition for crisaborole in Example 28, Cream Formulation B for C17, [Akama, pg. 193, [1517-1519]:
PNG
media_image2.png
406
551
media_image2.png
Greyscale
Akama’s above Crisaborole topical composition comprises preservatives (benzyl alcohol); (glyceryl monostearate SE, octyldodecanol), [Akama, pg. 67, [0444]], antioxidants (butylated hydroxytoluene), [Akama, Pg. 69, [0449]], etc.
Akama’s above Example topical composition comprises oil phase (oleyl alcohol, diisopropyl adipate); aqueous phase and Crisaborole. The oil phase, oleyl alcohol and diisopropyl adipate of the Akama above composition are liquid oils at 25°C, as evidenced by the instant specification. [Instant specification, pg. 6, ln. 5-6].
Akama’s above topical composition include 0.25% w/w surfactant, Pemulen Tr-2. Pemulen Tr-2 defines by instant specification as a surfactant: Suitable surfactants include … Pemulen Tr-1 and Pemulen Tr-2. [Pg. 8, ln. 25-33]. The surfactant at an amount of 0.25% w/w reads on the claim 1 “less that 5wt% surfactant.”
Akama teaches that the topical pharmaceutical compositions include oils like castor oil, triglycerides of caprylic/capric acid, and fatty esters. [Pg. 67, [0447]].
However, While Akama’s composition comprises Crisaborole, surfactant, diisopropyl adipate, oil phase and aqueous phase, one of ordinary skill need to specifically pick triglycerides of caprylic/capric acid from the list of emollients. Also, Akama’s above topical formulation comprises wax component, glyceryl monostearate of more than 5%.
With regard to caprylic/capric triglycerides, Lopes teaches the effectiveness of caprylic/capric triglycerides in skin penetration of drugs. Lopes teaches that significant increase in skin penetration of the drug for formulation with caprylic/capric triglycerides compared to formulation without caprylic/capric triglycerides. Lopes also teaches that caprylic/capric triglyceride shows superiority over skin penetration enhancers [Pg. 1351, col. 1, skin penetration Assays -col. 2]. Lopes teaches the caprylic/capric triglyceride is effective in decreasing the skin barrier function and electrical resistance. [Pg. 1353, col. 1, 1st para.]. Lopes teaches that The antioxidant activity of caprylic/capric triglycerides-treated skin was about 10 times higher than the untreated skin. [Pg. 1353, col. 2 1st para.]. Lopes teaches that the superiority of caprylic/capric triglycerides is maintained even when different drugs are formulated. [Pg. 1354, col. 2, last para.]. Lopes teaches that caprylic/capric triglycerides improves the drug stability and increase its concentration in the skin. [Pg. 1355, col. 1, 1st para.].
Moreover, Safety Assessment of Triglycerides teaches that FDA have attested to the safety of Caprylic/Capric Triglyceride as a vehicle for topically applied pharmaceuticals. [Pg. 6, 8th para.]. Safety Assessment of Triglycerides teaches that Application of skin formulation containing Caprylic/Capric Triglyceride to the shaved skin of female rats did not result in any localized skin effects, and Caprylic/Capric Triglyceride was not a sensitizer in guinea pigs. Caprylic/Capric Triglyceride was not an irritant or sensitizer when tested using groups in 128 subjects. [Pg. 10, 6th para.]. Safety Assessment of Triglycerides teaches that 95.51% Caprylic/Capric Triglyceride did not possess a detectable photo contact-sensitizing potential in human skin even at more than 95% concentration [Pg. 11, 2nd para.], and no toxicologically-relevant signs of toxicity were observed at the highest doses [Pg. 8, 7th para.]. Safety Assessment of Triglycerides teaches that Caprylic/Capric Triglycerides enhanced the skin penetration of drugs [Pg. 7, 3rd para.], and dermal absorption of other chemicals [Pg. 13, 9th para.].
With regard to the wax content of less than 5% and less that 3%, Kim teaches a topical spironolactone composition useful for treating acne, hirsutism, and other disorders caused by excess androgenic activity, wherein the topical composition permits the administration of spironolactone at the affected skin site in order to reduce the likelihood of subjecting the patient to the systemic effects of spironolactone. The composition of the present invention comprises a topical formulation of spironolactone which has the advantages of being very stable during long-term storage and having good cosmetic acceptability, [Pg. 2, 4-9], wherein the composition contains from about 1-12w% of the active ingredient, diisopropyl adipate as a solvent, cetearyl alcohol, or glycerol monostearate and polyoxyethylene stearate, as emulsifying agents, water as a carrier, along with buffering agent, ointment and preservatives, [Pg. 3, 29-35], wherein the emulsifier present as mixture of glycerol monostearate and polyoxyethylene stearate, [Pg. 3, 46-55], preferably the amount of 50:50 mixture of glycerol monostearate: polyoxyethylene stearate is 1-6.5%, [Pg. 4, Ln. 9 and 21]. Kim teaches that the formulation has the ability to penetrate the skin and stay there with very little systemic absorption of the spironolactone active ingredient, which is a desirable characteristic. [Pg. 4, Ln. 36-37].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to specifically pick Caprylic/Capric Triglycerides from Akama’s list of emollients and utilize it in the above Akama’s composition in view of the teachings of Lopes and Safety Assessment of Triglycerides. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Lopes teaches that caprylic/capric triglycerides significantly increase skin penetration of the drug, improves the drug stability and increase its concentration in the skin, effective in decreasing the skin barrier function and electrical resistance, and superior over the other skin penetration enhancers and that the superiority is maintained even when different drugs are formulated; and the Safety Assessment of Triglycerides teaches that Caprylic/Capric Triglyceride is FDA safe, recommended by FDA as a vehicle for topically applied pharmaceuticals, not a sensitizer in animal, not an irritant or sensitizer when tested on human, enhances the skin penetration of drugs, improves dermal absorption of other chemicals, and higher concentration of more than 95% did not possess a detectable photo contact-sensitizing potential in human skin. Therefore, one of ordinary skill would be motivated to utilize Akama’s Caprylic/Capric Triglyceride in the Crisaborole composition.
One of ordinary skill in the art would be motivated to prepare Akama’s Crisaborole topical composition with less than 5% or less that 3% (per newly added claim 20) wax component and modify the wax component, glyceryl monostearate of Akama’s Example 8 above from 8% to less than 5%/3% in view of the teachings of Akama and Kim with reasonable expectation of success because Akama teaches that emulsifiers i.e., glycerol monostearate, in the topical composition is preferably 0.5% or 2.0% (either of which are less than 3%), and Kim teaches topical formulation comprising 1-6.5% of emulsifying mixture containing glycerol monostearate that provide high stability during long-term storage and having good cosmetic acceptability with the ability to penetrate the skin and stay there with very little systemic absorption. As such, one of ordinary skill would have been motivated to use lower amount of glycerol monostearate as the amount taught by Akama, 0.5-2.0%, to produce topical formulation with high stability and penetration as taught by Akama. Note that Kim’s amount of 1-6.5% is a 50:50 mixture of glycerol monostearate: polyoxyethylene stearate, which bring the amount of glycerol monostearate (wax component) to 0.5-3.25%.
Moreover, Akama teaches all the components of the instant claimed composition, and only differs in that the claimed composition required less than 5% of glycerol monostearate while Akama Ex. 28 uses 8%, as provide in MPEP 2144.05.II.A “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Therefore, the combination of Akama, Lopes, Safety Assessment of Triglycerides, and Kim teaches each and every limitation of claims 1 and 20.
The amount of Crisaborole of 2% in Akama’s above Example meets the limitations of claim 3.
Akama’s above Example surfactant, pemulen TR-2 at an amount of 0.25% w/w meets the limitations of claims 8 and 9.
Akama’s above Example meets the limitations of claim 10 because the Crisaborole topical composition comprises 5%w/w propylene glycol.
The Akama’s above Example meets the limitations of claim 11 because the amount of water is more than 10% w/w.
Akama discloses the process of preparing the above topical composition wherein Crisaborole dissolved in the oil phase until a clear solution is obtained. [Akama, pg. 193, 1515]. Forming clear solution indicates that Crisaborole is completely dissolved in the oil phase, and therefore, Akama meets the limitations of claims 4 and 13.
With regard to claim 5, Akama discloses that the composition is used in combination with a second therapeutic agent active for treating the same disease such as autoinflammatory, steroid, vitamin D analog, PDE4 inhibitor, etc. [Akama, pg. 52, 0332].
With regard to claim 12, Akama discloses that the topical composition can be made into variety of formulations include lotions and creams. [Akama, pg. 65, 0432].
Akama Crisaborole topical composition meets claim 15 because the composition does not comprise polyaphron.
With regard to claim 16, Akama discloses that the composition is for treating an animal, wherein the animal is selected from human, cattle, deer, etc. [Akama, pg. 62, 0400].
With regard to claim 17, Akama discloses that the boron-containing compound i.e., Crisaborole used to treat a condition selected from psoriasis, eczema, atopic dermatitis, contact dermatitis, inflammatory alopecia or acne. [Akama, pg. 61, 0385].
Claim 14 is drawn to the stability of the claim 1 topical composition. It is recognized that the prior art of the combination of Akama and Kim teaches substantially identical components of the claimed composition (Crisaborole, oil liquid phase and aqueous phase). As such, it is reasonable to assume that the prior arts composition will also be chemically and/or physically stable for at least 12 months at 25°C and 60% relative humidity or 6 months at 40°C and 60% relative humidity. Applicants are reminded that the office does not have the facilities and resources to determine the stability of the topical composition. In the absence of evidence to the contrary, the burden is on applicants to show that this property is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
§ 103 Rejection over Akama, Lopes, Safety Assessment of Triglycerides, Kim in view of the Handbook of Pharmaceutical Excipient
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over T. Akama et al. (US PG-PUB 2009/0291917A1, 11/26/2009, “Akama” cited in the PTO-892 dated 08/23/2023) in view of L. Lopes, Journal of Pharmaceutical Sciences, 2010, VL 99, IS 3, P. 1346-1357, “Lopes” cited in the PTO-892), Safety Assessment of Triglycerides, 02/14/2018, retrieved from Internet Archive, website: https://www.cir-safety.org/sites/default/files/trygly122017FAR.pdf, cited in the PTO-892) and C. Kim et al. (EP 0410348 A1, 1991, “Kim” cited in the PTO-892 dated 10/11/2024), as applied above to claims 1, 3-5, and 9-17, further in view of R. Rowe et al. (Handbook of Pharmaceutical Excipients, 5th edition 2006, Retrieved from Internet archive, website: https://www.gmpua.com/RD/RD/HandbookPharmaceutical%20Excipients.pdf, cited in the PTO-892).
The combination of Akama, Lopes, Safety Assessment of Triglycerides, and Kim teaches a composition for topical application comprising a continuous aqueous phase, a discontinuous liquid oil phase, crisaborole, and a surfactant, diisopropyl adipate, caprylic/capric triglycerides, wherein the discontinuous liquid oil phase is a liquid at 25°C wherein the composition comprises less than 5 wt.% by weight of the composition of a wax component that is solid at 25°C and wherein the composition has a total surfactant content of less than 5 wt.% by weight of the composition.
With regard to claim 7, Akama’s above Example includes diisopropyl adipate at an amount of 10% w/w, and the Safety Assessment of Triglycerides teaching that Caprylic/Capric Triglyceride is used at maximum concentrations of 38% w/w in formulations [Pg. 6, 2nd para.], and Caprylic/Capric Triglycerides is reported to be safe with no toxicity when administered at a dose of 22 w/w %, [Pg. 8, 3rdpara.].
Akama teaches that the topical pharmaceutical compositions include oils like castor oil, triglycerides of caprylic/capric acid, and fatty esters. [Pg. 67, [0447]].
Instant claim 7 differs from the composition taught by the combination of Akama, Lopes, Safety Assessment of Triglycerides, and Kim to the extent that one of ordinary skill in the art would have to specifically select castor oil from Akama’s list of emollients.
The handbook of pharmaceutical excipient teaches the use of castor oil in pharmaceutical as emollient, vehicle and solvent, and its widely used in topical creams and ointment at concentrations of 5–12.5%. The Handbook teaches the pharmacopeial properties of castor oil including viscosity, surface tension and melting point. The Handbook teaches that castor oil is stable and does not rancid in normal temperature. The Handbook teaches that castor oil is used in topical pharmaceutical formulations because its nontoxic and nonirritant. [Pg. 128-129].
Therefore, one of ordinary skill in the art would have been motivated with reasonable expectation of success to specifically pick castor oil from Akama’s list of emollients because the Handbook of pharmaceutical Excipient teaches that castor oil is widely used in topical formulation because castor oil is safe, nontoxic, nonirritant, and can be use as emollient vehicle and solvent; and because the Handbook provide skilled artisan with the physical and pharmacopeial properties of castor oil. One of ordinary skill in the art would have been motivated to use castor oil at the concentration of 5-45wt% (claim 7) because the Handbook teaches that in topical creams and ointment, castor oil used at concentrations of 5–12.5%. Moreover, MPEP 2144.05 explains that in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Furthermore, “Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).” Therefore, the combination of Akama, Lopes, Safety Assessment of Triglycerides, and Kim teach a composition comprises diisopropyl adipate in an amount of 10% w/w, and Caprylic/Capric Triglyceride in an amount of 22 w/w% and the Handbook teaches the castor oil at a concentration of 5-12.5%, therefore, claim 7 is rendered obvious.
§ 103 Rejection over Akama, Lopes, Safety Assessment of Triglycerides, and Kim in view of Coronado
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over T. Akama et al. (US PG-PUB 2009/0291917A1, 11/26/2009, “Akama” cited in the previous PTO-892 dated 08/23/2023) in view of C. Kim et al. (EP 0410348 A1, 1991, “Kim” cited in the PTO-892 dated 10/11/2024), L. Lopes, Journal of Pharmaceutical Sciences, 2010, VL 99, IS 3, P. 1346-1357, “Lopes” cited in the PTO-892), and Safety Assessment of Triglycerides, 02/14/2018, retrieved from Internet Archive, website: https://www.cir-safety.org/sites/default/files/trygly122017FAR.pdf, cited in the PTO-892), as applied above to claims 1, 3-5, and 9-17, further in view of D. Coronado et al. (WO2017093857A1, 06/08/2017, “Coronado” cited in the previous PTO-892 dated 08/23/2023).
As discussed above and incorporated herein by reference, The combination of Akama, Lopes, Safety Assessment of Triglycerides, and Kim teaches a composition for topical application comprising a continuous aqueous phase, a discontinuous liquid oil phase, crisaborole, and a surfactant, diisopropyl adipate, caprylic/capric triglycerides, wherein the discontinuous liquid oil phase is a liquid at 25°C wherein the composition comprises less than 5 wt.% by weight of the composition of a wax component that is solid at 25°C and wherein the composition has a total surfactant content of less than 5 wt.% by weight of the composition.
Akama teaches that the topical compositions can be made into a wide variety of product types include, but are not limited to, lotions, creams, gels, sticks, sprays, ointments, pastes, foams. [Pg. 65, [0432]]. Kim also teaches that the composition cooled and blended and transferred to appropriate containers. [Pg. 5, 45-46].
The combination of Akama, Lopes, Safety Assessment of Triglycerides and Kim does not teach that the Crisaborole topical composition is packaged in a package comprising 20-300 g.
The instant specification defines the package as the package is a jar, a tube, an airless pump, a sachet, a bottle, a tub, a pump action sealed container, or a spray applicator. [Specification, pg. 17, ln. 30].
Coronado teaches a topical composition for treating atopic dermatitis and/or psoriasis comprising of Crisaborole, propylene glycol, petrolatum, etc. [Coronado, pg. 1, ln. 5-10; pg. 2, ln. 1-16]. Coronado teaches that the topical composition stored in tubes, including 60-g laminate tubes. [Coronado, pg. 54, ln. 12].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to store Akama, Lopes, Safety Assessment of Triglycerides and Kim Crisaborole topical composition in a tube in view of the teachings of Coronado. One of ordinary skill in the art would be motivated to do so with reasonable expectation of success because Coronado teaches a Crisaborole composition packaged in a tube and that the tube stabilized the composition and are commercially available. [Coronado, pg. 54, ln. 12].
Response to Argument
Applicant argues:
Claim 1 provides that "the discontinuous oil phase is a liquid at 25 °C" and this feature is not met by the Cream Formulation B of Example 28 of Akama et al. See the Rule 132 Declaration at paragraph 6 reporting a physical test where the 2.0 w/w C17 version of the formulation of Cream Formulation B of Example 28 of Akama et al. was reproduced and a portion of the oil mixture was reserved and allowed to cool and was clearly not a liquid at 25 °C. See also the Rule 132 Declaration at paragraph 7 which explains why one having ordinary skill in the art would understand that the oil phase of the Cream Formulation B of Example 28 of Akama et al. is in a solid phase at 25 and see the Rule 132 Declaration at paragraph 16 summarizing the results. The outstanding Office Action contends that Cream Formulation B of Example 28 of Akama et al. has a liquid oil phase. See page 5, third complete paragraph of the Office Action. This is contrary to what the Office Action dated 11 October 2024 recognized at page 13("Applicant provide evidence that the oil mixture of Akama's oil phase to be solidified at room temperature..."). See the Rule 132 Declaration at paragraph 6 where the 2.0 w/w C17 version of the formulation was reproduced and a portion of the oil mixture was reserved and allowed to cool and was clearly not a liquid at 25 °C. See also the Rule 132 Declaration at paragraph 7 which explains why one having ordinary skill in the art would understand that the oil phase of the Cream Formulation B of Example 28 of Akama et al. is in a solid phase at 25 °C, and see the Rule 132 Declaration at paragraph 16.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive. The Declaration was responded to in the office action dated 10/11/2024. Applicant provided evidence that the oil mixture of Akama’s oil phase solidified at room temperature, however, Applicant does not provide criticality of the oil phase in the final composition, as the final composition in the prior art and in instant Example 9 are emulsion/cream of oil in water, and that one would expect that the emulsion/cream of prior art would be same as the claimed emulsion/cream regardless of how these are prepared. This would impact the medical topical composition only if the active ingredient, crisaborole does not dissolved in Akama’s oil phase due to the wax nature of solidification of the mixture, however, this was not true due to the teaching of Akama that the crisaborole was completely dissolved until clear solution was obtained. Moreover, Applicant does not provide evidence that the active ingredient, crisaborole would degrade at a temperature of around 60°C. Furthermore, while instant Example 9 recites a composition without glyceryl monostearate, instant claim 1 recites a composition comprising less than 5% of glyceryl monostearate, and while claim 1 is broader, neither Example 9 nor claim 1 provide evidence of the negative role of glyceryl monostearate on the final composition. Furthermore, there is no comparison between Akama’s composition and the claimed composition on stability, skin penetration, physical or chemical properties that would show superiority of the claimed composition over Akama’s. Moreover, the instant composition with less than 5% wax component i.e., glyceryl monostearate, is found to be obvious over Akama in view of Kim, see 103 Rejection above.”
Applicant appears to argue the process involved in formulating the claimed composition, however, as explained in MPEP § 2113: "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). As such, the product by process limitations of claims 3-4 are not given patentable weight. In the instant case, both the claimed composition and the prior art composition are oil phase/aqueous phase creamy” formulations.
Applicant argues:
Claim 1 provides that "the composition comprises less than 5 wt. of the composition of a wax component that is solid at 25 °C" and this feature is not met by Cream Formulation B of Example 28 of Akama et al. which contains 8 wt. glyceryl monostearate SE which is clearly a wax component that is solid at 25 °C. See the Rule 132 Declaration at paragraphs 10-13.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive for the following reasons. While the office action acknowledged that Akama’s topical formulation comprises wax component, glyceryl monostearate, in a concentration of 8% instead of less than 5%, one of ordinary skill in the art would have been motivated to prepare Akama’s crisaborole topical composition with less than 5% wax component and modify the wax component, glyceryl monostearate, of Akama’s Example 8 from 8% to less than 5% in view of the teachings of Akama and Kim, with reasonable expectation of success, because Akama teaches that emulsifiers i.e., glycerol monostearate, in the topical composition are preferably present in concentrations of 0.5% or 2.0% (either of which are less than 5%), and Kim teaches topical formulations comprising 0.5-3.25 % of glycerol monostearate (1-6.5% of 50% glycerol monostearate emulsifying mixture) that provide high stability during long-term storage and have good cosmetic acceptability with the ability to penetrate the skin and stay there with very little systemic absorption. As such, one of ordinary skill would have been motivated to use lower amount of glycerol monostearate as the amount taught by Akama, 0.5-2.0% to produce topical formulation with high stability and penetration as taught by Kim. Moreover, Akama teaches all the components of the instant claimed composition, and only differs in that the claimed composition required less than 5% of glycerol monostearate while Akama Ex. 28 uses 8%, as provide in MPEP 2144.05.II.A “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Applicant argues:
Claim 1 provides that "the composition has a total surfactant content of less than 5% by weight of the composition" and this feature is not met by the Cream Formulation B of Akama et al. In Cream Formulation B of Example 28 of Akama et al., the total surfactant content is at least 18.25 wt. This includes: 8.0 wt. glyceryl monostearate (identified as a surfactant at paragraph [0444] in the section running from paragraphs [0442] to [0446] of Akama et al.); 0.25 wt.% Pemulen Tr-2; and 10.0 wt.% octyldodecanol (identified as a surfactant at paragraph [0444] in the section running from paragraphs [0442] to [0446] of Akama et al.).
In the Office Action (see page 5, penultimate paragraph), the Office Action refers to the Pemulen Tr-2 component and contends that the amount of this component (0.2500 w/w) reads on the "less than 5 wt.%" surfactant limitation in claim 1. However, claim 1 actually refers to the "total surfactant content of less than 5 wt0 by weight of the composition total surfactant content is less than 5 wt.% ." As indicated above, it would be clear to one having ordinary skill in the art that the total surfactant content of Cream Formulation B of Example 28 of Akama et al. greatly exceeds 5 wt.% . It is pointed out that one skilled in the art would understand that certain components can be considered both as surfactants and waxes. Glyceryl monostearate is a very clear example of this. Some waxes (e.g. Beeswax, paraffin wax) have essentially no surfactant- like properties, whereas others (e.g. glyceryl monostearate) have very significant surfactant properties, and one having ordinary skill in the art would clearly consider such waxes to be surfactants because they have significant surfactant properties.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive for the following reasons. Applicant asserted that Akama’s composition comprises 18.25 wt.%. However, Akama teaches:
In another exemplary embodiment, the pharmaceutical formulation includes C17 and an alcohol. In another exemplary embodiment, the pharmaceutical formulation includes C27 and an alcohol. In another exemplary embodiment, the alcohol is a long chain alcohol or a fatty alcohol. In another exemplary embodiment, the alcohol is a member selected from benzyl alcohol, octyldodecanol, stearyl alcohol, cetyl alcohol, oleyl alcohol. In an exemplary embodiment, the formulation comprises a member selected from benzyl alcohol, octyl comprises at least one compound which is a member selected from hydrocarbon oils, waxes, silicone, cetyl alcohol, isopropyl myristate, stearyl alcohol, oleyl alcohol, ethylhexyl hydroxystearate, octyl hydroxystearate, glycerin, other fatty alcohols hydroxystearate. [0491]
In preparing formulation B, Akama teaches:
In a stainless-steel vessel, add oleyl alcohol, benzyl alcohol, diisopropyl adipate, glyceryl monostearate SE, octyldodecanol, butylated hydroxytoluene and C17. Propeller mix while heating to 60±5° C. until a clear solution is obtained. Maintain the temperature. With continuous propeller mixing, add pemulen TR-2. Mix until the oily components are visually homogeneous. [1515]
Akama’s oleyl alcohol, diisopropyl adipate and octyldodecanol appears to be the oil phase components in view of Akama’s [0491 and 1515] teachings and as evidenced by the instant specification. [Instant specification, pg. 6, ln. 5-6]. Akama’s composition comprises oil phase components which includes oleyl alcohol, diisopropyl adipate and octyldodecanol, and the surfactant in Akama’s topical composition B is 0.25 wt.% Pemulen Tr-2. In the preparation method [1515], the oil phase mixed first until clear solution obtained (the oil phase), the surfactant Pemulen Tr-2 is added following by water (the aqueous phase). It is known in the art to add a surfactant to emulsify the oil and aqueous phase to form emulsion/cream. Note that instant claim 1 recites less than 5% wax component and less than 5% surfactant, and per instant specification and Declaration, glyceryl monostearate is a wax component not a surfactant, and therefore, the 8.0 wt.% glyceryl monostearate should not be included as surfactant. Thus, Akama’s topical composition include 0.25% w/w surfactant, Pemulen Tr-2. Pemulen Tr-2 defines by instant specification as a surfactant: Suitable surfactants include … Pemulen Tr-1 and Pemulen Tr-2. [Pg. 8, ln. 25-33]. The surfactant at an amount of 0.25% w/w reads on the claim 1 “less that 5wt% surfactant.”
Applicant argues:
Claim 1 provides that "the discontinuous liquid oil phase comprises at least one of diisopropyl adipate, diethyl sebacate, or dibutyl adipate, and at least one of castor oil or caprylic/capric triglycerides" and this feature is not disclosed in Cream Formulation B of Example 28 of Akama et al. It is noted that the table above identifying the Cream Formulation B of Example 28 includes 10 wt.% diisopropyl adipate, but there is no mention of castor oil or caprylic/capric triglycerides according to claim 1.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive for the following reasons. Akama teaches that the topical pharmaceutical compositions include oils like castor oil, triglycerides of caprylic/capric acid, and fatty esters. [Pg. 67, [0447]]. One of ordinary skill in the art would have been motivated to specifically pick Caprylic/Capric Triglycerides from Akama’s list of emollients and utilize it in the above Akama’s composition with reasonable expectation of success because Lopes teaches that caprylic/capric triglycerides significantly increase skin penetration of the drug, improves the drug stability and increase its concentration in the skin, effective in decreasing the skin barrier function and electrical resistance, and superior over the other skin penetration enhancers and that the superiority is maintained even when different drugs are formulated; and the Safety Assessment of Triglycerides teaches that Caprylic/Capric Triglyceride is FDA safe, recommended by FDA as a vehicle for topically applied pharmaceuticals, not a sensitizer in animal, not an irritant or sensitizer when tested on human, enhances the skin penetration of drugs, improves dermal absorption of other chemicals, and higher concentration of more than 95% did not possess a detectable photo contact-sensitizing potential in human skin. Therefore, one of ordinary skill would be motivated to utilize Akama’s Caprylic/Capric Triglyceride in the crisaborole composition.
Applicant argues:
The unexpected results relate to the use of a liquid discontinuous oil phase and is associated with at least two unexpected benefits: (i) the chemical stability of the crisaborole against degradation is significantly improved; and (ii) the skin penetration of the crisaborole is significantly improved.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive for the following reasons. Applicant presents a comparison between two formulations, the formulation of Example 9 without glyceryl monostearate and the formulation identical to Akama’s formulation 28B comprising 8% glyceryl monostearate. In view of the comparisons between the instant claimed composition, Example 9, and Example 28B composition of Akama, it appears that the instant claimed composition provides significant stability over Akama’s Example 28B composition. However, Example 9 includes Laureth-4, a known skin penetration enhancer, and was described by the instant specification as the preferred surfactant, [see specification page 9, 1st para.]. instant specification stated that:
It may also improve the physical stability of the composition especially when low levels of surfactant are used. [Pg. 6, ln. 27-28].
As provided in MPEP 716 (b)(III) “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971). In the instant comparison, the compared formulations are not equivalent as Example 9 includes Laureth-4, a known skin penetration enhancer and physical stabilizer. Therefore, one of ordinary skill in the art would not know if the enhancement in the stability and skin penetration is due to the presence of Laureth-4 or absence of glycerol monostearate. As provided in MPEP 716 (b), the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). "[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). However, because the comparable prior art example includes laureth-4, one cannot tell if the Applicant unexpected results is in fact statistical and practical significance.
Regarding Applicant’s reference to the Declaration (02/10/2025):
This is to clarify that the small quantity of liquid surfactant (Laureth-4) in Example 9 (0.3 wt.%) was incorporated to allow an oil-in-water dispersion to be formed following the removal of the glyceryl monostearate SE. It is submitted that one skilled in the art would understand that it is the discontinuous liquid oil phase that is responsible for the significantly improved chemical stability of the crisaborole against degradation and improved skin permeation, and not the very small amount of added surfactant Laureth-4) which simply allows an oil-in-water dispersion to be formed. Furthermore, one skilled in the art would not realistically expect significant improvements in skin permeation and chemical stability observed for the present invention in Examples 10 and 11 are a result of adding such a small amount (0.30 wt.%) of surfactant.
As provided in MPEP 2145, If a prima facie case of obviousness is established, the burden shifts to the applicant to come forward with arguments and/or evidence to rebut the prima facie case. See, e.g., In re Dillon, 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc). Rebuttal evidence and arguments can be presented in the specification, In re Soni, 54 F.3d 746, 750, 34 USPQ2d 1684, 1687 (Fed. Cir. 1995), by counsel, In re Chu, 66 F.3d 292, 299, 36 USPQ2d 1089, 1094-95 (Fed. Cir. 1995), or by way of an affidavit or declaration under 37 CFR 1.132, e.g., Soni, 54 F.3d at 750, 34 USPQ2d at 1687; In re Piasecki, 745 F.2d 1468, 1474, 223 USPQ 785, 789-90 (Fed. Cir. 1984). However, arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Applicant did not provide factual evidence that the instant formulation of Example 9 would also be superior over Akama’s formulation even without the skin penetration and stability enhancer laureth-4. If Applicant are intended to distinguish the claimed composition from the prior art composition by the amount of the wax component, it would be beneficial to reproduce exactly the same composition as Akama’s with less than 5% wax component i.e., glyceryl monostearate, instead of 8% and show superior skin penetration and stability as described in instant Examples 10 and 11. However, it is still stand that the instant claims are obvious over the cited prior art, and the unexpected result over the comparable Example 9 composition is insufficient to overcome the rejection.
Applicant argues:
Akama et al. refer to a huge number of boron-containing small molecules that have different physical and chemical properties. Crisaborole (C 17) presents special challenges for formulators stemming from its poor aqueous solubility and hydrolytic instability and the skilled person would recognize that a suitable formulation strategy will depend on the specific active ingredient. Simply picking and choosing from the multitude of optional features disclosed in Akama et al. is not an approach that one having ordinary skill in the art would take.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive. Applicant argues that Akama discloses compounds differ chemically and physically from crisaborole. It appears that Applicant intends to argue that the listing of the excipients discloses in Akama is directed to the other boron-containing compounds, not crisaborole, and that crisaborole excipient are only disclose in [0490], [0494], [0497], and castor oil or caprylic/capric triglycerides are not listed as crisaborole excipients.
As provided in MPEP 2144 (IV). the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991). In the instant case Akama teaches an exemplary topical formulation 28B comprises oil phase (oleyl alcohol, diisopropyl adipate); aqueous phase and Crisaborole; 0.25% w/w surfactant, Pemulen Tr-2; and teaches that the topical pharmaceutical compositions include oils like castor oil, triglycerides of caprylic/capric acid, and fatty esters. [Pg. 67, [0447]]. Lopes provide motivation to one of ordinary skill in the art to specifically select caprylic/capric triglycerides from Akama’s list, and Kim provide one of ordinary skill in the art with the motivation to decrease the amount of glycerol monostearate to less than 5%, see above obviousness rationale. Therefore, Applicant argument is not persuasive.
Applicant argues:
It is not possible to infer from Lopes that caprylic/capric triglycerides (CCT) themselves provide improved permeation. Rather, it can only be inferred that the MG/TG-containing microemulsions tested achieve improved skin permeation compared with the control solution. Indeed, this is the conclusion reached by the authors: "In conclusion, BRIJ-based microemulsions containing medium chain triglycerides (especially mono- and diglycerides) are promising delivery systems to promote the cutaneous delivery of lycopene and improve the antioxidant activity in the skin." (See page 1355, 1st column, second complete paragraph, emphasis added). It is further noted that the authors express a preference for mono- and diglycerides over triglycerides in the tested formulations: By using mono/diglycerides instead of triglycerides in microemulsions, the structure of the system was affected and its ability to modulate the barrier function of the skin and to deliver lipophilic compounds into the skin was increased..." (See page 1355, 1st column, second complete paragraph). The Office Action appears to have cited Safety Assessment of Triglycerides primarily as evidence that CCT are safe to use in pharmaceutical formulations. The Office Action contends that this document "teaches that Caprylic/Capric Triglycerides enhanced the skin penetration of drugs [Pg. 7, 3rd para.] and dermal absorption of other chemicals [Pg. 13, 9th para.]." It appears that the Examiner intended to refer to the 10th paragraph on page 13. Nevertheless, this contention is not correct. Both of these passages refer to tricaprylin, not CCT. Reference is made to the following excerpts from pages 15 and 17 of Safety Assessment of Triglycerides: Moreover, page 7, 3rd paragraph states: "Tricaprylin enhanced the skin penetration of drugs in vivo (Wistar rats) and in vitro (hairless mice).4" The drugs that were actually tested to support this statement were tegafur, alclofenac, ibuprofen, and ketoprofen. None of these drugs are remotely similar to crisaborole in terms of structure or chemical/physical properties. Page 9, 10th paragraph simply indicates that tricaprylin (and triolein) can enhance the skin penetration of "other chemicals." These statements would not lead the skilled person to expect that tricaprylin - let alone CCT - would improve skin penetration of crisaborole in a formulation of the type claimed.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive for the following reasons. In response to applicant's argument that caprylic/capric triglycerides improved skin permeation when combined with other penetration enhancers, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). However, Lopes clearly teaches how Caprylic/Capric Triglycerides (MG)-containing microemulsions, ME-MG increased skin penetration by 6-fold, with Figure 2 below shows the superiority of ME-MG over the ME-TG:
PNG
media_image3.png
300
446
media_image3.png
Greyscale
PNG
media_image4.png
330
448
media_image4.png
Greyscale
One of ordinary skill in the art having access to Lopes’ teachings would have been motivated with reasonable expectation of success to select Caprylic/Capric Triglycerides from Akama and added to the Akama’s crisaborole e topical formulation to enhance the skin penetration of crisaborole.
The Safety Assessment of Triglycerides document provide additional motivation to skilled artisan to select and incorporate Caprylic/Capric Triglycerides into Akama’s topical formulation because Safety Assessment of Triglycerides teaches that Caprylic/Capric Triglycerides is not an irritant or sensitizer, did not possess a detectable photo contact-sensitizing potential in human skin even at more than 95% concentration and no toxicologically-relevant signs of toxicity were observed at the highest doses. With regard to applicant statement that page 13, 9th para. stated that Tricaprylin enhanced the skin penetration, Tricaprylin is a Triglyceride of Caprylic/Capric with glycerin. Note that Applicant’s argument that the Safety Assessment of Triglycerides teaches enhancing the skin penetration of drugs different than crisaborole, this argument is not persuasive when the teachings of the Safety Assessment of Triglycerides is combined with the primary reference Akama.
Applicant argues:
the skilled person would not have been motivated to lower both the glyceryl monostearate and total surfactant contents to less than 5 wt.%. The Office Action continues to refer to the disclosure in Kim et al. of a composition comprising 1-6.5 wt.% of an emulsifying mixture comprising glycerol monostearate (page 4, line 9) but neglects to mention the other wax and surfactant components present in the composition. Specifically, the composition disclosed at page 4, lines 6-17 of Kim et al. There is no disclosure of a composition comprising less than 5 wt.% wax component and less than 5 wt.% total surfactants Kim et al. provide no suggestion or motivation to do this. The more preferred formulation disclosed at page 4, lines 18-29 of Kim et al. comprises: 7.2-10.8 wto of a 90:10 mixture of cetearyl alcohol and sodium lauryl sulfate; 4.0-6.0 wt.% of a 50:50 mixture of glycerol monostearate and polyoxyethylene stearate; and 8.4-12.6 wto white petrolatum. Accordingly, Kim et al. teach away from simultaneously working at the bottom end of all three of the above ranges in the embodiment disclosed at page 4, lines 6-17. It is further pointed out that the disclosure of Kim et al. is directed to spirolactone, crisaborole has a water solubility approximately 12 times higher than spirolactone. different active ingredients will require different excipients and amounts to achieve a chemically and physically stable formulation. While not part of the obviousness objection against claim 1, a further reference ("the Handbook of Pharmaceutical Excipient") has been cited against claim 7. The reference seems have been cited because it teaches that castor oil is used in topical formulations. However, it provides no suggestion that castor oil would provide improved skin permeation, chemical stability of crisaborole against degradation and physical stability in a formulation of the type claimed. Coronado et al. has been cited against claim 18 and appears to have been relied upon for the disclosure of a topical composition stored in tubes. This would not have motivated one having ordinary skill in the art to modify the Cream Formulation B of Akama et al. to provide the composition according to claim 1.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive for the following reasons. As provided in 2145 (D. 1.), the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023) ("Although Oez [the prior art] used a white pigment with a cross-linking polymer, it does not discourage a skilled artisan from using the white pigment without a cross-linking polymer or lead the skilled artisan in a direction divergent from the path taken in the Appealed Patents. Thus, Oez's disclosure is substantial evidence that supports the Board's finding that Oez does not teach away from the proposed combination." In the instant case, Kim teaches a topical formulation for treating skin conditions, wherein the formulation formulated to reduce the systemic effects and provide stability, long-term storage and having good cosmetic acceptability [Pg. 2, 4-9], [Pg. 3, 29-35]. In addition of the oil phase and aqueous phase, Kim formulation comprises mixture of glycerol monostearate and polyoxyethylene stearate, [Pg. 3, 46-55], preferably the amount of 50:50 mixture of glycerol monostearate: polyoxyethylene stearate is 1-6.5%, [Pg. 4, Ln. 9 and 21]. Kim teaches that the formulation has the ability to penetrate the skin and stay there with very little systemic absorption of the active ingredient, which is a desirable characteristic. [Pg. 4, Ln. 36-37]. The primary reference, Akama teaches topical formulation 28B that teaches the claimed oil phase and aqueous phase with glycerol monostearate at a concentration of 8%. Thus, One of ordinary skill in the art would be motivated to prepare Akama’s crisaborole topical composition with less than 5% wax component and modify the wax component, glyceryl monostearate of Akama’s Example 8 above from 8% to less than 5% in view of the teachings of Akama and Kim with reasonable expectation of success because Akama teaches that emulsifiers i.e., glycerol monostearate, in the topical composition is preferably 0.5% or 2.0% (either of which are less than 5%), and Kim teaches topical formulation comprising 1-6.5% (0.5-3.25% of glycerol monostearate) of emulsifying mixture containing glycerol monostearate that provide high stability during long-term storage and having good cosmetic acceptability with the ability to penetrate the skin and stay there with very little systemic absorption.
With respect to Applicant arguments against the Handbook of Pharmaceutical Excipient and Coronado, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Claim 7 required diisopropyl adipate 4-45 wt.%, and caprylic/capric triglycerides and castor oil 5-45 wt.%. The primary reference, Akama in view of Lopes and Kim teaches claim 7 composition diisopropyl adipate 4-45 wt.%, and caprylic/capric triglycerides, and Akama teaches castor oil as an excipient for the crisaborole formulation. The Handbook of pharmaceutical Excipient would provide one of orinary skill in the art with the motivation to specifically pick castor oil from Akama’s list because the Handbook of Pharmaceutical Excipient teaches that castor oil is widely used in topical formulation because castor oil is safe, nontoxic, nonirritant, and can be use as emollient vehicle and solvent; and because the Handbook provide skilled artisan with the physical and pharmacopeial properties of castor oil. One of ordinary skill in the art prior to the effective filing date of instantly claimed invention to store the Crisaborole topical composition in a tube in view of the teachings of Coronado because Coronado teaches a Crisaborole composition packaged in a tube and that the tube stabilized the composition and are commercially available. See the above 103 Rejections. Thus, Applicant’s arguments against the Handbook of Pharmaceutical Excipient and Coronado is not persuasive.
Conclusion
Claims 1, 3-5, 7, 9-18 and 20 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MANAHIL MIRGHANI ALI ABDALHAMEED whose telephone number is (571)272-1242. The examiner can normally be reached M-F 7:30 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622