Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
Claims 14-15, 18-25, 28, 30, 33, 38-39 have been canceled.
Claims 1-13, 16-17, 26-27, 29, 31-32 and 34-37 are under examination.
Maintained Rejections
The following rejections are maintained from the previous Office Action (01/06/2026) since the art that was previously cited continues to read on the newly amended limitations.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. § 103 (a) are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-13, 16-17, 26-27, 29, 31-32 and 34-37 are rejected under 35 U.S.C. § 103 as being unpatentable over Wortzman et al. (WO2009/051839A1, as cited on IDS) in view of Patel et al. (Clinical Assessment of the Combination Therapy with Liposomal Gels of Tretinoin and Benzoyl Peroxide in Acne, AAPS Pharm SciTech 2, Technical Note 4, 2001) and Lapidot et al. (US2010/0255107A1, as cited on IDS).
Wortzman et al. teach a composition comprising about 1.0% to about 0.01%, preferably 0.025% tretinoin, and comprising about 3% to about 9%, preferably about 5% benzoyl peroxide, a high molecular weight polymeric gelling agent, and water ([13], [20], claim 16). Acne is treated by applying peas sized amount of tretinoin/benzoyl peroxide gel to the fingertips and spread over the face ([52], Ex. 10).
Wortzman et al. differ from the instant regimen wherein the application of the composition occurs daily for at least 4 weeks; wherein the tretinoin and benzoyl peroxide are individually encapsulated by a semi-metal oxide or metal oxide and/or the composition is a cream.
However, Patel et al. disclose a treatment of acne comprising applying benzoyl peroxide to the face in the morning and then tretinoin to the face before bedtime for a treatment period of 3 months (at least 12 weeks) (page 2, col. 1, para. 1-2).
Patel et al. differ from the claimed regimen wherein the treatment comprises topically applying once a day.
However, Lapidot et al. disclose a topical composition comprising at least one of benzoyl peroxide and retinoid encapsulated in a microcapsules having a core-shell structure, wherein said core includes said active ingredient, and wherein said shell comprises at least one metal oxide inorganic polymer obtained by a sol-gel process ([0019], claim 1). The combinations of benzoyl peroxide and oxidation-sensitive active ingredients such as retinoids and antibiotics are highly useful in formulations for the treatment of acne, and therefore the encapsulation of benzoyl peroxide can facilitate obtaining a stable formulation containing both ingredients ([0253], Ex. 7). An emulsion and a cream is the preferred final form of the composition ([0052], [0142]).
It would have been prima facie obvious to one of ordinary skill in the art ahead of the effective filing date of the claimed invention to apply the composition of Wortzman et al. for at least 12 weeks once daily with expected results. One would have been motivated to do so because Patel et al. teach that this is a well-established and common treatment regimen. It would have been prima facie obvious to one of ordinary skill in the art at the time of the filing of the instant application to adjust the amount of tretinoin to 0.1%, and the benzoyl peroxide to 3% with an expectation of success. In the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists.
The reduction in lesion count after about 2 weeks being at least about twice that during the period starting at about week 2 and ending at about week 4 (instant claim 1) and the percentage decrease in lesions of about 25.2% after about 2 weeks, compared to the 17.8% after treatment with vehicle control for about 2 weeks (instant claim 6) would necessarily be present in the method of Wortzman et al. as modified by the teachings of Patel et al. since the composition and method steps of the prior art are indistinguishable from the instant claims.
It would have been prima facie obvious to one of ordinary skill in the art at the time of
the filing of the instant application to encapsulate the tretinoin and benzoyl peroxide of
Wortzman et al. in the microcapsule of Lapidot et al. and reasonably expect success. One would have been motivated to do so in order to provide a more stable composition by preventing contact between the active agents. Specifically, Lapidot et al. provide enhanced stability of benzoyl peroxide, by its encapsulation within the microcapsules and that the benzoyl peroxide is present in the microcapsular core, preferably as an oil-in-water emulsion or as a solid-in-oil-in-water emulsion, and is encapsulated by the microcapsular shell. The microcapsular shell protects the benzoyl peroxide from contacting the is environment and thus reduces its reactivity and/or sensitivity ([0204]). The microcapsular shell further protects the benzoyl peroxide from reacting with other active ingredients in the composition ([0204]).
It would have been prima facie obvious to one of ordinary skill in the art at the time of
the filing of the instant application to formulate the composition of Wortzman et al. into a
cream and have a reasonable expectation of success. One would have been motivated to do so
since Lapidot et al. teach that the composition can be formed into a variety of preferred forms ([0052], [0142]). Further, Lapidot et al. highlight the benefits of microcapsule cream formulations in which the release/delivery of the active ingredient is produced by disintegration of the micro-capsules upon topical application thereof via for example sheer forces applied by a spreading action commonly used to spread creams, gels or ointments ([0152], claim 20).
Claims 1-13, 16-17, 26-27, 29, 31-32 and 34-37 are rejected under 35 U.S.C. § 103 as being unpatentable over Mallard et al. (US2009/0318550A1) in view of Patel et al. (Clinical Assessment of the Combination Therapy with Liposomal Gels of Tretinoin and Benzoyl Peroxide in Acne, AAPS Pharm SciTech 2, Technical Note 4, 2001) and further in view of Toledano et al. (US2012/0202695A1, cited on IDS) evidenced by Rosso et al. (Absence of Degradation of Tretinoin When Benzoyl Peroxide is Combined with an Optimized Formulation of Tretinoin Gel (0.05%), J Clin Aesthet Dermatol, 2010; 3(10):26-28) and Casanova and Santos (Encapsulation of cosmetic active ingredients for topical application, J Microencapsulation, 2016; 33(1):1-17).
Mallard et al. disclose stable dermatological/cosmetic emulsions useful for the treatment of acne vulgaris formulated into a physiologically acceptable medium, a homogeneous dispersion of at least one dispersed retinoid, dispersed benzoyl peroxide, at least one fatty phase, at least one hydrophilic phase and at least one emulsifier (abstract, [0040], claim 1) wherein the emulsion comprises from 0.0001% to 20% of at least one retinoid and from 0.0001% to 20% of benzoyl peroxide ([0062], claims 2-3), wherein an exemplary retinoid may be retinoic acid, tretinoin and/or tazarotene ([0077], claim 11). The benzoyl peroxide is preferably included at concentrations ranging from 2.5% to 5% by weight, and the retinoid for its part is included in this type of composition at concentrations generally ranging from 0.01% to 1% by weight ([0114]). A regimen is taught for the prevention or treatment of acne vulgaris, comprising topically applying onto the skin of an individual in need of such treatment, an effective amount of the stable dermatological emulsion as disclosed (claim 27).
Mallard et al. differ from the claimed regimen wherein the application occurs daily for at least 4 weeks; and wherein the tretinoin and benzoyl peroxide are individually encapsulated by a semi-metal oxide or metal oxide.
Patel et al. teach a treatment of acne comprising applying benzoyl peroxide to the face in the morning and then tretinoin to the face before bedtime for a treatment period of 3 months (at least 12 weeks) (page 2, col. 1, para. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the filing of the instant application apply the composition of Mallard et al. for at least 12 weeks once daily and have a reasonable expectation of success. One would have been motivated to do so since Patel et al. teach that this is a well-established and common treatment regimen. It would have been prima facie obvious to one of ordinary skill in the art at the time of the filing of the instant application to adjust the amount of tretinoin to 0.1% and benzoyl peroxide to 3% and have a reasonable expectation of success. In the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists.
The reduction in lesion count after about 2 weeks being at least about twice that during the period starting at about week 2 and ending at about week 4 (instant claim 1) and the percentage decrease in lesions of about 25.2% after about 2 weeks, compared to the 17.8% after treatment with vehicle control for about 2 weeks (instant claim 6) would necessarily be present in the method of Mallard et al. as modified by the teachings of Patel et al. since the composition and method steps of the prior art are indistinguishable from the instant claims.
Regarding the claimed invention wherein the medicament is a cream, Mallard et al. provide cream type formulations where adapalene (i.e., retinoid) is at 0.1% and the benzoyl peroxide is at 2.5% ([0244]). It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to substitute one known retinoid of Mallard et al. with the tretinoin taught by Mallard et al. for a similar purpose of providing a regimen in the treatment of acne. Simple substitution of one retinoid for another is within the purview of the skilled artisan and would yield predictable results.
It is noted that Mallard et al. cite a study published in the late 1990’s to compare adapalene and tretinoin henceforth illustrating that the decomposition of benzoyl peroxide is not desirable insofar as it is harmful to the effectiveness of the composition in which they are present ([0028]). Yet, over a decade later, Rosso et al. substantiate that no benzoyl peroxide-induced degradation of tretinoin exists when the formulation is optimized and suggests that this particular combination may be utilized concurrently without concerns about tretinoin oxidation and degradation (abstract). Nonetheless, Toledano et al. evidenced by Casanova and Santo et al. address Mallard’s concerns of the effectiveness of such compositions.
Toledano et al. provide core-stabilized microcapsules wherein said core comprises at least one active agent encapsulated within a metal oxide shell, processes for their preparations, comparisons comprising them and uses thereof (abstract, [0031], claim 50). Toledano et al. teach that obtaining a microcapsule having a metal-oxide shell wherein the incorporation of phase changing material into the core of said microcapsule provides unexpected stability to the encapsulated active agents in the core of said microcapsule ([0029]). Toledano et al. teach that the term “core” refers to the inside part of the microcapsules comprising at least one active agent and at least one phase changing material that are both surrounded by a metal oxide shell of a microcapsule ([0034]).
Toledano et al. teach said core comprises a dermatological agent selected from anti-acne agents selected from benzoyl peroxide, retinoid, and mixtures thereof, wherein the retinoid may be for example tretinoin (all trans retinoic acid, ATRA), tazarotene, iso-tretinoin, adapalene or mixtures thereof ([0055-0058], claims 53, 64). Toledano et al. teach a composition comprising the discloses microcapsules, wherein the core comprises a dermatological agent, for the treatment of a disease or disorder selected from acne, infection, inflammation ([0110-0112], claims 52, 63). Toledano et al. disclose formulations of encapsulated ATRA and encapsulated BPO (E-ATRA 0.1%/E-BPO 6%) ([0210], Ex. 16).
Toledo et al. teach a microcapsule capable of being stable (i.e., maintain at least about 0 to 5% of said encapsulated at least one active agent) for a period of between about 2 weeks to about 2 years at room temperature ([0053], [0093], claim 65). However Toledo et al. do not specifically address Mallard’s concerns surrounding effectiveness. As evidenced by Casanova and Santos, encapsulation and stabilization of oxidatively sensitive dermatological agents (i.e., Vitamin C) can be achieved with metal oxide further providing improved controlled release behavior, biological activity and transdermal delivery efficiency (page 5, para. 3).
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to combine the metal-oxide shell taught by Toledano et al. evidenced by Casanova and Santos with the teachings of Mallard et al. in view of Patel et al. with expected results. One would be motivated to do so with a reasonable expectation of success because Toledano et al. further note that the microcapsules obtained demonstrate a higher stability, as measured in the amount of leakage measured upon long storage of said microcapsules ([0052]) would contribute to the art, absent a clear showing of evidence to the contrary. In addition, Toledano et al. complement Mallard’s cream formulations by teaching that emulsions wherein the core of said microcapsule comprise said at least one active agent and at least one phase forming material ([0032-0034]); material to be crucially important in cream formulations.
Response to Arguments
Applicant’s arguments filed 03/31/2026 have been fully considered but they are not persuasive.
103 Wortzman, Patel, and Lapidot
Applicants argue Wortzman’s statement, “The stability of the tretinoin in aqueous gel was significantly better than tretinoin in a cream,” discourages a person of ordinary skill in the art from pursuing cream formulation for tretinoin/benzoyl peroxide (BPO) combination due to demonstrated inferior stability. Applicants argue Wortzman’s discouragement to select a cream is not overcome by Lapidot because there is no specific teaching on how to achieve stability and efficacy for this particular combination (see Remarks, page 7, paragraph 2).
The Examiner respectfully submits that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments. Lapidot teaches active ingredients useful for topical application i.e., tretinoin, and provides stability specifically to anti-acne combinations of benzoyl peroxide and oxidation-sensitive active ingredients such as retinoids ([0010], [0169], [0253] Ex. 7).
Applicants argue that because of 0.1% vs. 0.05% with 3% BPO demonstrated improved efficacy with no increase of side effects provides unexpected results in a cream, citing Table 21 (see also Spec., [0095]) in which 44.8% of subjects that complained about burning at 12 weeks of using 0.05% tretinoin and 3% benzoyl peroxide but at 0.1% tretinoin 38.1% complained of burning (see Remarks, bridging pages 7-8).
Applicants argue that data in paragraphs [00263] Table 24 and [00261] Table 23 demonstrate an unexpected early onset of action and efficacy as early as after two weeks of treatment and further suggest a composition comprising 0.1% tretinoin, 3% BPO demonstrate synergism (see Remarks, page 8, paragraphs 3-4). Applicants argue the results from Tables 5 and 6 provide specific, quantifiable and clinical benefits achieved by a cream composition comprising 0.1% tretinoin and 3% BPO to be novel, non-obvious and are not inherently present in the prior art (see Remarks, page 10, paragraph 1).
Regarding Applicants’ arguments (numbered 2 and 3 directly above), Applicants’ claimed regimen employs a greater ratio of actives (see Patel, Materials and Methods). As such, one would expect a higher reduction. Even as Patel uses less TRE and BPO, reduction was observed after two weeks, to suggest enhanced efficacy. The combination of references when taken together, suggest applying single composition of 0.1% tretinoin and 3% benzoyl peroxide in the form of cream to treat acne by applying such a composition to the face of a patient suffering from acne once a day for at least 4 weeks. Given that the composition is suggested and the method steps are suggested by the prior art, an early onset of action and reduction in non-inflammatory lesion count would be inherent to the method suggested by the cite prior art.
Regarding the argument that the 3% BPO and 0.1% tretinoin enhances the efficacy of the composition for the treatment of acne, paragraph [00261] Table 23; paragraph [00262] of the instant disclosure show differences from the baseline over time of the said composition “compared to the change from baseline after treatment with vehicle alone.” The Examiner submits that the composition and method of Wortzman inherently possess the instantly claimed effect. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer." There is no requirement that the skilled artisan would have recognized the inherent disclosure at the relevant time; only that the subject matter is in fact inherent in the prior art reference.
Applicants argue there is no motivation to combine and no reasonable expectation of success when considering Wortzman, Patel, and Lapidot (see Remarks, page 10, paragraphs 2-3).
Lapidot teaches that the described preferred embodiments the acceptable carrier and the final form of the composition is selected from the group that includes an emulsion, and a cream ([0048], [0052], [0142]). Lapidot underscores how cream formulations would benefit from micro-capsules of microcapsule cream formulations by teaching that the release/delivery of the active ingredient is achieved by disintegration of the micro-capsules upon topical application thereof via for example sheer forces applied by a spreading action commonly used to spread creams, gels or ointments ([0152], claim 20).
103 Mallard, Patel, Toledano, Rosso, Casanova & Santos
Applicants argue Mallard primarily teaches adapalene in combination with BPO with Examples 1-5 and suggests to not administer tretinoin and BPO concomitantly (see Remarks, page 11, paragraph 2).
Mallard et al. disclose stable dermatological/cosmetic emulsions useful for the treatment of acne vulgaris formulated into a physiologically acceptable medium, a homogeneous dispersion of at least one dispersed retinoid, dispersed benzoyl peroxide, at least one fatty phase, at least one hydrophilic phase and at least one emulsifier (abstract, [0040], claim 1) wherein the emulsion comprises from 0.0001% to 20% of at least one retinoid and from 0.0001% to 20% of benzoyl peroxide ([0062], claims 2-3), wherein an exemplary retinoid may be retinoic acid, tretinoin and/or tazarotene ([0077], claim 11). Cream type formulations are taught where adapalene (i.e., retinoid) is at 0.1% and the benzoyl peroxide is at 2.5% ([0244]). It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to substitute one known retinoid of Mallard et al. with the tretinoin taught by Mallard et al. for a similar purpose of providing a regimen in the treatment of acne. Simple substitution of one retinoid for another is within the purview of the skilled artisan and would yield predictable results.
Applicants argue Toledano does not teach a cream with Formulations 12-15 as being gels and the 0.1% tretinoin and 6% BPO differs from the claimed invention (see Remarks, bridging pages 11-12). Applicants argue Patel does not teach and suggest combining two actives in a single formulation, Rosso focuses on gel formulations and Casanova & Santos do not teach a specific combination of 0.1% tretinoin and 3% BPO in a cream (see Remarks, pg. 12, paragraphs 1-3).
Rosso et al. is provided to rule out tretinoin being degraded by benzoyl peroxide, so the combination may be utilized (abstract). One would be motivated to combine the metal-oxide shell taught by Toledano et al. evidenced by Casanova and Santos with the teachings of Mallard et al. in view of Patel et al. because Toledano et al. further note that the microcapsules obtained demonstrate a higher stability, as measured in the amount of leakage measured upon long storage of said microcapsules ([0052]). And also, Toledano et al. teach that emulsions wherein the core of said microcapsule comprise said at least one active agent and at least one phase forming material ([0032-0034]); material to be crucially important in cream formulations.
For these reasons, Applicants’ arguments are found unpersuasive.
Conclusion
All claims under consideration remain rejected; no claims are allowed. Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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.
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/Karen A Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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