DETAILED ACTION
Claims 1-8 and 12 are currently pending in the instant application.
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 .
Response to Arguments
Applicant's arguments filed 04/30/2026 have been fully considered but they are not persuasive.
Applicant argues that the prior art of Choi, Im, Lee and Sozio fail to teach or suggest the introduction of isopropanol as a co-solvent for use in preparing the donepezil-containing matrix layer composition of the preparation for percutaneous absorption. However, the claim itself is drawn to a preparation for percutaneous absorption, comprising a drug-containing matrix layer. Applicant has amended the claim so the limitations of the drug-containing matrix layer appear to be a product by process. MPEP 2113 states that “[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) (citations omitted). It is unclear what the final components are necessary for the drug-containing matrix layer as the instant claim does not discuss how the drug-containing matrix layer is prepared from a composition.
Regarding the preparation of the drug-containing matrix layer, US PG Pub 2022/0226296, the publication of the instant application, hereafter referred to as US ‘296, states that the drug-containing matrix layer is prepared so that following homogeneously mixing of all the raw materials, the air bubbles are removed, the mixture is applied to a release liner coated with silicone and dried (see paragraph [0039]). Thus, based on the Specification, it does not appear that the drug-containing matrix layer itself has isopropanol.
Further, the prior art of IM does teach the use of the solvent, ethanol in the preparation of the drug-containing matrix layer, specifically that the polyvinylpyrrolidone dissolved in ethanol (see paragraph [0034]). Thus, it would still be considered obvious to substitute the solvent isopropanol for ethanol, which are both alcohol solvents. The adjustment of particular conventional working conditions (e.g. determining result effective amounts of the ingredients beneficially taught by the cited references), as well as adjustment of reaction temperature, reaction time and use of solvents, rearranging steps in a reaction sequence, is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan (See In re Mostovych, Weber, Mitchell and Aulbach, 339F.2d 455; 144 USPQ 38).
Regarding Applicant’s argument of unobvious, unexpected results exhibited by the claimed preparation, specifically that the presently claimed preparation demonstrates excellent long-term stability as evidence by lack of donepezil crystal generation after 4 weeks of storage at room temperature which is not exhibited in similar transdermal preparation having different drug-containing matrix layer composition components and/or isopropanol co-solvent at a concentration above 2.5 parts by weight based on 100 parts by weight of the total weight of components (a), (b) and (c), thus establishing criticality of presently claimed component (d) isopropanol co-solvent. Applicant submits a declaration to support the claim of superiority, unexpected results and criticality.
The declaration under 37 CFR 1.132 filed 04/30/2026 is insufficient to overcome the rejection of claims 1-8 and 12 based upon 35 U.S.C. 103 as set forth in the last Office action because: Applicant states that Preparation Examples 2-14 and 2-15 demonstrate excellent stability as evidenced by little to no solid crystal generation. Applicant further states that Preparation Example 2-16 having isopropanol co-solvent concentration of 5.18 parts by weight shows crystals precipitated. Applicant contends that the unexpected result occurs when the drug-containing matrix layer is preparation from a composition comprising 1.0 to 2.5 parts by weight of isopropanol as a co-solvent based on 100 parts by weight of the total weight of components (a), (b) and (c).
Table 9 from the Specification which has the components of the raw materials in Preparation Examples 2-14, 2-15 and 2-16 is reproduced below:
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254
450
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. Preparation Example 2-14 has 16.8 / (54 + 968.3 + 5.6) = 16.8/ / 1027.9 = 1.6 parts by weight of isopropanol based on 100 parts by weight of the total weight of components (a),(b)and (c) in the drug-containing matrix composition. Preparation Example 2-15 is 39.2 / (54 + 968.3 + 5.6) = 3.8 parts by weight of isopropanol rather than 2.48 as alleged by Applicant. Thus, Preparation Example 2-15 does not fall within the claimed range, and Applicant’s allegation that the unexpected properties which results from the critical combination of components (a), (b), (c), and (d) at the claimed range appears unfounded given that Preparation Example 2-15 has 3.8 parts by weight of isopropanol, which is outside the claimed range and Preparation Example 2-15 still demonstrates the stability with little to no donepezil crystal formation observed after 4 weeks.
Further, MPEP 716.02 (d) states that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). It is the burden of Applicants to demonstrate unexpected results, explain the results, and place the claims commensurate in scope with those results. MPEP 716.02. Given that Applicant only shows one example having the alleged unexpected result, this would not be sufficient to meet applicants burden of demonstrating an unexpected result commensurate in scope with the instant claims, particularly where the instantly claimed ranges take the form of a product by process.
Thus, the 103 rejections have been maintained.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-8 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over CHOI (see U.S. Pub No. 2016/0051486, pub. 02/25/2016) in view of IM (see US 2015/0045749, pub. 02/12/2015) and LEE (see US Pat. No. 9,993,466, issued 06/12/2018).
CHOI teaches a transdermal delivery system comprising a drug-containing matrix layer, a backing layer (corresponds to support layer of instant claims) and a release layer. The drug-containing layer comprises (a) donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, (b) a mixture of high molecular weight polyisobutylene having a weight-average molecular weight ranging from 400,000 to 3,000,000 and low molecular weight polyisobutylene having a weight-average molecular weight ranging from 25,000 to 300,000 as an adhesive. Donepezil is taught in 5 to 10% by weight based on the total weight of the drug-containing matrix layer (see paragraph [0012]). The high molecular weight polyisobutylene may have a weight-average molecular weight ranging from 800,000 to 1,500,000, and the low molecular weight polyisobutylene may have a weight-average molecular weight ranging from 25,000 to 200,000. In an embodiment, the adhesive may be a mixture of high molecular weight polyisobutylene having a weight-average molecular weight of 1,000,000 and low molecular weight polyisobutylene having a weight-average molecular weight of 75,000. A weight ratio of the high molecular weight polyisobutylene and the low molecular weight polyisobutylene may be 1:0.3 to 1:2. And also, the adhesive may be present in an amount of 40 to 50% by weight based on the total weight of the drug-containing matrix layer (see paragraph [0013]). These correspond to the limitations of claims 1-2 and 4-8. Further, CHOI teaches the drug-containing matrix layer may further comprise one or more excipients selected from the group consisting of a stabilizer, an oil, and a thickening agent (see paragraph [0015]). This corresponds to the limitation of claim 12. CHOI also teaches skin permeation rate of the transdermal delivery systems between 4.5-7.2 ug/cm2/hr (see Table 1, p. 4). This reads on claim 1. CHOI is silent as to dose per unit area of donepezil in the preparation for percutaneous absorption.
Regarding the dose per unit area of donepezil, LEE teaches patches for a transdermal delivery system and the patch has a size in the range of about 16 cm2-225 cm2 (see col. 15, lines 22-24) and Example 5 teaches 10 mg donepezil per day (see col. 25) transdermally, which is 0.6 mg/cm2. According to 2144.05, Section II, Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). One of ordinary skill in the art would be motivated to increase the dose of donepezil per unit patch to deliver more drug, thereby providing more dosage options of the drug to treat Alzheimer’s dementia.
CHOI does not teach a crystallization inhibitor. However, CHOI teaches that solid crystal is observed when silicon type adhesive is used at donepezil content of not less than 5% by weight so a drug containing matrix layer cannot be formed with high amounts of donepezil. Thus, when the silicone type adhesive was used, a drug-containing matrix layer cannot be formed at high amounts of donepezil (see paragraph [0056]). Further CHOI teaches crystallization of drug substance in a transdermal delivery system causes various problems, such as decrease in adhesive force, variation in skin permeation rate, storage problems, etc., which make it difficult to incorporate drug substance in a high concentration into a transdermal delivery system (see paragraph [0007]).
IM teaches a formulation for a patch having a drug containing matrix layer and adhesive layer. Specifically, IM teaches if amount of donepezil is increased in conventional transdermal delivery system, donepezil becomes crystallized in formulation causing reduction in adhesive strength. Additionally with transdermal delivery system of a triple-layer form designed to control release rate of donepezil, production process is complicated (see paragraph [0004], p. 1). IM teaches that polyvinylpyrrolidone (PVP) in solution with donepezil does not show any crystallization of donepezil (see paragraph [0014]) since PVP increases solubility of donepezil and enables complete dissolution of donepezil in transdermal delivery system (see paragraph [0020]). Further IM may be used in an amount of 1-20 wt %, based on the total weight of the drug-containing matrix layer (see paragraph [0020]). IM teaches use of the solvent ethanol in the preparation of a drug-containing matrix layer (see Table 3, p. 4). Given that ethanol and isopropanol are both alcohol solvents, it would still be considered obvious to substitute isopropanol for ethanol as a solvent. The adjustment of particular conventional working conditions (e.g. determining result effective amounts of the ingredients beneficially taught by the cited references), as well as adjustment of reaction temperature, reaction time and use of solvents, rearranging steps in a reaction sequence, is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan (See In re Mostovych, Weber, Mitchell and Aulbach, 339F.2d 455; 144 USPQ 38).
Thus, it would have been prima facie obvious to one of ordinary skill in the art to utilize the PV as a crystallization inhibitor and use preparation methods taught in the art of IM to the art of CHOI. CHOI teaches that crystallization of drug substance in transdermal delivery system may cause various problems, such as decrease in adhesive force, variation in skin permeation rate, storage problems, which makes it difficult to incorporate drug substance in high concentrations into a transdermal delivery system (see paragraph [0007]). Further, CHOI discloses formation of crystals when the silicone type adhesive was used so that a drug-containing matrix layer cannot be formed at high amounts of donepezil. Further, it would be obvious to apply the teachings of IM who states that polyvinylpyrrolidone (PVP) in solution with donepezil does not show any crystallization of donepezil to the art of CHOI who teaches crystallization of the drug causes various issues and occurs when a silicon type adhesive is used in order to prevent crystallization of the active ingredient so that more of the drug can be delivered effectively. Regarding preparation of the drug-containing matrix layer, IM teaches the solvent ethanol rather than isopropanol, which would be considered obvious, and by using the teachings of IM with CHOI, a drug-containing matrix layer could be prepared from a composition comprising the components of instant claims.
Regarding the limitation “the preparation exhibits no crystallization of donepezil or the pharmaceutically acceptable salt thereof after storage at room temperature for 4 weeks”, it is unclear what the actual components of the preparation are other than a support layer, drug-containing matrix layer and release layer. As the prior art meets these limitations, artisans of ordinary skill may not recognize inherent characteristics or functioning of the prior art. However, the 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. See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347-49 (Fed. Cir. 1999); accord Toro Co. v. Deere & Co., 355 F.3d 1313, 1320-21 (Fed. Cir. 2004).
Conclusion
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 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 KAREN CHENG whose telephone number is (703)756-4699. The examiner can normally be reached M-F, 9AM-6PM PST.
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/KAREN CHENG/Primary Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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