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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/10/2025 has been entered.
Response to Arguments
Applicant's arguments filed 11/10/2025 have been fully considered but they are not persuasive.
Applicant argues that the teaching of Sozio is directed towards drug permeation rate rather than a donepezil dosage range. Sozio teaches that patches deliver donepezil through normal skin contact into patient’s blood stream in range of about 0.5 μg/cm2/hr to about 20 μg/cm2/hr. The dosage is controlled by active surface of patch that comes in contact with the skin and can be adjusted by prescribing a patch with a larger or smaller active surface area. Dose size and frequency should be determined by trained medical professional and depend on many factors, including patient weight and disease severity (see p. 365, last paragraph). Thus, Sozio teaches parameters for dosage range and skin permeability rate for delivery of donepezil. Thus, one of ordinary skill in the art would then calculate the actual dose per unit area (i.e. amount of donepezil in the patch) to arrive at this parameter. As Sozio teaches skin permeability rate that falls within the limitations of the claim, and the limitations of the components of the patch are met in the prior art. According to MPEP 2112.01, Section II, “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.
Applicant further argues that the performance of the skin patch would not have been expected based on the proposed combination of Choi in view of Lee and the specific amount of PVP is necessary to prevent donepezil crystallization and for the stability of the formulation. However, LEE teaches the crystallization inhibitor may be used in an amount of 0.05 to 5 wt %, preferably 0.05 to 2.5 wt %, based on the total weight of the drug-containing adhesive layer (see paragraph [0027]). MPEP 2144.05 states In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Thus, the range of PVP in the composition is taught by the prior art. As a result, since the limitations for the components of the drug-containing matrix layer have been met by the prior art, the properties such as the donepezil dose range and skin permeability would expected to be met. Applicant argues that prior art formulation cannot deliver high dose of donepezil without sacrificing formulation stability and have donepezil in lower concentrations (5 to 10 wt%). However, the instant claim teaches 9 to 14 wt%. One of ordinary skill in the art would be motivated to increase the amount of drug delivered to the patient, and 2144.05, Section II teaches that “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). see also 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
Applicant argues that there is a lack of motivation to combine Choi with Lee as Lee suggests PVP would avoid crystallization of melatonin and is silent regarding inhibition of donepezil. The rejection has been modified and the art of IM (see US 2015/0045749) teaches polyvinylpyrrolidone increases the solubility of donepezil and thus plays a role in enabling the complete dissolution of donepezil in the transdermal delivery system (see paragraph [0020]). Thus, one would be motivated to add polyvinyl pyrrolidone to donepezil regardless of the adhesive system used.
Regarding Applicant’s arguments about synergy, according to MPEP 2145, 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 has not presented actual objective evidence to support allegation of superior long-term formulation stability, high skin permeability and patient medication convenience and compliance.
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), LEE (see US Pat. No. 9,993,466, issued 06/12/2018) and SOZIO (see Neuropsychiatric Disease and Treatment, 2012, Vol. 8, p. 361-368).
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. Additionally, SOZIO teaches that the capacity of a drug, specifically donepezil, to penetrate the skin is an important issue for clinical relevance of transdermal delivery system. The patches deliver donepezil through normal skin contact into patient’s blood stream in range of about 0.5 μg/cm2/hr to about 20 μg/cm2/hr. The dosage is controlled by active surface of patch that comes in contact with the skin and can be adjusted by prescribing a patch with a larger or smaller active surface area. Dose size and frequency should be determined by trained medical professional and depend on many factors, including patient weight and disease severity (see p. 365, last paragraph). Thus, Sozio teaches parameters for dosage range and skin permeability rate for delivery of donepezil. One would be motivated to increase the dosage of donepezil per unit area patch using LEE as a starting point to provide desired treatment for Alzheimer’s symptoms, thereby allowing large doses of donepezil to be delivered.
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]).
Thus it would be prima facie obvious to one of ordinary skill in the art to utilize the PVP as a crystallization inhibitor in 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. Thus, 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.
Conclusion
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