`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`First Inventor Name:
`
`.luan Mantelle
`
`Title:
`
`'I‘ransdermal Estrogen Device and Delivery
`
`Prior App]. No.:
`
`13/553,972
`
`Prior Appl. Filing
`Date:
`
`7/20/2012
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
`
`TRANSMITTAL LETTER
`
`Commissioner for Patents
`
`PO. Box 1450
`
`Alexandria, VA 22313—1450
`
`Commissioner:
`
`Transmitted herewith for filing under 37 CPR. § l.53(b) is a:
`
`[X ] Continuation
`
`[
`
`] Division
`
`[
`
`] Continuation-In—Part (CIP)
`
`of the above-identified copending prior application in which no patenting, abandonment, or
`
`termination of proceedings has occurred. Priority to the above—identified prior application is
`
`hereby claimed under 35 U.S.C. § 120 for this continuing application. The entire disclosure of
`
`the above—identified prior application is considered as being part of the disclosure of the
`
`accompanying continuing application and is hereby incorporated by reference therein.
`
`4827-6562-35731
`
`MYLAN - EXHIBIT 1004
`
`
`
`
`
`
`Pafiilof2
`
`0001
`
`
`
`Atty. Dkt. No. 041457—1016
`
`[Enclosed are:
`
`{i X 1 Application Data Sheet (37 CFR 1.76).
`
`[ X ] Description, Claim(s), and Abstract (27 pages).
`
`1 X 1 Drawing (1 sheet, Figure 1).
`
`The adjustment to the number of sheets for EFS-Web filing follows:
`
`
`Number of
`
`EFS~Web
`
`Number of Sheets for EFS-Web
`
`Sheets
`
`28
`
`Adjustment
`21
`x
`75%
`
`The filing fee is calculated below at the large entity rate:
`
`Fee
`Rate
`Number
`Included
`Extra
`
`H
`
`H
`
`H
`
`H
`
`H
`
`Totals
`
`$280.00
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`$600.00
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`$720.00
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`$0.00
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`$0.00
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`$0.00
`
`$0.00
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`$140.00
`
`$0.00
`
`$0.00
`
`$1740.00
`
`$280.00
`
`$600.00
`
`$720.00
`
`$400.00
`
`$80.00
`
`$420.00
`
`$780.00
`
`$140.00
`
`Filed
`
`in
`
`Basic Fee
`
`Basic Filing
`Fee
`
`Search Fee
`
`Examination
`
`Fee
`
`Size Fee
`
`Total
`
`Claims:
`
`21
`
`20
`
`Independents
`
`3
`
`ll
`
`ll
`
`—
`
`—
`
`-
`
`100
`
`20
`
`3
`
`+ +
`
`If any Multiple Dependent Claim(s) present:
`
`Surcharge under 37 CFR 1.16(e) for late filing of
`Executed Declaration and late payment of filing fee
`
`Prioritized Examination fee (Track 1) under 37 CFR. § 1.17 (c)
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`Processing Fee (Track I) under 37 CFR. § 1.17 (i)
`TOTAL FILING FEE:
`
`The required filing fees are not enclosed but will be submitted in response to the Notice
`
`to File Missing Parts of Application.
`
`4827-6562-35731
`
`
`
`0002
`
`
`
`Atty. Dkt. No. 041457—1016
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Respectfully submitted,
`
`
`
`By
`
`{ 522; i,”
`
`Data’s,“ TEMPE/fife» 33A
`
`“g 3
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 295—4094
`Facsimile:
`(202) 672—5399
`
`Courtenay C. Brinckerhoff
`Attorney for Applicant
`Registration No. 37.288
`
`4827—6562-35731
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`0003
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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number
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`Application Number
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`Transdermal Estrogen Device and Delivery
`
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`Inventor Information:
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`Inventor
`1
`EOE
`
`Legal Name
`
`
`Prefix Given Name
`Juan
`
`
`
`Middle Name Suffix Family Name
`
`Mantelle
`
`
`
`
`
`
`Residence information (Select One) © US Residency 0 Non US Residency 0 Active US Military Sen/ice
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`Miami
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`FL
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`Title of the Invention
`Transdermal Estrogen Device and Delivery
`
`Attorney Docket Number
`041457—1016
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`Subject Matter
`Utility
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`0008
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`Attorney Docket No: 041457~0857
`
`TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`
`[0001] Described herein are compositions and methods for the transdcrmal delivery
`
`FIELD OF THE INVENTION
`
`of estrogen.
`
`BACKGROUND
`
`[0002] This invention relates generally to transderrnal drug delivery systems, and
`
`more particularly, to transderrnal drug delivery systems for the delivery of estrogen.
`
`The use of a transdermal system, for example, a patch comprising a pressure—sensitive
`
`adhesive containing a drug, as a means of delivering drug through the skin is well
`
`known. However, there remains a need for transdermal drug delivery systems
`
`designed for the delivery of specific drugs, such as estrogen, and there remains a
`
`particular need for smaller transderrnal drug delivery systems that exhibit desired
`
`phannacokinetic properties.
`
`[0003] Transdermal delivery systems (adhesive patches) as dosage forms have been
`
`the subject of a vast number of patent applications over the last 25 years, yielding
`
`many patents but few commercial products in comparison. To those working in the
`
`field, the relatively small number of commercial products is not surprising. Although
`
`regulatory, economic, and market hurdles play a role in limiting the number of
`
`products on the market, the task of developing a transdermal delivery system that
`
`achieves desired physical and pharmacokinetic parameters to satisfy physician and
`
`patient demand is more daunting. Parameters to be considered during commercial
`
`product development may include drug solubility, drug stability (e.g., as may arise
`
`from interaction with other component materials and/or the environment), delivery of
`
`a therapeutic amount of drug at a desired delivery rate over the intended duration of
`
`use, adequate adhesion at the anatomical site of application, integrity (e.g., minimal
`
`curling, wrinkling, delarninating and slippage) with minimal discomfort, irritation and
`
`sensitization both during use and during and after removal, and minimal residual
`
`adhesive (or other components) after removal. Size also may be important from a
`
`manufacturing and patient viewpoint, and appearance may be important from a patient
`
`viewpoint. The physical manufacturing and production aspects of commercial
`
`product development (e.g., the identity and costs of materials, equipment, and labor)
`
`
`
`0009
`
`
`
`Attorney Docket No.: 041457—0857
`
`and supporting analytical methods required for regulatory compliance also can be
`
`significant.
`
`[0004] Of the physical parameters that are considered when developing a
`
`commercial transdennal drug delivery system, size, e.g., surface area at the site of
`
`application, is often dictated and limited by other physical and phannacokin tic
`
`requirements, such as desired drug delivery rates and daily dosages. In general, it is
`
`easier to develop a relatively “large" transdermal drug delivery system that will
`
`achieve drug delivery at target therapeutic levels over an intended duration of therapy,
`
`than it is to develop a smaller transdermal drug delivery system that still exhibits
`
`acceptable pharmacokinetic properties. Still, because size directly impacts costs (cg,
`
`costs of component materials, costs of packaging materials, costs for production and
`
`manufacturing equipment, labor costs relative to product yield per run time, etc.) and
`
`patients generally prefer smaller systems to larger ones (both for aesthetic reasons and
`
`comfort, since a smaller sm’face may permit the use of less aggressive adhesives),
`
`there is a need for smaller transdennal drug delivery systems.
`
`SUMMARY
`
`[0005]
`
`In accordance with one embodiment, there is provided a transdermal drug
`
`delivery system comprising a drug containing layer defining an active surface area
`
`and comprising a polymer matrix comprising estradiol, wherein the system includes
`
`greater than 0.156 mg/cm2 estradiol and achieves an estradiol flux that is greater than
`
`0.01 mg/cmz/day, based on the active surface area. In some embodiments, the
`
`polymer matrix comprises a polymer blend comprising an acrylic adhesive, a silicone
`
`adhesive, and soluble PVP.
`
`In some embodiments, the polymer matrix comprises
`
`about 2—25% by weight acrylic adhesive, about 45—70% by weight silicone adhesive,
`
`about 2~25% by weight soluble PVP, about 5-15% penetration enhancer, and about
`
`01-10% by weight estradiol, all based on the total dry weight of the polymer matrix.
`
`In some embodiments, the polymer matrix comprises about 20% by weight acrylic
`
`adhesive, about 56.9% by weight silicone adhesive, about 7.5% by weight soluble
`
`PVP, about 6.0% by weight oleyl alcohol, about 8.0% by weight dipropylene glycol,
`
`and about 1.6 % by weight estradiol. In some embodiments, the acrylic adhesive and
`
`silicone adhesive are present in a ratio of &0m about 1:2 to about 1:6, based on the
`
`total weight of the acrylic and silicone adhesives.
`
`
`
`0010
`
`
`
`Attorney Docket No.: 041457-0857
`
`[0006]
`
`In some embodiments, the penetration enhancer comprises oleyl alchol or
`
`dipropylene glycol, or both.
`
`[0007]
`
`In some embodiments, the polymer matrix comprises an amount of estradiol
`
`effective to deliver a therapeutically effective amount of estradiol over a period of
`
`time selected from the group consisting of at least 1 day, at least 2 days, at least 3
`
`days, at least 4 days, at least 5 days, at least 6 days and at least 7 days.
`
`In some
`
`embodiments, the polymer matrix comprises an amount of estradiol effective to
`
`deliver an amount of estradiol selected from the group consisting of about 0.025,
`
`0.0375, 0.05, 0.075 and 0.1 mg/day.
`
`[0008]
`
`In some embodiments, the polymer matrix has a coat weight of greater than
`
`about 10 mg/cmz. In some embodiments, the polymer matrix has a coat weight
`
`selected from the group consisting of about 12.5 and about 15 mg/ cmz.
`
`[0009]
`
`In accordance with some embodiments, there is provided a transdermal drug
`
`delivery system comprising a polymer matrix comprising estradiol, wherein the
`
`system has an active surface area that is about 60% of a size selected from the group
`
`consisting 0f2.5, 3.75, 5.0, 7.5 and 10.0 cm2 and is efl'ective to deliver an amount of
`
`estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.
`
`[0010]
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`In accordance with some embodiments, there is provided a method for
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`administering estradiol, comprising applying to the skin or mucosa ofa subject in
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`need thereofa transdennal drug delivery system comprising a dmg-containing layer
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`defining an active surface area and comprising a polymer matrix comprising estradiol,
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`wherein the system includes greater than 0.156 mg/cm2 estradiol and achieves an
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`estradiol flux that is greater than 0.01 mg/cmZ/day, based on the active surface area.
`
`In some embodiments, the system has an active surface area that is about 60% ofa
`
`size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cml and is
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`effective to deliver an amount of estradiol per day of about 0.025, 0.0375, 0.05, 0.075
`
`and 0.] mg/day, respectively.
`
`[0011]
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`In accordance with some embodiments, there is provided a method of
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`making a transdermal drug delivery system for administering estrogen, comprising
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`forming a polymer matrix comprising estrogen and a polymer blend comprising an
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`acrylic adhesive, a silicone adhesive, and soluble PVP, and applying the polymer
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`matrix to a support layer such that the system includes greater than 0.156 mg/crn2
`
`
`
`0011
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`
`
`Attorney Docket No; 0414570857
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`estradiol. In some embodiments, the system has an active surface area that is about
`
`60% ofa size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cmz.
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`In some embodiments, the polymer matrix comprises about 20% by weight acrylic
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`adhesive, about 56.9% by weight silicone adhesive, about 7.5% by weight soluble
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`PVP, about 6.0% by weight oleyl alcohol, about 8.0% by weight dipropylcne glycol,
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`and about 1.6% by weight estradiol.
`
`In some embodiments, the polymer matrix is
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`applied to the support layer at a coat weight of greater than about 10 mg/cmz. In some
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`embodiments, the polymer matrix coat weight is selected from the group consisting of
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`about 12.5 and about 15 mg/ cmz.
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`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0012]
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`Figure 1 illustrates the estradiol flux (pg/cmZ/hr) over time (0-81 hours) from
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`transdermal delivery systems according to the invention (A & O), as compared to
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`Vivelle-Dot® (0).
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`DETAILED DESCRIPTION
`
`[0013] The field oftransdermal delivery systems suffers from the problem of
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`needing to balance many different competing factors to develop a commercial product
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`that exhibits, for example both clinical efficacy and satisfactory wear properties while
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`remaining acceptable to patients. For example, when selecting the size of a
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`transdermal delivery system, it is necessary to balance factors that favor a smaller size
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`(such as lower cost , better adhesive performance and improved aesthetics) against
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`factors that favor a larger size (such as the target delivery rate (flux) and daily dose).
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`The VivelIe-Dot® transderrnal estradiol product (manufactured by Noven
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`Pharmaceutcials Inc.) is available in five different active surface areas (2.5, 3.75, 5.0,
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`7.5 and 100 cm2) which each deliver different amounts of drug per day (0.025,
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`0.0375, 0.05, 0.075 and 0.1 mg/day, respectively). Each of the VivelIe-Dot®
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`products include 0.156 mg/cmz estradiol.
`
`[0014]
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`In accordance with some embodiments, the present invention provides
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`transdermal drug delivery systems for the transdermal delivery of estrogen that have a
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`smaller active surface area than Vivelle-Dot® but achieve daily dosages that are about
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`equzfl to or greater than the Vivelle-Dot® products. For example, the present
`
`
`
`0012
`
`
`
`Attorney Docket No: 041457-0857
`
`invention includes transdermal drug delivery systems that achieve daily dosages that
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`are about equal to a Vivelle~Dot® product, in a smaller sized system. The ability to
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`provide a smaller system Mthout sacrificing daily dosage represents a significant
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`advance.
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`[0015] Applicant surprisingly discovered that increasing the coat weight ofthe
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`drug-containing adhesive layer resulted in an increased flux per unit area, and thus
`
`permitted the development of smaller transdermal drug delivery systems that achieve
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`comparable daily dosages. This result was surprising because coat weight is typically
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`selected to control the duration of delivery, but is not generally understood to impact
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`delivery rate. Thus, while it is known in the art to increase coat weight to provide
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`delivery over a longer period of time, it was not known that increasing coat weight
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`could increase delivery rate or flux, and thus permit the development ofa smaller
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`system while maintaining daily dosage.
`
`[0016]
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`In accordance with some aspects, there are provided transdermal drug
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`delivery systems and methods for the transdermal delivery of estrogen.
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`In specific
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`embodiments, the systems exhibit increased flux than other known estrogen devices
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`(such as Vivelle-Dot®, manufactured by Noven Pharmaceutcials Inc.) and, therefore,
`
`exhibit increased drug delivery per unit area. For example, in some embodiments, the
`
`systems exhibit a flux greater than the 0.01 mg/cml/day exhibited by the Vivelle-
`
`Dot® products, such as a flux that is about 1.25, 1.33, 1.5, 1.67, 1.75, 2, 3, 4, or 5
`
`times the flux ofthe Vivelle—Dot® products. In some embodiments, the systems have
`a greater coat weight than other known estrogen devices. For example, in some
`
`embodiments, the systems have a coat weight such that the amount of estradiol per
`
`unit area is greater than the 0.156 mg/cm2 estradiol of the Vivelle~Dot® products,
`
`such as a coat weight that is about 1.25, 1.33, 1.5, 1.67, 1.75, 2, or 3 times the coat
`
`weight of the Vivelle~Dot® products, or greater. Thus, in accordance with some
`
`aspects, the invention permits the use of smaller devices to achieve comparable drug
`
`delivery.
`
`DEFINITIONS
`
`[0017] Technical and scientific terms used herein have the meanings commonly
`
`understood by one of ordinary skill in the art to which the present invention pertains,
`
`unless otherwise defined. Reference is made herein to various methodologies known
`
`
`
`0013
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`
`
`Attorney Docket No.: 041457—0857
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`to those of ordinary skill in the art. Publications and other materials setting forth such
`
`known methodologies to which reference is made are incorporated herein by
`
`reference in their entireties as though set forth in full. Any suitable materials and/or
`
`methods known to those of ordinary skill in the art can be utilized in carrying out the
`
`present invention. However, specific materials and methods are described. Materials,
`
`reagents and the like to which reference is made in the following description and
`
`examples are obtainable from commercial sources, unless otherwise noted.
`
`[0018] As used herein, the singular forms “a," “an,” and “the” designate both the
`
`singular and the plural, unless expressly stated to designate the singular only.
`
`[0019] The term “about" and the use of ranges in general, whether or not qualified
`
`by the term about, means that the number comprehended is not limited to the exact
`
`number set forth herein, and is intended to refer to ranges substantially within the
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`quoted range while not departing from the scope of the invention. As used herein,
`
`“about” will be understood by persons of ordinary skill in the art and will vary to
`
`some extent on the context in which it is used. If there are uses of the term which are
`
`not clear to persons of ordinary skill in the art given the context in which it is used,
`
`“about” will mean up to plus or minus 10% ofthe particular term.
`
`[0020] The phrase “substantially free" as used herein generally means that the
`
`described composition (e.g., transdermal drug delivery system, polymer matrix, etc.)
`
`comprises less than about 5%, less than about 3%, or less than about 1% by weight,
`
`based on the total weight of the composition at issue, of the excluded component.
`
`[0021] As used herein “subject" denotes any animal in need of drug therapy,
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`including humans. For example, a subject may be suffering from or at risk of
`
`developing a condition that can be treated or prevented with estrogen, or may be
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`taking estrogen for health maintenance purposes.
`
`[0022] As used herein, the phrases “therapeutically effective amount” and
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`“therapeutic level” mean that drug dosage or plasma concentration in a subject,
`
`respectively, that provides the specific pharmacological response for which the drug is
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`administered in a subject in need of such treatment.
`
`It is emphasized that a
`
`therapeutically effective amount or therapeutic level of a drug will not always be
`
`effective in treating the conditions/diseases described herein, even though such
`
`dosage is deemed to be a therapeutically effective amount by those of skill in the art.
`
`-5-
`
`
`
`0014
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`
`
`Attorney Docket No.: 04145 7-0857
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`For convenience Only, exemplary dosages, drug delivery amounts, therapeutically
`
`effective amounts and therapeutic levels are provided below with reference to adult
`
`human subjects. Those skilled in the art can adjust such amounts in accordance with
`
`standard practices as needed to treat a specific subject and/or condition/disease.
`
`[0023] As used herein, “active surface area" means the surface area of the drug—
`
`containing layer of the transdermal drug delivery system.
`
`[0024] As used herein, “coat weight" refers to the weight of the drug~containing
`
`layer per unit area of the active surface area of the transdennal drug delivery system.
`
`[0025] As used herein, “estrogen” includes estrogenic steroids such as estradiol
`
`(17~B~estradiol), estradiol benzoate, estradiol 17B—cypionate, estropipate, equilenin,
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`equilin, estniol, estrone, ethinyl estradiol, conjugated estrogens, esterified estrogens,
`
`and mixtures thereof.
`
`[0026] As used herein, “flux” (also called "permeation rate") is defined as the
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`absorption ofa drug through skin or mucosal tissue, and is described by Fick's first
`
`law of diffusion:
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`J : -D (de/dx)
`
`where J is the flux in g/cmZ/sec, D is the difiilsion coefficient of the drug through the
`
`skin or mucosa in cmZ/sec and dCrn/dx is the concentration gradient of the drug across
`
`the skin or mucosa.
`
`[0027] As used herein, the term “transderrnal” refers to delivery, administration or
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`application of a drug by means of direct contact with skin or mucosa. Such delivery,
`
`administration or application i