Atty. Dkt. No. 041457-0992
`
`IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`Applicant:
`
`Juan Mantelle
`
`Title:
`
`Transdermal Estrogen Device and Delivery
`
`Prior Appl. No.:—12/216,811
`
`Prior Appl.
`Filing Date:
`
`7/10/2008
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
`TRANSMITTAL LETTER
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`Transmitted herewith for filing under 37 C.F.R. § 1.53(b) is a:
`
`[ X | Continuation
`
`[|
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`] Division
`
`[
`
`] Continuation-In-Part (CIP)
`
`of the above-identified copending prior application in which no patenting, abandonment, or
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`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.
`
`Enclosedare:
`
`[X] Application Data Sheet (37 CFR 1.76) (2 pages).
`
`[X] Description, Claim(s), and Abstract (27 pages).
`
`[X] Drawing (1 sheet, Figure 1).
`
`{[X] Executed Declaration and Power of Attorney(3 pages).
`
`4822-8678-9904,.1
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`MYLAN- EXHIBIT 1004
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`  
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`

 
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`Part 1 of 2
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`0001
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`

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`Atty. Dkt. No. 041457-0992
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`The adjustment to the numberof sheets for EFS-Webfiling follows:
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`EFS-Web
`Numberof
`Adjustment
`Sheets
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`28 75% 21
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`Numberof Sheets for EFS-Web
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`Thefiling fee is calculated below:
`
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Extra
`
`Rate
`
`oe
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`$380.00 =
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`$620.00
`$250.00
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`$310.00
`$60.00 =
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`Fee
`Totals
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`$380.00
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`$620.00
`$250.00
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`$0.00
`$0.00
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`$250.00 =
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`$250.00
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`$0.00
`$130.00
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`Rasic Filing
`Fee
`Search Fee
`Examination
`Fee
`Size Fee
`Total
`Claims:
`Independents
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`21
`20
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`4
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`-
`-
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`-
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`100
`20
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`3
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`= 0
`= 0
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`= 1
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`Xx
`X
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`x
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`+
`If any Multiple Dependent Claim(s) present:
`Surcharge under 37 CFR 1.16(e) for late payment of +
`filing fee
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`[
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`]
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`$450.00 =
`$130.00 _
`7
`$1630.00_
`SUBTOTAL: =
`0
`Small Entity Fees Apply (subtract % of above): =
`$0.00
`Basic Filing Fee Reduction for Filing via EFS-Web
`TOTALFILING FEE: = $1630.00
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`The requiredfiling fees are not enclosed but will be submitted in response to the
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`Notice to File Missing Parts of Application.
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`4822-8678-9904.1
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`
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`0002
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`

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`Atty. Dkt. No. 041457-0992
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`Please direct all correspondenceto the undersigned attorney or agent at the address
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`indicated below.
`
`Respectfully submitted,
`
` Date
`
`4
`
`sn
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 295-4094
`Facsimile:
`(202) 672-5399
`
`Courtenay C. Brinckerhoff
`Attorney for Applicant
`Registration No. 37,288
`
`4822-8678-9904.1
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`-3-
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`0003
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`

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`Application Data Sheet
`
`Application Information
`
`Application Type::
`
`Subject Matter::
`
`Suggested classification::
`
`Suggested Group Art Unit::
`
`Regular
`
`Utility
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`CD-ROMor CD-R?::
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`None
`
`Computer Readable Form (CRF)?::
`
`No
`
`Title::
`
`Transdermal Estrogen Device and Delivery
`
`Attorney Docket Number::
`
`041457-0992
`
`Request for Early Publication?::
`
`Request for Non-Publication?::
`
`Suggested Drawing Figure::
`
`Total Drawing Sheets::
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`Small Entity?::
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`Petition included?::
`
`Secrecy Order in Parent Appl.?::
`
`No
`
`No
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`1
`
`1
`
`No
`
`No
`
`No
`
`Applicant Information
`
`Applicant Authority Type::
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`Inventor
`
`Primary Citizenship Country::
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`US
`
`Status::
`
`Given Name::
`
`Family Name::
`
`City of Residence::
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`State or Province of
`
`Residence::
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`Full Capacity
`
`Juan
`
`Manteile
`
`Miami
`
`FL
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`Country of Residence::
`
`US
`
`Street of mailing address::
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`10821 S.W. 92 Avenue
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`4829-2360-3216.1
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`Page # 1
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`Initial 07/20/12
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`
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`0004
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`

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`City of mailing address::
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`Miami
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`State or Province of mailing
`
`FL
`
`address::
`
`Postal or Zip Code of mailing
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`33176
`
`address::
`
`Correspondence Information
`
`Correspondence Customer Number::
`
`22428
`
`E-Mail address::
`
`PTOMailWashington@foley.com
`
`Representative Information
`
`
`
`Representative Customer
`
`22428
`
`
`
`
`Number::
`
`Domestic Priority Information
`
`
`
`Application::
`
`Continuity Type::
`
`Parent
`
`ParentFiling
`
`
`
`
`This Application
`
`Continuation of
`
`Application::
`| 12/216,811
`
`Date::
`7/10/2008
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`Foreign Priority Information
`
`
`Country::
`Application
`Filing Date::
`Priority Claimed::
`number::
`
`
`
`
`Assignee Information
`
`Assignee Name::
`
`NOVEN PHARMACEUTICALS, INC.
`
`4829-2360-3216. 1
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`Page # 2
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`Initial 07/20/12
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`
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`0005
`
`

`

`Attorney Docket No.: 041457-0857
`
`TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`
`[0001] Described herein are compositions and methodsfor the transdermaldelivery
`
`FIELD OF THE INVENTION
`
`of estrogen.
`
`BACKGROUND
`
`[0002] This invention relates generally to transdermal drug delivery systems, and
`
`moreparticularly, to transdermal drug delivery systems for the delivery of estrogen.
`
`The use of a transdermal system, for example, a patch comprisinga pressure-sensitive
`
`adhesive containing a drug, as a meansof 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 transdermal drug delivery systems that exhibit desired
`
`pharmacokinetic properties.
`
`[0003] Transdermal delivery systems (adhesive patches) as dosage forms have been
`
`the subject of a vast numberof patent applications over the last 25 years, yielding
`
`many patents but few commercial products in comparison. To those workingin the
`
`field, the relatively small number of commercial products is not surprising. Although
`
`regulatory, economic, and market hurdlesplay 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 mayinclude drug solubility, drug stability (e.g., as may arise
`
`from interaction with other component materials and/or the environment), delivery of
`a therapeutic amountof drug at a desired delivery rate over the intended duration of
`
`use, adequate adhesionat the anatomical site of application, integrity (e.g., minimal
`
`curling, wrinkling, delaminating and slippage) with minimal discomfort, irritation and
`
`sensitization both during use and during andafter removal, and minimalresidual
`
`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)
`
`
`
`0006
`
`

`

`Attomey Docket No.: 041457-0857
`
`and supporting analytical methods required for regulatory compliance also can be
`significant.
`
`[0004] Ofthe physical parameters that are considered when developing a
`commercial transdermal drug delivery system,size, e.g., surface area at the site of
`application, is often dictated and limited by other physical and pharmacokin °tic
`requirements, such as desired drug delivery rates and daily dosages. In general,it is
`easier to developa 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 (e.g.,
`costs of componentmaterials, costs of packaging materials, costs for production and
`manufacturing equipment, laborcosts relative to product yield per min time, etc.) and
`patients generally prefer smaller systemsto larger ones (both for aesthetic reasons and
`comfort, since a smaller surface may permit the use of less aggressive adhesives),
`there is a need for smaller transdermal drug delivery systems.
`
`SUMMARY
`
`In accordance with one embodiment, there is provided a transdermal drug
`[0005]
`delivery system comprising a dmgcontaining layer defining an active surface area
`and comprising a polymer matrix comprising estradiol, wherein the system includes
`greater than 0.156 mg/cm’estradiol and achievesan estradiol flux thatis greater than
`0.01 mg/cm’/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
`0.1-10% by weightestradiol, 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 weightsilicone adhesive, about 7.5% by weight soluble
`PVP,about 6.0% by weightoleyl alcohol, about 8.0% by weight dipropylene glycol,
`and about 1.6 % by weightestradiol. In some embodiments, the acrylic adhesive and
`silicone adhesive are presentin a ratio of from about 1:2 to about 1:6, based on the
`total weight of the acrylic and silicone adhesives.
`
`
`
`0007
`
`

`

`Attorney Docket No.: 041457-0857
`
`(0006]
`
`In some embodiments, the penetration enhancer comprises oley] alchol or
`
`dipropyleneglycol, or both.
`
`[9007]
`
`In some embodiments, the polymer matrix comprises an amountofestradiol
`
`effective to deliver a therapeutically effective amountof 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 amountofestradiol effective to
`
`deliver an amountof estradiol selected from the group consisting of about 0.025,
`
`0.0375, 0.05, 0.075 and 0.1 mg/day.
`
`In some embodiments, the polymer matrix has a coat weight of greater than
`[0008]
`about 10 mg/cm”. In some embodiments, the polymer matrix has a coat weight
`selected from the group consisting of about 12.5 and about 15 mg/ cm’.
`[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 areathat is about 60% ofa size selected from the group
`consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm?andis effective to deliver an amount of
`
`estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.
`
`In accordance with some embodiments, there is provided a method for
`[0010]
`administering estradiol, comprising applying to the skin or mucosa of a subjectin
`need thereof a transdermal drug delivery system comprising a drug-containing layer
`defining an active surface area and comprising a polymer matrix comprisingestradiol,
`wherein the system includes greater than 0.156 mg/cm’estradiol and achieves an
`estradiol flux that is greater than 0.01 meg/cm7/day, based onthe active surface area.
`In some embodiments, the system has an active surface area that is about 60% of a
`size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm?andis
`
`effective to deliver an amountofestradiol per day of about 0.025, 0.0375, 0.05, 0.075
`
`and 0.1 mg/day, respectively.
`
`[0011]
`
`In accordance with some embodiments, there is provided a method of
`
`making a transdermal drug delivery system for administering estrogen, comprising
`
`forming a polymer matnix comprising estrogen and a polymer blend comprising an
`
`acrylic adhesive, a silicone adhesive, and soluble PVP, and applying the polymer
`matrix to a support layer such that the system includesgreater than 0.156 mg/cm”
`
`-3-
`
`
`
`0008
`
`

`

`Attomey Docket No.: 041457-0857
`
`estradiol]. In some embodiments, the system has an active surface area that is about
`60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm’.
`
`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 oley] alcohol, about 8.0% by weight dipropylene glycol,
`
`and about 1.6% by weight estradiol. In some embodiments, the polymer matrix is
`applied to the support layer at a coat weightof greater than about 10 mg/cm”. In some
`embodiments, the polymer matrix coat weight is selected from the group consisting of
`about 12.5 and about 15 mg/ cm’.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0012] Figure 1 illustrates the estradiol flux (g/cm”/hr) over time (0-81 hours) from
`
`transdermaldelivery systems according to the invention (A & ©), as compared to
`
`Vivelle-Dot® (¢).
`
`DETAILED DESCRIPTION
`
`[0013] The field of transdermal delivery systems suffers from the problem of
`
`needing to balance many different competing factors to develop a commercial product
`
`that exhibits, for example both clinical efficacy and satisfactory wear properties while
`
`remaining acceptable to patients. For example, whenselecting the size of a
`
`transdermal delivery system, it is necessary to balance factors that favor a smaller size
`
`(such as lower cost , better adhesive performance and improvedaesthetics) against
`
`factors that favor a larger size (such as the target delivery rate (flux) and daily dose).
`
`The Vivelle-Dot® transdermalestradiol product (manufactured by Noven
`
`Pharmaceutcials Inc.) is available in five different active surface areas (2.5, 3.75, 5.0,
`7.5 and 10.0 cm?) which each deliverdifferent amounts of drug per day (0.025,
`
`0.0375, 0.05, 0.075 and 0.1 mg/day, respectively). Each of the Vivelle-Dot®
`products include 0.156 mg/cm’estradiol.
`[0014]
`In accordance with some embodiments, the present invention provides
`
`transdermaldrug delivery systemsfor the transdermaldelivery of estrogen that have a
`
`smaller active surface area than Vivelle-Dot® but achieve daily dosages that are about
`
`equalto or greater than the Vivelle-Dot® products. For example, the present
`
`
`
`0009
`
`

`

`Attorney Docket No.: 041457-0857
`
`invention includes transdermal drug delivery systemsthat achieve daily dosages that
`
`are about equalto a Vivelle-Dot® product, in a smaller sized system. The ability to
`provide a smaller system withoutsacrificing daily dosage represents a significant
`
`advance.
`
`[0015] Applicant surprisingly discovered that increasing the coat weight of the
`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
`comparable daily dosages. This result was surprising because coat weightis typically
`
`selected to contro! the duration of delivery, but is not generally understood to impact
`delivery rate. Thus, while it is known in the art to increase coat weight to provide
`delivery over a longerperiod oftime, it was not known that increasing coat weight
`
`could increase delivery rate or flux, and thus permit the developmentof a smaller
`
`system while maintaining daily dosage.
`
`[0016]
`In accordance with someaspects, there are provided transdermal drug
`delivery systems and methodsfor the transdermal delivery of estrogen. In specific
`embodiments, the systems exhibit increased flux than other known estrogen devices
`
`(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/cm?/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 of the 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 amountof estradio! per
`unit area is greater than the 0.156 mg/cm’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 oneof ordinary skill in the art to which the present invention pertains,
`
`unless otherwise defined. Reference is madeherein to various methodologies known
`
`-5-
`
` 
`
`0010
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`

`

`Attorney Docket No.: 041457-0857
`
`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 methodsare described. Materials,
`
`reagents andthelike 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 andthe 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 comprehendedis not limited to the exact
`
`numberset forth herein, and is intended to refer to ranges substantially within the
`
`quoted range while not departing from the scopeof the invention. As used herein,
`
`“about” will be understood by personsof ordinary skill in the art and will vary to
`
`some extent on the context in whichit is used. If there are uses of the term which are
`
`not clear to personsof ordinary skill in the art given the context in whichit is used,
`
`“about” will mean up to plus or minus 10% of the 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 onthetotal weight of the composition at issue, of the excluded component.
`
`[0021] As used herein “subject” denotes any animal in need of drug therapy,
`
`including humans. For example, a subject maybe suffering from orat risk of
`
`developing a condition that can be treated or prevented with estrogen, or may be
`
`taking estrogen for health maintenance purposes.
`
`[0022] As usedherein, the phrases “therapeutically effective amount” and
`
`“therapeutic level” mean that drug dosageor plasma concentration in a subject,
`respectively, that provides the specific pharmacological response for which the drug is
`
`administered in a subject in need of such treatment. It is emphasized that a
`
`therapeutically effective amountor therapeutic level of a drug will not always be
`
`effective in treating the conditions/diseases described herein, even though such
`
`dosage is deemedto be a therapeutically effective amountby those of skill in the art.
`
`-6-
`
`
`
`0011
`
`

`

`Attorney Docket No.: 041457-0857
`
`For convenience only, exemplary dosages, drug delivery amounts, therapeutically
`
`effective amounts and therapeutic levels are provided below with reference to adult
`
`human subjects. Thoseskilled in the art can adjust such amounts in accordance with
`
`standard practices as neededto treat a specific subject and/or condition/disease.
`
`[0023] As used herein, “active surface area” meansthe surface area of the drug-
`
`containing layer of the transdermal drug delivery system.
`
`[0024] As usedherein,“coat weight” refers to the weight of the drug-containing
`
`layer per unit area of the active surface area of the transdermal drug delivery system.
`
`[0025] As usedherein, “estrogen” includes estrogenic steroids such as estradiol
`
`(17-B-estradiol), estradiol benzoate, estradiol 17B-cypionate, estropipate, equilenin,
`
`equilin, estriol, estrone, ethinyl estradiol, conjugated estrogens, esterified estrogens,
`
`and mixtures thereof.
`
`[0026] As used herein, “flux” (also called "permeation rate") is defined as the
`
`absorption of a drug through skin or mucosaltissue, and is described by Fick's first
`
`law of diffusion:
`
`J = -D (dCm/dx)
`
`where J is the flux in g/cm7/sec, D is the diffusion coefficient of the drug through the
`skin or mucosa in cm?/sec and dCm/dx is the concentration gradient of the drug across
`
`the skin or mucosa.
`
`[0027] As used herein, the term “transdermal”refers to delivery, administration or
`
`application of a drug by meansof direct contact with skin or mucosa. Such delivery,
`
`administration or application is also known as dermal, percutaneous, transmucosal
`
`and buccal. Asused herein,“dermal” includes skin and mucosa, whichincludesoral,
`
`buccal, nasal, rectal and vaginal mucosa.
`
`[0028] As used herein, “transdermal drug delivery system”refers to a system (e.g., a
`
`device) comprising a composition that releases estrogen upon application to the skin
`
`(or any other surface noted above). A transdermal drug delivery system may
`
`comprise a backing layer, a drug-containing layer, and a release liner layer. In some
`
`embodiments,the transdermal drug delivery system is a substantially non-aqueous,
`
`solid form, capable of conformingto the surface with whichit comes into contact, and
`
`capable of maintaining such contactso as to facilitate topical application without
`
`-7-
`
` 
`
`0012
`
`

`

`Attorney Docket No.: 041457-0857
`
`adverse physiological response, and without being appreciably decomposed by
`
`aqueouscontact during topical application to a subject. Many such systemsare
`
`known in the art and commercially available, such as transdermal drug delivery
`
`patches. As described below, in one embodiment, the transdermal drug delivery
`
`system comprises a drug-containing polymer matrix that comprises a pressure-
`
`sensitive adhesive or bioadhesive, and is adopted for direct application to a user’s
`
`(e.g., a subject’s) skin. In other embodiments, the polymer matrix is non-adhesive
`and may be provided with separate adhesion means(such as a separate adhesive
`layer) for application and adherenceto the user’s skin.
`
`[9029] As used herein, “polymer matrix”refers to a polymer composition which
`
`contains one or more drugs. In some embodiments, the matrix comprises a pressure-
`
`sensitive adhesive polymeror a bioadhesive polymer. In other embodiments, the
`
`matrix does not comprise a pressure-sensitive adhesive or bioadhesive. As used
`
`herein, a polymeris an “adhesive”if it has the properties of an adhesive perse, orif it
`
`functions as an adhesiveby the addition oftackifiers, plasticizers, crosslinking agents
`
`or other additives. Thus, in some embodiments, the polymer matrix comprises a
`
`pressure-sensitive adhesive polymer or a bioadhesive polymer, with estrogen
`
`dissolved or dispersed therein. The polymer matrix also may comprise tackifiers,
`
`plasticizers, crosslinking agents or other additives described herein. U.S. Patent
`
`6,024,976 describes polymer blendsthat are useful in accordance with the transdermal
`
`systems described herein. The entire contents of U.S. Patent 6,024,976is
`
`incorporated herein byreference.
`
`[0030] As used herein, the term "pressure-sensitive adhesive" refers to a viscoelastic
`
`material which adheres instantaneously to most substrates with the application of very
`
`slight pressure and remains permanently tacky. A polymeris a pressure-sensitive
`
`adhesive within the meaning of the term as used herein if it has the properties of a
`
`pressure-sensitive adhesive per se or functions as a pressure-sensitive adhesive by
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`admixture with tackifiers, plasticizers or other additives.
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`[0031]
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`The term pressure-sensitive adhesive also includes mixtures of different
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`polymers and mixtures of polymers, such as polyisobutylenes (PIB), of different
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`molecular weights, wherein each resultant mixture is a pressure-sensitive adhesive. In
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`the last case, the polymers of lower molecular weight in the mixture are not
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`considered to be "tackifiers," said term being reserved for additives which differ other
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`than in molecular weight from the polymers to which they are added.
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`[0032]
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`In some embodiments, the polymer matrix is a pressure-sensitive adhesive at
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`room temperature and hasother desirable characteristics for adhesives used in the
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`transdermal drug delivery art. Such characteristics include good adherence to skin,
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`ability to be peeled or otherwise removed without substantial traumato the skin,
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`retention of tack with aging, etc. In some embodiments, the polymer matrix has a
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`glass transition temperature (T,), measured using a differential scanning calorimeter,
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`of between about -70 °C. and 0 °C.
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`[0033] As used herein, the term “rubber-based pressure-sensitive adhesive" refers to
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`a viscoelastic material which has the properties of a pressure-sensitive adhesive and
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`which containsat least one natural or synthetic elastomeric polymer.
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`[0034]
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`In some embodiments, the transdermal drug delivery system includes one or
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`more additional layers, such as one or moreadditional polymer matrix layers, or one
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`or more adhesive layers that adhere the transdermal drug delivery system to the user’s
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`skin. In other embodiments, the transdermal drug delivery system is monolithic,
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`meaning that it comprises a single polymer matrix layer comprising a pressure-
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`sensitive adhesive or bioadhesive with drug dissolved or dispersed therein, and no
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`rate-controlling membrane.
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`[0035] The transdermal drug delivery system also may include a drug impermeable
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`backing layer or film. In some embodiments, the backing layer is adjacent one face of
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`the polymer matrix layer. When present, the backing layer protects the polymer
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`matrix layer (and any other layers present) from the environmentand prevents loss of
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`the drug and/or release of other components to the environment during use. Materials
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`suitable for use as backing layers are well-known known inthe art and can comprise
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`films of polyester, polyethylene, vinyl acetate resins, ethylene/vinyl acetate
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`copolymers, polyviny! chloride, polyurethane, and the like, metal foils, non-woven
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`fabric, cloth and commercially available laminates. A typical backing material has a
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`thickness in the range of 2 to 1000 micrometers.
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`[0036] The transdermal drug delivery system also may include a releaseliner,
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`typically located adjacent the opposite face of the system as comparedto the backing
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`layer. Whenpresent, the release liner is removed from the system prior to use to
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`expose the polymer matrix layer and/or an adhesive layerprior to topical application.
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`Materials suitable for use as release liners are well-known known in the art and
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`include the commercially available products of Dow Corning Corporation designated
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`Bio-Release® liner and Syl-off® 7610 and 3M's 1022 Scotch Pak.
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`[0037] A used herein, a “monolithic” transdermal! drug delivery system mayinclude
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`a backing layer and/or release liner.
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`[0038]
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`In accordance with some embodiments, the transdermal dug delivery system
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`comprises a drug-containing polymermatrix layer that comprises a pressure-sensitive
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`adhesive blend comprising an acrylic polymer, a silicone polymer, and a soluble PVP.
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`Acrylic Polymers
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`[0039] The term "acrylic polymer"is used hereas in the art interchangeably with
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`“polyacrylate," "polyacrylic polymer,” and "acrylic adhesive." The acrylic-based
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`polymers can be any of the homopolymers, copolymers, terpolymers, and the like of
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`various acrylic acids or esters. In some embodiments, the acrylic-based polymers are
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`adhesive polymers. In other embodiments, the acrylic-based polymers function as an
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`adhesive by the addition of tackifiers, plasticizers, crosslinking agents or other
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`additives.
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`[0040] The acrylic polymer can include copolymers, terpolymers and
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`multipolymers. For example, the acrylic polymer can be any of the homopolymers,
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`copolymers, terpolymers, and the like of various acrylic acids. In some embodiments,
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`the acrylic polymerconstitutes from about 2% to about 95% by weight ofthe polymer
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`content of the polymer matrix, including about 3% to about 90% and about 5% to
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`about 85%, such as 2% to 95%, 3% to 90% and 5% to 85%. In some embodiments,
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`the amountandtype of acrylic polymer is dependent on the type and amount of
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`estrogen used.
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`[0041] Acrylic polymers useful in practicing the invention include polymers of one
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`or more monomersof acrylic acids and other copolymerizable monomers. Theacrylic
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`polymersalso include copolymers of alkyl acrylates and/or methacrylates and/or
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`copolymerizable secondary monomers or monomerswith functional groups.
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`Combinations of acrylic-based polymers based on their functional groupsis also
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`contemplated. Acrylic-based polymers having functional groups include copolymers
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`and terpolymers which contain, in addition to nonfunctional monomerunits, further
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`monomer units having free functional groups. The monomers can be monofunctional
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`or polyfunctional. By varying the amount of each type of monomeradded, the
`cohesive properties of the resulting acrylic polymer can be changed as is known in the
`art. In some embodiments,the acrylic polymer is composed ofat least 50% by weight
`of an acrylate or alkyl acrylate monomer, from 0 to 20% of a functional monomer
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`copolymerizable with the acrylate, and from 0 to 40% of other monomers.
`[0042] Acrylate monomers which can be used include acrylic acid and methacrylic
`acid and alkyl acrylic or methacrylic esters such as methyl acrylate, ethyl acrylate,
`propyl acrylate, amyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate,
`hexyl methacrylate, heptyl acrylate, octyl acrylate, nony] acrylate, 2-ethylbuty|
`acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-
`ethylhexyl acrylate, 2-ethylhexyl methacrylate, decy! acrylate, decyl methacrylate,
`dodecy! acrylate, dodecyl methacrylate, tridecy] acrylate, tridecyl methacrylate,
`glycidyl acrylate, and corresponding methacrylicesters.
`[0043] Non-functional acrylic-based polymers can include any acrylic based
`polymer havingno or substantially no free functional groups.
`[0044] Functional monomers, copolymerizable with the above alkyl! acrylates or
`methacrylates, which can be used includeacrylic acid, methacrylic acid, maleic acid,
`maleic anhydride, hydroxyethyl!acrylate, hydroxypropyl acrylate, acrylamide,
`dimethylacrylamide, acrylonitrile, dimethylaminoethy! acrylate, dimethylaminoethyl
`methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,
`methoxyethyl acrylate and methoxyethy! methacrylate.
`[0045]
`Asused herein,“functional monomers or groups,” are monomerunits
`typically in acrylic-based polymers which have reactive chemical groups which
`modify the acrylic-based polymersdirectly or which provide sites for further
`reactions. Examples of functional groups include carboxyl, epoxy, hydroxyl,
`sulfoxyl, and amino groups. Acrylic-based polymers having functional groups
`contain, in addition to the nonfunctional monomerunits described above,further
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`monomerunits having free functional groups. The monomers can be monofunctional
`or polyfunctional. These functional groups include carboxyl groups, hydroxy groups,
`amino groups, amido groups, epoxy groups, etc. Typical carboxyl functional
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`monomers include acrylic acid, methacrylic acid, itaconic acid, maleic acid, and
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`crotonic acid. Typical hydroxy functional monomers include 2-hydroxyethy]
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`methacrylate, 2-hydroxyethy] acrylate, hydroxymethylacrylate, hydroxymethyl
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`methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropy]
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`acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybuty]
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`methacrylate, hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl!
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`acrylate, hydroxyhexyl methacrylate. As noted above, in some embodiments, the
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`acrylic polymer does not include such functional groups.
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`[0046] Further details and examples of acrylic adhesives whichare suitable in the
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`practice of the invention are describedin Satas, "Acrylic Adhesives," Handbook of
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`Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van
`Nostrand Reinhold, New York (1989); “Acrylic and Methacrylic Ester Polymers,”
`Polymer Science and Engineering, Vol. 1, 2nd ed., pp 234-268, John Wiley & Sons,
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`(1984); U.S. Patent No. 4,390,520; and U.S. Patent No. 4,994,267, all of which are
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`expressly incorporated by referencein their entireties.
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`[0047] Suitable acrylic polymers also include pressure-sensitive adhesives which
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`are commercially available, such as the acrylic-based adhesives sold underthe
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`tradem