Atty. Dkt. No. 041457-1016
`
`IN THE UNITED STATES
`First Inventor Name:
`Juan Mantelle
`
`PATENT AND TRADEMARK OFFICE
`
`Title:
`
`Transdermal ELstrogen Device and Delivery
`
`Prior Appl. No.:
`
`13/553,972
`
`Prior Appl. Filing
`Date:
`
`lixaminer:
`
`Art Unit:
`
`7/20/2012
`
`Unassigned
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
`TRANSMITTAL LETTER
`
`for Patents
`
`Commissioner
`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
`
`[ ] 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
`
`application. The entire disclosure
`hereby claimed under 35 U.S.C. § 120 for this continuing
`
`
`being part of the disclosure the
`of
`the above-identified prior application is considered as
`accompanying continuing
`
`application is hereby incorporated by reference therein. and
`
`
`of
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`4827-6562-3573.1
`
`
`
` 
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`Part 1 of 2
`0001
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`MYLAN - EXHIBIT 1038
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`

`

`Atty. Dkt. No. 041457-1016
`
`Enclosed are:
`
`[ X ] Application Data Sheet (37 CFR 1.76).
`
`[ X ] Description, Claim(s), and Abstract (27 pages).
`
`[ X ] Drawing (1 sheet, Figure 1).
`
`The adjustment to the number of sheets for EFS-Web filing follows:
`
`Number of
`Sheets
`28
`
`EFS-Web
`Adjustment
`75%
`
`x
`
`Number of Sheets for EFS-Web
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`21
`
`The filing fee is calculated below at the large entity rate:
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Extra
`
`Rate
`
`Basic Filing
`Fee
`Search Fee
`Examination
`Fee
`Size Fee
`Total
`Claims:
`Independents
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`21
`20
`
`3
`
`100
`20
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`= 0
`= 0
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`= 0
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`x
`x
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`x
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`$280.00 =
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`$600.00
`$720.00
`
`$400.00
`$80.00 =
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`$420.00 =
`
`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 I) under 37 C.F.R. § 1.17 (c)
`Processing Fee (Track I) under 37 C.F.R. § 1.17 (i)
`TOTAL FILING FEE: =
`
`$780.00 =
`$140.00
`
`+
`+
`
`Fee
`Totals
`
`$280.00
`
`$600.00
`$720.00
`
`$0.00
`$0.00
`
`$0.00
`
`$0.00
`$140.00
`
`$0.00
`$0.00
`$1740.00
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`The required filing fees are not enclosed but will be submitted in response to the Notice
`
`to File Missing Parts of Application.
`
`4827-6562-3573.1
`
`0002 
`
`

`

`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Atty. Dkt. No. 041457-1016
`
`Dateugjr^
`
`r\
`
`J !>'
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`(202) 295-4094
`Telephone:
`(202) 672-5399
`Facsimile:
`
`Respectfully submitted,
`
`A
`
`By
`
`i...
`
`/
`
`J/YV v y
`
`Courtenay C. Brinckerhoff
`Attorney ftir Applicant
`Registration No. 37,288
`
`4827-6562-3573.1
`
`0003 
`
`

`

`PTO/AiA/14 (03-13)
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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number
`Application Number
`
`041457-1016
`
`Title of Invention
`
`Transdermal Estrogen Device and Delivery
`
`The application data sheet is part of the provisional or nonprovisional application for which it is being submitted. The following form contains the
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`Juan
`Mantelle
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`City
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`Miami
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`US
`FL
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`
`9827 S.W. 106th Terrace
`
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`Country i
`33176
`US
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`Transdermal Estrogen Device and Delivery
`Attorney Docket Number 041457-1016
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`Application Data Sheet 37 CFR 1.76
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`Application Data Sheet 37 CFR 1.76
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`Transdermal Estrogen Device and Delivery
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`Application Data Sheet 37 CFR 1.76
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`Title of Invention
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`Transdermal Estrogen Device and Delivery
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`NOVEN PHARMACEUTICALS, INC.
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`33186
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`Brinckerhoff
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`0008 
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`

`

`Attorney Docket No.: 041457-0857
`
`TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`
`FIELD OF THE INVENTION
`[00011 Described herein are compositions and methods for the transdermal delivery
`of estrogen.
`
`BACKGROUND
`[0002] This invention relates generally to transdermal drug delivery systems, and
`more particularly, to transdermal 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 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 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, delaminating 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.
`[00041 Of the 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 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 (e.g.,
`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 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 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/cm2/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 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 from about 1:2 to about 1:6, based on the
`total weight of the acrylic and silicone adhesives.
`
`0010 
`
`

`

`Attorney Docket No.: 041457-0857
`
`In some embodiments, the penetration enhancer comprises oleyl alchol or
`[0006]
`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/cm2. In some embodiments, the polymer matrix has a coat weight
`selected from the group consisting of about 12.5 and about 15 mg/ cm2.
`[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 of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2 and is 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.
`[0010|
`In accordance with some embodiments, there is provided a method for
`administering estradiol, comprising applying to the skin or mucosa of a subject in
`need thereof 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/cm2/day, based on the 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 cm2 and is
`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.
`[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 matrix 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 includes greater than 0.156 mg/cm2
`
`0011 
`
`

`

`Attorney 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 cm2.
`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 polymer matrix is
`applied to the support layer at a coat weight of greater than about 10 mg/cm2. In some
`embodiments, the polymer matrix coat weight is selected from the group consisting of
`about 12.5 and about 15 mg/ cm2.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0012] Figure 1 illustrates the estradiol flux (jag/cm2/hr) over time (0-81 hours) from
`transdermal delivery 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, when selecting 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 improved aesthetics) against
`factors that favor a larger size (such as the target delivery rate (flux) and daily dose).
`The Vivelle-Dot® transdermal estradiol 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 cm2) which each deliver different 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/cm2 estradiol.
`[0014]
`In accordance with some embodiments, the present invention provides
`transdermal drug delivery systems for the transdermal delivery of estrogen that have a
`smaller active surface area than Vivelle-Dot® but achieve daily dosages that are about
`equal to or greater than the Vivelle-Dot® products. For example, the present
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`invention includes transdermal drug delivery systems that achieve daily dosages that
`are about equal to a Vivelle-Dot® product, in a smaller sized system. The ability to
`provide a smaller system without sacrificing 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 weight is typically
`selected to control 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 longer period of time, it was not known that increasing coat weight
`could increase delivery rate or flux, and thus permit the development of a smaller
`system while maintaining daily dosage.
`[0016]
`In accordance with some aspects, there are provided transdermal drug
`delivery systems and methods for 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/cm2/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 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
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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.
`[0019J 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
`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% 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 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,
`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
`taking estrogen for health maintenance purposes.
`[0022] As used herein, the phrases "therapeutically effective amount" and
`"therapeutic level" mean that drug dosage or 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 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.
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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 transdermal drug delivery system.
`[0025] As used herein, "estrogen" includes estrogenic steroids such as estradiol
`(17-p-estradiol), estradiol benzoate, estradiol 17P-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 mucosal tissue, and is described by Pick's first
`law of diffusion:
`J = -D (dCm/dx)
`
`where J is the flux in g/cm2/sec, D is the diffusion coefficient of the drug through the
`skin or mucosa in cm2/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
`