`
`Atty. Dkt. No. 041457-1160
`
`First Inventor Name:
`
`Juan Mantelle
`
`Title:
`
`Transdermal Estrogen Device and
`Delivery
`
`Prior Appl. No.:
`
`14/738,255
`
`Prior Appl. Filing
`Date:
`
`6/12/2015
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
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`Commissioner for Patents
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`Commissioner:
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`Transmitted herewith for filing under 37 C.F.R. § 1.53(b) is a:
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`[ X ] Continuation
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`[ ] Division
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`[ ] Continuation-In-Part (CIP)
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`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
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`hereby claimed under 35 U.S.C. § 120 for this continuing application. The entire disclosure of
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`Enclosed are:
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`[ X ] Application Data Sheet (37 CFR 1.76).
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`[ X ] Description, Claim(s), and Abstract (27 pages).
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`[ X ] Drawing (1 sheet, Figure 1).
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`4846-4076-3177.1
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`-1-
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`0001
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`MYLAN - EXHIBIT 1004
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`[ X ] Declaration
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`Atty. Dkt. No. 041457-1160
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`The adjustment to the number of sheets for EFS-Web filing follows:
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`EFS-Web
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`21
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`Included
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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
`
`3
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`= 0
`= 0
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`= 1
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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
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`$400.00
`$80.00
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`$420.00
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`Fee
`Totals
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`$280.00
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`$600.00
`$720.00
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`$0.00
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`$420.00
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`$0.00
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`4846-4076-3177.1
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`-2-
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`0002
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`
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`Please direct all correspondence to the undersigned attorney or agent at the address
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`indicated below.
`
`Atty. Dkt. No. 041457-1160
`
`Date
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 295-4094
`Facsimile:
`(202) 672-5399
`
`Respectfully submitted,
`
`Courtenay C. Brinckerhoff
`Attorney for Applicant
`Registration No. 37,288
`
`4846-4076-3177.1
`
`-3-
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`0003
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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number
`
`041457-1160
`
`Application Number
`
`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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`Inventor 1
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`Legal Name
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`Prefix Given Name
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`Mantelle
`Juan
`Residence Information (Select One) ® US Residency Q Non US Residency 0 Active US Military Service
`US
`FL
`State/Province
`City Miami
`Country of Residencd
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`Mailing Address of Inventor:
`
`Address 1
`
`9827 S.W. 106th Terrace
`
`Address 2
`City
`
`Miami
`
`State/Province
`US
`Country i
`33176
`Postal Code
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`Attorney Docket Number 041457-1160
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`Application Data Sheet 37 CFR 1.76
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`Transdermal Estrogen Device and Delivery
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`041457-1160
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`Transdermal Estrogen Device and Delivery
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`Application Data Sheet 37 CFR 1.76
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`041457-1160
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`Title of Invention
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`Transdermal Estrogen Device and Delivery
`
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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number A
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`041457-1160
`
`Application Number
`
`Title of Invention
`
`Transdermal Estrogen Device and Delivery
`
`First Name
`
`Courtenay C
`
`Last Name
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`Brinckerhoff
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`Registration Number
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`37288
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`0009
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`Attorney Docket No.: 041457-0g57
`
`TRANS DE MAL ESTROGEN DEVICE AND DELIVERY
`
`FIELD OF THE INVENTION
`[0001] Described herein are compositions and methods for the transdermal delivery
`of estrogen.
`
`BACKGROUND
`[0002J 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)
`
`0010
`
`
`
`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 transderrnal 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.
`
`-2-
`
`0011
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`
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`Attorney Docket No.: 041457-0857
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`100061
`
`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 I 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.
`
`100081
`
`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.
`[00091
`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.
`[00101
`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.
`[00111
`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
`
`-3-
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`0012
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`Attorney Docket No.: 041457-0857
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`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 I illustrates the estradiol flux (µg/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.
`In accordance with some embodiments, the present invention provides
`[0014]
`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
`
`4-
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`0013
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`Attorney Docket No.: 041457-1)857
`
`invention includes transdennal 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.
`100151 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.
`
`[00161
`
`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-
`
`DoM 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
`10017] 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
`
`-5-
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`0014
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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 andfor
`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
`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 I% 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 exa