`Paper No. ____
`Filed: December 4, 2017
`
`Filed on behalf of: Mylan Technologies, Inc.
`By: Steven W. Parmelee (sparmelee@wsgr.com)
`
`Michael T. Rosato (mrosato@wsgr.com)
`
`Jad A. Mills (jmills@wsgr.com)
`
`Wilson Sonsini Goodrich & Rosati
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MYLAN TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`NOVEN PHARMACEUTICALS, INC.
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2018-00174
`Patent No. 9,730,900
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,730,900
`
`
`

`

`
`
`I.
`
`TABLE OF CONTENTS
`
`Introduction .................................................................................................. 1
`A. Brief Overview of the ’900 Patent .............................................................. 5
`B. Brief Overview of the Prosecution History ................................................. 5
`C. Brief Overview of the Scope and Content of the Prior Art .......................... 8
`D. Brief Overview of the Level of Skill in the Art......................................... 15
`E. Background Knowledge in the Art Prior to July 10, 2008 ........................ 16
`II.
`Grounds for Standing .................................................................................. 19
`III. Mandatory Notices under 37 C.F.R. § 42.8 ................................................. 20
`IV. Statement of the Precise Relief Requested .................................................. 21
`V.
`Claim Construction ..................................................................................... 22
`A.
`“About” .................................................................................................... 24
`B.
`“Coat weight” ........................................................................................... 25
`C.
`“Flux” ...................................................................................................... 26
`D.
`“Therapeutically Effective Amount” ........................................................ 27
`VI. Detailed Explanation Of Grounds For Unpatentability ................................ 28
`A. [Ground 1] Claims 1-2, 8, 10-16, and 18-23 are Anticipated under 35
`U.S.C. §102 by Mueller. ........................................................................... 28
`B. [Ground 2] Claims 1-2 and 8-23 are Obvious under 35 U.S.C. §103
`over Mueller and Vivelle-Dot® Label ....................................................... 44
`C. [Ground 3] Claims 3-7 are Obvious under 35 U.S.C. §103 over Mueller,
`Vivelle-Dot® Label, and Kanios. .............................................................. 52
`D. [Ground 4] Claims 1-23 are Obvious under 35 U.S.C. §103 over
`Mueller, Vivelle-Dot® Label, Kanios, and Chien. ..................................... 59
`VII. Secondary Indicia of Non-obviousness ....................................................... 63
`VIII. Conclusion .................................................................................................. 66
`IX. Certificate of Compliance ........................................................................... 67
`X.
`Payment of Fees under 37 C.F.R. §§42.15(a) and 42.103............................ 68
`XI. Appendix – List of Exhibits ........................................................................ 69
`
`-i-
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Mylan Technologies, Inc. (“Mylan”) requests review of U.S. Patent No.
`
`9,730,900 to Mantelle (“the ’900 patent,” EX1001), which issued on August 15,
`
`2017. PTO records indicate that the ’900 patent is assigned to Noven
`
`Pharmaceuticals, Inc. (Patent Owner, “PO”). This Petition demonstrates that there
`
`is a reasonable likelihood that claims 1-23 of the ’900 patent are unpatentable for
`
`failure to distinguish over the prior art asserted herein. An additional petition is
`
`being filed simultaneously to address similar claims of related U.S. Patent No.
`
`9,724,310, also assigned to PO.
`
`These patents are directed to a monolithic (single drug-containing layer)
`
`transdermal drug delivery system (i.e., a transdermal patch) for the administration
`
`of estradiol, and to conventional methods of making and administering them. The
`
`patch comprises a backing layer, and a single drug-containing adhesive polymer
`
`matrix, and optionally a release liner. The claims specify parameters for coat
`
`weight, drug loading (dose per-unit-area), and estradiol flux (permeation over time)
`
`that were each known in the prior art.
`
`The art of transdermal delivery of estradiol using monolithic patches was
`
`well developed by the time of the ’900 patent’s earliest claimed priority in July,
`
`2008. In fact, PO had obtained FDA approval for one patch system, termed
`
`Vivelle®, as early as 1994. EX1008 (Vivelle® Label); EX1034 (Orange Book
`
`-1-
`
`

`

`
`
`Listing), 0175. In 1999, PO received FDA approval for a second-generation patch
`
`system with higher estradiol flux, termed Vivelle-Dot®, which permitted the
`
`delivery of the same amount of estradiol as Vivelle®, but in smaller patches.
`
`EX1006 (Vivelle-Dot® Label); EX1034, 0175. The art made clear that smaller
`
`adhesive patches were desirable for a number of reasons, both aesthetic and
`
`practical (e.g., reduced skin irritation, better adhesive properties, improved patient
`
`satisfaction, improved compliance, and reduced packaging costs).
`
`Thus, before July, 2008, it was well recognized in the art that one could
`
`deliver more of a drug more efficiently, and reduce the patch size for a given dose,
`
`by increasing the flux of a patch. The prior art described several methods for
`
`increasing the flux of monolithic transdermal patches, including for estradiol. For
`
`example, the prior art taught that higher flux can be achieved by increasing the
`
`amount of hydrophiles within the adhesive polymer matrix, or by using increased
`
`amounts of penetration enhancers. EX1005, ¶¶3, 5, 17-18, 27, 31; EX1007
`
`(Kanios), ¶¶118-22, 126-28.
`
`The prior art Mueller reference (EX1005) describes a monolithic
`
`transdermal estradiol delivery system in Example 3 that satisfies each of the
`
`elements of independent claims 1 and 16 and their dependent claims 2, 8, 10-15,
`
`and 18-22. The Mueller system comprises a single drug-containing adhesive
`
`polymer matrix layer, a backing layer, and a release liner. Mueller teaches that the
`
`-2-
`
`

`

`
`
`polymer matrix comprises greater than 0.156 mg/cm2 estradiol, acrylic and silicone
`
`adhesives, soluble polyvinylpyrrolidone (PVP), dipropylene glycol as a penetration
`
`enhancer, and a coat weight above 10 mg/cm2. Moreover, Mueller teaches that it
`
`provides a constant release of estradiol over a period of 72 hours, and achieves an
`
`estradiol flux of 0.015 mg/cm2/day, within the claimed range of “from about
`
`0.0125 to about 0.05 mg/cm2/day.” Mueller Example 3 achieves a higher estradiol
`
`flux than was reported for the prior art Vivelle-Dot® patch. Mueller expressly
`
`teaches that higher flux permits the use of smaller patches to deliver a given
`
`amount of estradiol.
`
`The prior art also teaches that increasing the coat weight of the drug-matrix
`
`layer of a patch results in an increased flux per-unit-area. For example, Chien,
`
`which was not of record during prosecution, explicitly teaches that increasing
`
`estradiol drug loading, or the coat weight of the adhesive polymer matrix of an
`
`estradiol patch, directly increased flux. EX1009, FIGS. 4-5. Yet, during
`
`prosecution, PO obtained allowance for the ’900 patent by repeatedly asserting that
`
`it was “surprising and unexpected” that increasing the amount of estradiol per-unit-
`
`area (increasing the coat weight) of the drug-containing matrix would increase the
`
`flux of the patch. See, e.g., EX1004, 0010; see also id., 0169-70, 0194, 0269, 0541-
`
`2.
`
`-3-
`
`

`

`
`
`Additional references besides Chien, such as Kim and Ghosh, which were
`
`not of record during prosecution but are discussed in this Petition, also teach that
`
`increasing the coat weight of a monolithic transdermal patch increases flux.
`
`EX1010, 82; EX1014, 287-88. Moreover, these references provide an explanation
`
`for how and why an increased coat weight increases flux, noting that, “as the
`
`thickness of the matrix increase[s], the occlusive effect of the matrix increase[s],
`
`resulting in the increased flux.” EX1010, 82. The art explicitly confirmed that
`
`“[o]cclusion significantly (p < 0.05) increase[s] the percutaneous absorption of
`
`estradiol,” and noted that “[o]f the various approaches employed to enhance the
`
`percutaneous absorption of drugs,” increasing occlusion “is the simplest and most
`
`common method in use.” EX1026, 86, 89.
`
`Thus, the person of ordinary skill in the art would not have found an increase
`
`in flux resulting from increased coat weight surprising or unexpected, contrary to
`
`that which was argued by PO during prosecution. The direct relationships between
`
`each of drug loading and coat weight with estradiol flux of a matrix-type
`
`monolithic patch was already described in the art. PO’s evidence of “surprising and
`
`unexpected” results merely confirms that, in view of the prior art, the results were
`
`entirely expected.
`
`-4-
`
`

`

`
`
`A. Brief Overview of the ’900 Patent
`
`The ’900 patent has an earliest claimed priority date of July 10, 2008.
`
`EX1002, ¶14. Claims 1 and 16 are independent claims that recite methods of
`
`administering or making a monolithic transdermal estradiol delivery system, i.e.,
`
`an estradiol patch. The patch comprises a backing layer and a single adhesive
`
`polymer matrix, wherein the matrix comprises estradiol as the only drug, has a coat
`
`weight of “greater than about 10 mg/cm2,” and includes “greater than 0.156
`
`mg/cm2 estradiol.” The patch also “achieves an estradiol flux of from about 0.0125
`
`to about 0.05 mg/cm2/day, based on the active surface area.” EX1002, ¶¶15, 19-20.
`
`Dependent claims recite minor limitations, including the delivery of standard daily
`
`doses of estradiol, patch sizes, known percentages of patch components, as well as
`
`flux values that fall within the range recited in claims 1 and 16. Id., ¶¶16-18, 21.
`
`The ’900 patent discloses that its patches may comprise a blend of polymers
`
`that “may be immiscible with each other” to entrap a hydrophobic drug, such as
`
`estradiol. EX1001, 10:27-33, claims 1-23. This blend of immiscible polymers
`
`forms microreservoirs within the single-layer polymer matrix. EX1002, ¶16.
`
`B.
`
`Brief Overview of the Prosecution History
`
`U.S. Application No. 13/553,972 (“the ’972 application”) was filed on July
`
`20, 2012, and issued on August 15, 2017 as the ’900 patent. EX1002, ¶22.
`
`The ’972 application claims the benefit of U.S. Application No. 12/216,811, filed
`
`-5-
`
`

`

`
`
`on July 10, 2008. Id. During prosecution, Applicant amended the claims in
`
`response to multiple prior art-based rejections (based on EX1029-33), and further
`
`amended the claims after receiving Notices of Allowance. EX1002, ¶¶23-36, 39-45,
`
`47-58.
`
`On June 15, 2017, Applicant submitted a Rule 132 Declaration signed by Dr.
`
`Richard Guy to allege “surprising and unexpected” results. EX1004, 0580;
`
`EX1002, ¶¶59-68. Dr. Guy presented an “in vitro flux study conducted to assess
`
`the flux of the estradiol from different systems” using a Franz diffusion cell. Id. Dr.
`
`Guy also provided “[a]n illustration of the type of experimental data collected with
`
`this approach…presented as the average cumulative amounts of drug delivered,
`
`and the average drug flux, as a function of time, with the corresponding standard
`
`deviations for 4 replicate Franz diffusion cells.” EX1004, 0581; EX1002, ¶59. The
`
`standard deviations of the replicate flux measurements Dr. Guy provided, however,
`
`show that measurements of flux of the same patch in the same experimental set-up,
`
`can deviate by more than 15%. EX1002, ¶¶59, 64-67, 82. Similarly, additional data
`
`submitted by Applicant, and addressed by Dr. Guy in often identical language,
`
`demonstrates the routinely high variability associated with flux. For example,
`
`Vivelle-Dot® patches were measured in the same Franz system to have flux ranging
`
`from 0.00696 to 0.02424 mg/cm2/day, a variation of more than 242%. EX1004,
`
`0591-99; EX1002, ¶¶ 64-67.
`
`-6-
`
`

`

`
`
`The average flux provided in the Guy Declaration was obtained by
`
`calculating the slope, or change in average cumulative amount of drug, between
`
`each time point. EX1004, 0581; EX1002, ¶¶61-63, 86-88 (e.g., flux at 23.95 hours
`
`calculated by taking the difference between drug permeation at 9.92 and 23.95
`
`hours, and dividing by the amount of time passed (10.09 µg/cm2/14.03h = 0.72
`
`µg/cm2/hr)). This Petition, and supporting expert declaration, discuss flux values
`
`defined by slope calculations of drug permeation data, the same definition of flux
`
`relied upon by Applicant during prosecution. EX1002, ¶¶61-63, 86-88.
`
`Dr. Guy also admitted in his declaration that “it was known in the art that the
`
`relative amounts of acrylic adhesive and silicone adhesive used in an estradiol
`
`polymer matrix can impact the flux[.]” EX1004, 0585-87, 0591; EX1002,¶¶68, 225,
`
`242. Moreover, Applicant did not dispute that transdermal patches with flux values
`
`of 0.0125 to 0.05 mg/cm2/day were known, nor did they dispute that those in the
`
`art had motivation and methods by which to improve the flux of a transdermal
`
`patch. EX1002, ¶¶38, 57, 68, 225, 242 (noting that even Vivelle-Dot® described in
`
`EX1004 achieved a flux well within this range). Instead, Applicant and Dr. Guy
`
`repeatedly asserted “surprising and unexpected results,” were present on the basis
`
`that “it was not known or expected that the coat weight of the polymer matrix
`
`would impact flux[.]”EX1004, 0587, see also id., 0010, 0169-70, 0194, 0269 ,
`
`0541-42, 0547-48, 0553-58, 0579-83, 0589-96, 0600; EX1002, ¶68. The
`
`-7-
`
`

`

`
`
`Examiner’s June 27, 2017 Notice of Allowance expressly invoked Applicant’s
`
`assertion of unexpected results made in the declaration of Dr. Guy as a basis for
`
`allowance. EX1004, 0689-90. However, neither Applicant nor the Guy declaration
`
`accounted for prior art references that were not of record during prosecution and
`
`that are discussed in this Petition.
`
`C. Brief Overview of the Scope and Content of the Prior Art
`
`A prior art reference anticipates a claim if it discloses all of the elements of
`
`the claim in the claimed combination, Wm. Wrigley Jr. Co. v. Cadbury Adams USA
`
`LLC, 683 F.3d 1356, 1361 (Fed. Cir. 2012). In obviousness cases, Graham v. John
`
`Deere Co. of Kansas City, requires an evaluation of any differences between the
`
`claimed subject matter and the asserted prior art. 383 U.S. 1, 17-18 (1966). As
`
`noted in KSR Int’l Co. v. Teleflex Inc., the obviousness inquiry may account for
`
`inferences that would be employed by a person of ordinary skill in the art. 550 U.S.
`
`398, 418 (2007). EX1002, ¶¶69-76, 113.
`
`i.
`
`Mueller
`
`U.S. Patent Application Publication No. US2003/0099695 (“Mueller,”
`
`EX1005) discloses “transdermal therapeutic systems (TTSs)” for the
`
`administration of estradiol. EX1005, ¶¶1, 56-61; EX1002, ¶115. Mueller’s patches
`
`comprise an “active substance matrix” that is “a single-layer structure and is self-
`
`-8-
`
`

`

`
`
`adhesive,” a backing layer, and a “releasable protective layer.” EX1005, ¶¶25-26;
`
`EX1002, ¶117.
`
`Mueller teaches that patches with increased hydrophile content (e.g.,
`
`polyacrylate adhesive and PVP) provide “further advantages such as improved or
`
`facilitated application…higher therapy safety through stabilization of the delivery
`
`behavior, as well as more efficient use of active substance.” EX1005, ¶22; EX1002,
`
`¶¶115-16, 118. Mueller continues:
`
`By improving the active substance release, the present invention
`
`further affords the possibility of broadening the range of applications
`
`of transdermal systems which are based on passive diffusion. In
`
`addition, the invention enables the manufacture of transdermal
`
`systems which can have a smaller surface area due to the high
`active substance release rates which can be achieved with the
`
`invention; this in turn is of advantage in manufacture and application.
`
`EX1005, ¶22 (emphasis added); EX1002, ¶116.
`
`Mueller teaches that patches with stabilizing hydrophile additives achieve
`
`higher flux than those without hydrophile additives. EX1005, FIGS. 1-3. Example
`
`3 (“Monolithic Transdermal System (TTS) Based on Silicone Adhesives With
`
`Hydrophile Additives”) achieves the highest estradiol flux in Mueller. EX1005,
`
`FIGS. 1-3; EX1002, ¶124. Figures 1-3 present the cumulative amount of estradiol
`
`delivered (in µg/cm2) over time. EX1005, FIGS. 1-3; EX1002, ¶¶124-30. The
`
`-9-
`
`

`

`
`
`slope at each time point in Mueller Figure 3 provides the flux that was achieved by
`
`the patches of Example 3:
`
`Time
`(hours)
`
`Estradiol Permeation
`(µg/cm2)
`
`Flux
`(µg/cm2/hour)
`
`Flux
`(mg/cm2/day)
`
`8
`
`24
`
`32
`
`48
`
`72
`
`3.2
`
`11
`
`16
`
`25
`
`33.8
`
`0.400
`
`0.488
`
`0.625
`
`0.563
`
`0.365
`
`0.010
`
`0.012
`
`0.015
`
`0.014
`
`0.009
`
`EX1005, FIG. 3; EX1002, ¶¶59-63, 86-88, 124-30; see also EX1004, 0543-44
`
`(Applicant defining flux the same way).
`
`The percent of each component in the dried Example 3 patch is provided
`
`below, as is the initial mass of the patch, and the mass after drying (derived from
`
`solids content). EX1005, ¶¶56-57; EX1002, ¶¶119-22.
`
`Component
`
`Initial Mass (g)
`
`Mass after
`Drying (g)
`
`Percent Total
`Dried Product
`
`Estradiol hemihydrate
`
`Estradiol
`
`Water
`
`
`
`Dipropylene glycol
`
`Hydroxypropyl cellulose
`
`
`
`1.16
`
`0.04
`
`
`
`1.50%
`
`0.05%
`
`(1.2 Total)
`
`(1.55% Total)
`
`9.0
`
`0.26
`
`11.62%
`
`0.34%
`
`
`1.16
`
`0.04
`
`
`
`9.0
`
`0.26
`
`-10-
`
`

`

`
`
`Component
`
`Initial Mass (g)
`
`Mass after
`Drying (g)
`
`Percent Total
`Dried Product
`
`Silicone adhesive
`
`Polyacrylate adhesive
`
`Kollidon 90F (PVP)
`
`88.0
`
`10.0
`
`1.2
`
`61.6
`
`5.1
`
`0.3
`
`Total Mass
`
`109.66 g
`
`77.46 g
`
`79.52%
`
`6.58%
`
`0.39%
`
`100%
`
`Once coated onto a backing layer and dried, the patches of Example 3 have a
`
`polymer matrix “coating weight of 115 g/m2” (i.e., 11.5 mg/cm2). EX1005, ¶57;
`
`EX1002, ¶123. This coat thickness affords the patches of Example 3 with an
`
`estradiol dose per-unit-area of ~0.1725 mg/cm2, calculated by multiplying coat
`
`weight with weight percent of estradiol. EX1005, ¶¶56-57; EX1002, ¶123; see also
`
`EX1004, 0126 (Applicant defining dose per-unit-area the same way).
`
`Mueller was published on May 29, 2003 and is prior art to the challenged
`
`claims of the ’900 patent under 35 U.S.C. §102(b). EX1002, ¶114. Mueller was
`
`cited in an Information Disclosure Statement (IDS), but not discussed during
`
`prosecution.
`
`ii.
`
`Vivelle-Dot® Label
`
`Vivelle-Dot® Label (EX1006) describes a second-generation monolithic
`
`transdermal estradiol patch, Vivelle-Dot®. EX1002, ¶¶132-36. Vivelle-Dot® was
`
`approved for the treatment of moderate-to-severe vasomotor symptoms associated
`
`with menopause, vulvar and vaginal atrophy, and hypoestrogenism, as well as the
`
`-11-
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`

`
`
`prevention of postmenopausal osteoporosis. EX1006, 0016-18; EX1002, ¶137.
`
`Vivelle-Dot® Label describes “Vivelle-Dot [as a] revised formulation with smaller
`
`system sizes,” that “was shown to be bioequivalent to the original formulation,
`
`Vivelle[.]” EX1006, 0014; EX1002, ¶132. Vivelle-Dot® “provide[s] nominal in
`
`vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day” in
`
`patches that are “2.5, 3.75, 5.0, 7.5, or 10.0 cm2” in size. EX1006, 0012; EX1002,
`
`¶133.
`
`Vivelle-Dot® Label was publicly available at least as early as April 14, 2006
`
`and is prior art to the challenged claims of the ’900 patent under 35 U.S.C. §102(b).
`
`EX1006, 0001 (affidavit from Freedom of Information Services confirming public
`
`availability from FDA at least as early as this date). EX1002, ¶131.
`
`iii.
`
`Kanios
`
`U.S. Patent Application Publication No. US2006/0078602 (“Kanios,”
`
`EX1007) discloses transdermal patches in which “the drug delivery rates, onset
`
`and profiles of at least one active agent are controlled by selectively manipulating
`
`the monomeric make up of an acrylic-based polymer in the transdermal drug
`
`delivery system.” EX1007, Abstract; EX1002, ¶139.
`
`The patches of Kanios comprise “(a) one or more acrylic based polymers…;
`
`(b) one or more silicone-based polymers; and (c) one or more active agents[.]”
`
`EX1007, Abstract; EX1002, ¶140. The patches further comprise one or more
`
`-12-
`
`

`

`
`
`penetration enhancers, including oleyl alcohol and dipropylene glycol. EX1007,
`
`¶¶106,131-33; EX1002, ¶¶140-41. Figure 1 provides “average flux profiles” of the
`
`patches of Examples 1-3. EX1007, FIG. 1; EX1002, ¶¶142-43. The Figure 1 flux
`
`values are shown in the table below. For example, Figure 1 teaches that Example 1
`
`achieves an estradiol flux of 0.875 µg/cm2/hr (equivalent to 0.021 mg/cm2/day) at
`
`11 hours. EX1007, FIG. 1; EX1002, ¶¶142-43. At 24 hours, both Examples 1 and 2
`
`achieve estradiol flux of 0.672 µg/cm2/hr (0.016 mg/cm2/day). EX1007, FIG. 1;
`
`EX1002, ¶¶142-43.
`
`Estradiol Flux
`µg/cm2/hour
`(mg/cm2/day)
`
`Example 1
`
`Example 2
`
`Example 3
`
`11 hours
`
`24 hours
`
`0.875
`(0.021)
`
`0.641
`(0.015)
`
`0.562
`(0.013)
`
`0.672
`(0.016)
`
`0.672
`(0.016)
`
`0.531
`(0.013)
`
`Kanios was published on April 13, 2006 and is prior art to the challenged
`
`claims of the ’900 patent under 35 U.S.C. §102(b). Kanios was cited in an IDS but
`
`was not discussed during prosecution. EX1002, ¶138.
`
`iv.
`
`Chien
`
`U.S. Patent No. 5,145,682 (“Chien,” EX1009) discloses “[t]ransdermal
`
`absorption dosage units…which comprise a backing layer, an adjoining adhesive
`
`-13-
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`

`

`
`
`polymer layer,” and an optional release liner, comprising “at least minimum
`
`effective daily doses of an estrogen[.]” EX1009, Abstract, 2:45-3:2; EX1002, ¶145.
`
`The patches of Chien comprise “estradiol or other estrogenic steroids used in
`
`formulating the polymer matrix,” wherein the estradiol is “suitably dispersed in the
`
`adhesive polymer.” EX1009, 3:14-17, 3:53-8, 4:5-6; EX1002, ¶146; see also
`
`EX1001, 10:27-33 (polymers that “may have different solubility parameters for the
`
`drug and which may be immiscible with each other, may be selected”); EX1002,
`
`¶16 (“The effect of using immiscible polymers with a hydrophobic drug such as
`
`estrogen is to encapsulate the drug and form microreservoirs of estrogen”). The
`
`estradiol-containing adhesive polymer layer comprises “suitable polyacrylic
`
`adhesive polymers, silicone adhesive polymer[s]” and a “transdermal absorption
`
`enhancing agent.” EX1009, 3:23-25, 3:53-60; EX1002, ¶¶145-46, 269. These
`
`patches “deliver at least minimum daily doses of the estrogen for at least one day
`
`or for multiple days, such as for one week.” EX1009, Abstract.
`
`Chien teaches the desirability of using penetration enhancers, the effect of
`
`drug loading in a dosage unit, and the effect of coating thickness in a dosage unit
`
`on the skin penetration rate of estradiol achieved by the patches. EX1009, 5:20-28,
`
`FIGS. 3-5; EX1002, ¶¶147-48. Figures 3-5 demonstrate that increasing the amount
`
`of penetration enhancer, estradiol loading, and coat weight (thickness) of the
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`polymer matrix layer each increase flux. Id.
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`Chien issued on September 8, 1992 and is prior art to the challenged claims
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`of the ’900 patent under 35 U.S.C. §102(b). Chien was not cited by Applicant or
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`Examiner, and was not of record during prosecution of the ’900 patent. EX1002,
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`¶144.
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`D. Brief Overview of the Level of Skill in the Art
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`A person of ordinary skill in the relevant field as of July 10, 2008, would
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`likely have an advanced degree, for example a Ph.D., in pharmaceutical chemistry,
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`physical chemistry, bioengineering, or a drug delivery related discipline. EX1002,
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`¶¶77-78. Alternatively, one could have a bachelor’s degree plus two to five years’
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`experience in the transdermal delivery industry. Id. The skilled artisan would likely
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`have familiarity with formulation of drugs for transdermal administration and
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`would have been able to understand and interpret the references discussed in the
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`field, including those discussed in this Petition. Id.
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`This Petition is supported by the declaration of Dr. Keith Brain. EX1002;
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`see also id., ¶¶12-13; EX1003 (Dr. Brain’s curriculum vitae, providing a summary
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`of his education, training, and experience). Dr. Brain is a pharmaceutical scientist
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`with over 50 years of experience whose research career focused on transdermal
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`drug delivery systems. EX1002, ¶¶1-11. Dr. Brain has the scientific background
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`and technical expertise to provide detailed analysis of the references discussed
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`herein in relation to the challenged claims and to explain the level of ordinary skill
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`in the art as of July 10, 2008. Id.
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`E.
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`Background Knowledge in the Art Prior to July 10, 2008
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`The following background publications document knowledge a skilled
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`artisan would bring to bear in reading the prior art. Ariosa Diagnostics v. Verinata
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`Health, Inc., 805 F.3d 1359, 1365 (Fed. Cir. 2015); EX1002, ¶90. This knowledge
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`assists in understanding why one of ordinary skill would have been motivated to
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`combine or modify the references asserted in the Grounds of this Petition to arrive
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`at the claimed invention. As KSR established, the knowledge of such an artisan is
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`part of the store of public knowledge that must be consulted when considering
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`whether a claimed invention would have been obvious. Randall Mfg. v. Rea, 733
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`F.3d 1355, 1362-63 (Fed. Cir. 2013) (citing 550 U.S. at 406).
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`Monolithic transdermal drug delivery systems were known to be useful for
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`the administration of estradiol many years prior to July 10, 2008. EX1018 (Müller),
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`Abstract, 1:4-9; EX1002, ¶91. Indeed, many monolithic estradiol patches had been
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`described in the art. EX1018, 1:10-19; see also, e.g., EX1011 (Miranda), 4:44-47;
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`EX1019 (Rovati), 1:10-44; EX1002, ¶92. Such patches were known to be useful
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`for the treatment of a variety of disorders in postmenopausal women. EX1019,
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`1:17-22. By 2008, several monolithic matrix-type transdermal estradiol delivery
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`systems were approved by FDA for hormone replacement therapy (“HRT”).
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`EX1034 (Orange Book), 0175; EX1008 (Vivelle® Label), 0012; EX1015
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`(Climara® Label), 0005-6; EX1016 (Alora® Label), 0018; EX1017 (Menostar®
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`Label), 0010; EX1002, ¶¶93-98. The daily doses approved for HRT prior to July
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`2008 included 0.025, 0.0375, 0.05, 0.075, and 0.1 mg/day. See EX1008, 0012;
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`EX1015, 0005-06; EX1016, 0018 ; EX1017, 0010; EX1002, ¶¶93-98. The
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`Vivelle® patch, for example, is a monolithic matrix-type transdermal estradiol
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`delivery system that provides these nominal daily doses in “an active surface area
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`of 7.25, 11.0, 14.5, 22.0, or 29.0 cm2,” respectively. EX1008, 0012; EX1002, ¶¶94-
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`97.
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`To determine the dose of estradiol delivered by a patch, the amount of
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`estradiol delivered per-unit-time and per-unit-area of the patch (i.e., flux) is
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`measured. U.S. Patent No. 6,521,250 teaches a method of measuring flux in which
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`a skin sample from a hairless mouse or from a human cadaver is placed in a Franz
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`diffusion cell. An estradiol-containing patch is applied to the skin and the active
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`substance release is measured at 37˚C. EX1020 (Meconi), 7:6-10:57, Table 2;
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`EX1002, ¶¶99-100, 107; see also EX1004, 0581-82; EX1002, ¶¶64-68.
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`Those in the art understood prior to 2008 that the size, dose, and flux of a
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`patch for transdermal drug delivery are interdependent variables. EX1025 (van der
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`Bijl), 507; EX1002, ¶108. For example, if patch size is held constant, increased
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`flux provides a proportional increase in the amount of drug delivered (dose). Id. If
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`dose is held constant, increased flux allows for a proportional decrease in patch
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`size. Id. It was well established in the art that smaller patches for a given dose were
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`desirable because they reduce skin irritation, provide better patch adhesion,
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`improve patient compliance, and reduce packaging costs. EX1012 (Fotinos),
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`15:31-16:1; EX1013 (Bevan); EX1002, ¶¶109-12.
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`Methods for increasing flux were known to those of skill in the art. For
`
`example, increasing polyacrylate content and including a penetration enhancer in
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`the polymer matrix were each methods known to increase flux. EX1011 (Miranda),
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`Figures 12, 16; EX1021 (Heiber), 10:1-14; EX1022 (Bucks), TABLE I-II, 32;
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`EX1002, ¶107. Kim teaches inclusion of penetration enhancers, such as oleyl
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`alcohol and hydrophobic glycols, to improve drug permeation across skin, thereby
`
`increasing flux. EX1010 (Kim), 83; EX1002, ¶¶101-02.
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`Kim also teaches that increasing the coat weight (thickness) of the adhesive
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`polymer matrix of a monolithic, matrix-type patch increases flux. EX1010, 79, 82;
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`EX1002, ¶¶101-02; EX1014 (Ghosh), 287, and Chien (EX1009), discussed above.
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`Kim further notes that “it seemed that the occlusive effect of adhesive matrix
`
`increased. The occlusive effect is usually provided by [a] backing membrane,
`
`however, as the thickness of the adhesive matrix increased, the matrix also
`
`contributes to [the] occlusive effect[.]” EX1010, 82. Kim teaches that “[a]s the
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`thickness of the matrix increased, the occlusive effect of the matrix increased,
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`resulting in the increased flux[.]” Id.; EX1002, ¶¶101-02.
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`As explained by Dr. Brain, the positive effect of occlusion on drug flux
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`observed by Kim was well-known in the art prior to 2008. EX1002, ¶¶103-05
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`(discussing EX1026 (Bronaugh), 86, 89). In fact, Bronaugh teaches that “[o]f the
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`various approaches employed to enhance the percutaneous absorption of drugs,
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`occlusion (defined as the complete impairment of passive transepidermal water
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`loss at the application site) is the simplest and most common method in use.”
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`EX1026, 86, 89; see also EX1022 (of which Dr. Richard Guy, proponent of the
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`Rule 132 declaration during prosecution of the ’900 patent, is a co-author), 32;
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`EX1004, 0269 (noting “the area of skin subject to occlusion”). Bronaugh further
`
`teaches that, while “occlusion does not necessarily increase the percutaneous
`
`absorption of all chemicals,” it “significantly increase[s] the percutaneous
`
`absorption (p<0.01) of the steroids,” including estradiol. EX1026, 86, 89
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`(“[o]cclusion significantly (p<0.05) increased the percutaneous absorption of
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`estradiol”); EX1002, ¶¶104-05.
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`II. GROUNDS FOR STANDING
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`Petitioner certifies under 37 C.F.R. § 42.104(a) that the ’900 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’900 patent on the grounds identified.
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
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`Real Parties-in-Interest (37 C.F.R. §42.8(b)(1)): Mylan Technologies, Inc.
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`and Mylan Pharmaceuticals Inc., each a wholly owned subsidiary of Mylan Inc., an
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`indirectly wholly-owned subsidiary of Mylan N.V., and Mylan N.V. are the real-
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`parties-in-interest.
`
`Related Matters (37 C.F.R. §42.8(b)(2)): A petition for inter partes review
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`of related U.S. Patent No. 9,724,310 (“the ’310 patent”) is also being filed by the
`
`present Petitioner as IPR2018-00173. The ’900 and the ’310 patents both claim the
`
`benefit of U.S. Application No. 12/216,811, filed on July 10, 2008, now U.S.
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`Patent No. 8,231,906.
`
`Litigation concerning the ’900 patent to which Petitioner is not a party is
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`currently pending in the District of Delaware: Noven Pharmaceuticals, Inc. v.
`
`Alvogen Pine Brook LLC, No. 1:17-cv-01429-LPS.
`
`Petitioner and other entities were previously involved in litigation
`
`concerning the related parent U.S. Patent No. 8,231,906 (“the ’906 patent”) in an
`
`action styled Noven Pharmaceuticals Inc. v. Mylan Technologies Inc., et al., Nos.
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`1:15-cv-00328 (D. Del.); 1:15-cv-00069 (N.D.W.V.), which terminated in
`
`February 2016. Litigation concerning the ’906 patent, to which Petitioner is not a
`
`party, apparently remains pending in the District of Delaware: Noven
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`Pharmaceuticals Inc. v. Actavis Laboratories UT, Inc., Nos. 1:15-cv-00249-LPS;
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`-20-
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`1:16-cv-00465-LPS – consolidated; Alvogen Pine Brook LLC v. Noven
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`Pharmaceuticals, Inc. No. 1:16-cv-00395-LPS.
`
`Lead and Back-Up Counsel (37 C.F.R. §42.8(b) (3)):
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`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
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`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
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`Back-Up Counsel: Jad A. Mills (Reg. No. 63,344)
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`Service Information – 37 C.F.R. §42.8(b)(4):
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`Peti