Paper No. ____
`Filed: May 18, 2018
`
`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. IPR2018-01119
`Patent No. 9,833,419
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,833,419
`
`
`
`Filed: May 18, 2018
`
`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. IPR2018-01119
`Patent No. 9,833,419
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,833,419
`
`
`
`
`
`
`I.
`
`Table of Contents
`
`Page
`
`Introduction .................................................................................................. 1
`A.
`Brief Overview of the ’419 Patent....................................................... 4
`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 .................................................................................. 20
`III. Mandatory Notices under 37 C.F.R. §42.8 .................................................. 20
`IV. Statement of the Precise Relief Requested .................................................. 22
`A. Asserted Grounds of Unpatentability ................................................ 22
`B.
`Evidence of Unpatentability Not Considered in Prosecution ............. 22
`V.
`Claim Construction ..................................................................................... 24
`A.
`“About” ............................................................................................ 24
`B.
`“Coat weight” ................................................................................... 25
`C.
`“Flux” ............................................................................................... 26
`D.
`“Therapeutically Effective Amount” ................................................. 28
`VI. Detailed Explanation Of Grounds For Unpatentability ................................ 29
`A.
`U.S.C. §102 by Mueller. ................................................................... 29
`B.
`§103 over Mueller in view of Vivelle-Dot® Label. ............................ 42
`
`[Ground 1] Claims 1, 2, 8, and 10-15 are Anticipated under 35
`
`[Ground 2] Claims 1, 2 and 8-15 are Obvious under 35 U.S.C.
`
`-i-
`
`
`
`
`
`[Ground 3] Claims 3-7 are Obvious under 35 U.S.C. §103 over
`
`C.
`Mueller, Vivelle-Dot® Label, and Kanios. ........................................ 48
`D.
`over Mueller, Vivelle-Dot® Label, Kanios, and Chien. ..................... 56
`VII. Secondary Indicia of Non-obviousness ....................................................... 60
`VIII. Conclusion .................................................................................................. 63
`IX. Certificate of Compliance ........................................................................... 65
`X.
`Payment of Fees under 37 C.F.R. §§42.15(a) and 42.103............................ 66
`XI. Appendix – List of Exhibits ........................................................................ 67
`
`[Ground 4] Claims 1-15 are Obvious under 35 U.S.C. §103
`
`-ii-
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`Mylan Technologies, Inc. (“Mylan”) requests review of U.S. Patent No.
`
`9,833,419 to Mantelle (“the ’419 patent,” EX1001), which issued on December 5,
`
`2017. PTO records indicate that the ’419 patent is assigned to Noven
`
`Pharmaceuticals, Inc. (Patent Owner, “PO”). This Petition demonstrates that there
`
`is a reasonable likelihood that claims 1-15 of the ’419 patent are unpatentable for
`
`failure to distinguish over the prior art asserted herein.
`
`The ’419 patent is 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 the same.
`
`The patch comprises a backing layer, 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 ’419 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
`
`Listing), 0175. In 1999, PO received FDA approval for a second-generation patch
`
`system with higher estradiol flux, termed Vivelle-Dot®, which permitted the
`
`-1-
`
`
`
`
`
`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 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 could be achieved by increasing the
`
`amount of hydrophile 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 claim 1 and its dependent claims 2, 8, and 10-15. The
`
`Mueller system comprises a single drug-containing adhesive polymer matrix layer,
`
`a backing layer, and a release liner. Mueller teaches that the polymer matrix
`
`comprises greater than 0.156 mg/cm2 estradiol, acrylic and silicone adhesives,
`
`soluble polyvinylpyrrolidone (PVP), dipropylene glycol as a penetration enhancer,
`
`-2-
`
`
`
`
`
`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 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, which was known to achieve a flux of
`
`0.01 mg/cm2/day. EX1006, 0012; EX1002, ¶¶41-42, 123, 192, 196. 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, teaches that increasing 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 ’419
`
`patent by repeatedly asserting that it was “surprising and unexpected” that
`
`increasing the coat weight of the drug-containing matrix would increase the flux of
`
`the patch. See, e.g., EX1004, 0165; see also id., 0014, 0159-62, 0190-0192, 0207-
`
`27.
`
`Additional references besides Chien, including Kim, Ghosh, and Wong
`
`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
`
`-3-
`
`
`
`
`
`flux. EX1010 (Kim), 82; EX1014 (Ghosh), 287-88; EX1028 (Wong), 9:64-10:24
`
`and FIG. 12-FIG. 13. Moreover, these references provide an explanation for how
`
`and why an increased coat weight increases flux, noting that, “[a]s 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 (Bronaugh), 86, 89. Moreover, the art explained that
`
`increasing occlusion increased water (“the most widely used and safest method to
`
`increase skin penetration”), which in turn increased flux. EX1039 (Benson), 28.
`
`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 relationship between
`
`increased coat weight with estradiol flux of a matrix-type monolithic patch was
`
`already described in the art. PO’s assertions of “surprising and unexpected” results
`
`merely confirms that, in view of the prior art, the results were entirely expected.
`
`A. Brief Overview of the ’419 Patent
`
`The ’419 patent has an earliest claimed priority date of July 10, 2008. Claim
`
`1 recites a monolithic transdermal estradiol delivery system, i.e., an estradiol patch.
`
`-4-
`
`
`
`
`
`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 10 mg/cm2,” and includes “greater than 0.156 mg/cm2 estradiol.” The
`
`patch also “achieves an estradiol flux of from 0.0125 to about 0.05 mg/cm2/day,
`
`based on the active surface area.” EX1002, ¶¶14-15. Dependent claims recite
`
`minor limitations of the estradiol patch, including the delivery of standard daily
`
`doses of estradiol, patch sizes, and known percentages of patch components, as
`
`well as flux values that fall within the range recited in claim 1. Id. at ¶¶16-17, 19-
`
`21.
`
`The ’419 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, 10:21-27, claims 1-15. This blend of immiscible polymers
`
`forms microreservoirs within the single-layer polymer matrix. EX1002, ¶18.
`
`B.
`
`Brief Overview of the Prosecution History
`
`U.S. Application No. 14/870,574 (“the ’574 application”) was filed on
`
`September 30, 2015, and issued on December 5, 2017 as the ’419 patent. EX1002,
`
`¶22. The ’419 patent claims the benefit of U.S. Application No. 12/216,811, filed
`
`on July 10, 2008. During prosecution, Applicant amended the claims in response to
`
`prior art-based rejections (based on EX1030-31). EX1002, ¶¶23-27.
`
`-5-
`
`
`
`
`
`On August 29, 2017, Applicant submitted a Rule 132 Declaration signed by
`
`Dr. Richard Guy to allege “surprising and unexpected” results. EX1004, 0200-
`
`0306; EX1002, ¶¶34-43. Dr. Guy presented an “in vitro flux study conducted to
`
`assess the flux of the estradiol from different systems” using a Franz diffusion cell.
`
`EX1004, 0207-09. 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.” Id. The standard deviations of the replicate flux measurements provided by
`
`Dr. Guy, however, show that measurements of flux of the same patch, in the same
`
`experimental set-up can deviate by more than 15%. EX1002, ¶¶39-43. 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%. Id., ¶41.
`
`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, 0207-09; EX1002, ¶¶34-37, 117, 149, 163, 188 (e.g.,
`
`flux at 23.95 hours calculated by taking the difference between drug permeation at
`
`-6-
`
`
`
`
`
`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. Id.
`
`Dr. Guy also states in his declaration that “it was known in the art that the
`
`relative amounts of acrylic adhesive and silicone adhesive in an estradiol polymer
`
`matrix can impact flux[.]” EX1004, 0208, 0214. 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, ¶¶31-32, 41-43, 198,
`
`204, 217. Even Vivelle-Dot® as described in EX1004 achieved a flux well within
`
`this range. EX1002, ¶41. 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, 0214; see also id., 0014, 0159-62, 0165, 0190-92, 0207-27. The
`
`Examiner’s June 27, 2017 Notice of Allowance expressly invokes Applicant’s
`
`assertion of unexpected results made in the declaration of Dr. Guy as a basis for
`
`allowance. EX1004, 0324-25. However, neither Applicant nor the Guy declaration
`
`accounts for prior art references that were not of record during prosecution, which
`
`are discussed in this Petition.
`
`-7-
`
`
`
`
`
`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, ¶¶44-51, 102.
`
`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, ¶¶103-106. Mueller’s
`
`patches comprise an “active substance matrix” that is “a single-layer structure and
`
`is self-adhesive,” a backing layer, and a “releasable protective layer.” EX1005,
`
`¶¶25-26; EX1002, ¶106.
`
`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
`
`-8-
`
`
`
`
`
`behavior, as well as more efficient use of active substance.” EX1005, ¶22; EX1002,
`
`¶¶104-07. 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, ¶105.
`
`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, ¶103. Figures 1-3 present the cumulative amount of estradiol
`
`delivered (in µg/cm2) over time. EX1005, FIGS. 1-3; EX1002, ¶¶113-19. The
`
`slope between each data point in Mueller Figure 3 provides the flux that was
`
`achieved by the patches of Example 3:
`
`-9-
`
`
`
`
`
`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, ¶¶113-120; see also EX1004, 0207-09 (Applicant
`
`defining flux the same way). As noted by Dr. Brain, a slight distortion in Figure 3
`
`of Mueller, which is not present in Mueller’s priority document, does not impact
`
`the above calculations. EX1042 (Application Number DE10012908; “Mueller
`
`priority document”), FIG.3.
`
`The percent of each component in the dried patch of Example 3 is provided
`
`below, as is the initial mass of the patch, and the mass after drying (derived from
`
`solids content). EX1005, ¶¶56-57; EX1002, ¶¶108-111.
`
`Component
`
`Initial Mass
`(g)
`
`Mass after
`Drying (g)
`
`Percent Total
`Dried Product
`
`Estradiol hemihydrate
`
`Estradiol
`
`Water
`
`
`
`Dipropylene glycol
`
`
`
`1.16
`
`0.04
`
`
`
`1.50%
`
`0.05%
`
`(1.2 Total)
`
`(1.55% Total)
`
`9.0
`
`11.62%
`
`
`1.16
`
`0.04
`
`
`
`9.0
`
`-10-
`
`
`
`
`
`Component
`
`Initial Mass
`(g)
`
`Mass after
`Drying (g)
`
`Percent Total
`Dried Product
`
`Hydroxypropyl cellulose
`
`Silicone adhesive
`
`Polyacrylate adhesive
`
`Kollidon 90F (PVP)
`
`0.26
`
`88.0
`
`10.0
`
`1.2
`
`0.26
`
`61.6
`
`5.1
`
`0.3
`
`Total Mass
`
`109.66 g
`
`77.46 g
`
`0.34%
`
`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, ¶112. 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, ¶112; see also
`
`EX1035 (File History of the ’900 patent), 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 ’419 patent under 35 U.S.C. §102(b). 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, ¶¶122, 124-26. Vivelle-Dot®
`
`was approved for the treatment of moderate-to-severe vasomotor symptoms
`
`-11-
`
`
`
`
`
`associated with menopause, vulvar and vaginal atrophy, and hypoestrogenism, as
`
`well as the prevention of postmenopausal osteoporosis. EX1006, 0016, 0018;
`
`EX1002, ¶127. 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, ¶122. 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, ¶123.
`
`Vivelle-Dot® Label was publicly available at least as early as April 14, 2006
`
`and is prior art to the challenged claims of the ’419 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, ¶121.
`
`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, ¶129.
`
`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[.]”
`
`-12-
`
`
`
`
`
`EX1007, Abstract; EX1002, ¶130. The patches further comprise one or more
`
`penetration enhancers, including oleyl alcohol and dipropylene glycol. EX1007,
`
`¶¶106, 131-33; EX1002, ¶131. Figure 1 provides “average flux profiles” of the
`
`patches of Examples 1-3. EX1007, FIG. 1; EX1002, ¶¶132-33. 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, ¶¶132-33. 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, ¶¶132-33.
`
`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 ’419 patent under 35 U.S.C. §102(b). Kanios was cited in an IDS but
`
`was not discussed during prosecution. EX1002, ¶128.
`
`-13-
`
`
`
`
`
`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
`
`polymer layer,” and an optional release liner, comprising “at least minimum
`
`effective daily doses of an estrogen[.]” EX1009, Abstract, 2:45-3:2; EX1002,
`
`¶134-35. 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,
`
`¶¶135-36; see also EX1001, 10:21-27 (polymers that “may have different
`
`solubility parameters for the drug and which may be immiscible with each other,
`
`may be selected”); EX1002, ¶18 (“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, ¶¶135-36. 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
`
`-14-
`
`
`
`
`
`on the estradiol flux through skin achieved by the patches. EX1009, 5:20-28, FIGS.
`
`3-5; EX1002, ¶¶137-38. Figures 3-5 demonstrate that increasing the amount of
`
`penetration enhancer, estradiol loading, and coat weight (thickness) of the polymer
`
`matrix layer each increase flux. Id.
`
`Chien issued on September 8, 1992 and is prior art to the challenged claims
`
`of the ’419 patent under 35 U.S.C. §102(b). Chien was not cited by Applicant or
`
`Examiner, and was not of record during prosecution of the ’419 patent. EX1002,
`
`¶137.
`
`D. Brief Overview of the Level of Skill in the Art
`
`A person of ordinary skill in the relevant field as of July 10, 2008, would
`
`likely have an advanced degree, for example a Ph.D., in pharmaceutical chemistry,
`
`physical chemistry, bioengineering, or a drug delivery related discipline. EX1002,
`
`¶¶52-53. Alternatively, one could have a bachelor’s degree plus two to five years’
`
`experience in the transdermal delivery industry. Id. The skilled artisan would likely
`
`have familiarity with formulation of drugs for transdermal administration and
`
`would have been able to understand and interpret the references discussed in the
`
`field, including those discussed in this Petition. Id.
`
`This Petition is supported by the declaration of Dr. Keith Brain. EX1002;
`
`see also id., ¶¶12-13; EX1003 (Dr. Brain’s curriculum vitae, providing a summary
`
`of his education, training, and experience). Dr. Brain is a pharmaceutical scientist
`
`-15-
`
`
`
`
`
`with decades of experience whose research career focused on transdermal drug
`
`delivery systems. Id., ¶¶1-11. Dr. Brain has the scientific background and technical
`
`expertise to provide detailed analysis of the references discussed herein in relation
`
`to the challenged claims and to explain the level of ordinary skill in the art as of
`
`July 10, 2008. Id.
`
`E.
`
`Background Knowledge in the Art Prior to July 10, 2008
`
`The following background publications document knowledge a skilled
`
`artisan would bring to bear in reading the prior art. Ariosa Diagnostics v. Verinata
`
`Health, Inc., 805 F.3d 1359, 1365 (Fed. Cir. 2015); EX1002, ¶65. This knowledge
`
`assists in understanding why one of ordinary skill would have been motivated to
`
`combine or modify the references asserted in the Grounds of this Petition to arrive
`
`at the claimed invention. As KSR established, the knowledge of such an artisan is
`
`part of the store of public knowledge that must be consulted when considering
`
`whether a claimed invention would have been obvious. Randall Mfg. v. Rea, 733
`
`F.3d 1355, 1362-63 (Fed. Cir. 2013) (citing 550 U.S. at 406).
`
`Monolithic transdermal drug delivery systems were known to be useful for
`
`the administration of estradiol many years prior to July 10, 2008. EX1018 (Müller),
`
`Abstract, 1:4-9; EX1002, ¶67. Indeed, many monolithic estradiol patches had been
`
`described in the art. EX1018, 1:10-19; see also, e.g., EX1011 (Miranda), 4:44-47;
`
`EX1019 (Rovati), 1:10-44; EX1002, ¶¶68-69. Such patches were known to be
`
`-16-
`
`
`
`
`
`useful for the treatment of a variety of disorders in postmenopausal women.
`
`EX1019, 1:17-22. By 2008, several monolithic matrix-type transdermal estradiol
`
`delivery systems were approved by FDA for hormone replacement therapy
`
`(“HRT”). EX1034, 0175; EX1008 (Vivelle® Label), 0012; EX1015 (Climara®
`
`Label), 0005-6; EX1016 (Alora® Label), 0018; EX1017 (Menostar® Label), 0010;
`
`EX1002, ¶¶70-75. The daily doses approved for HRT prior to July 2008 included
`
`0.025, 0.0375, 0.05, 0.075, and 0.1 mg/day. See EX1008, 0012; EX1015, 0005-06;
`
`EX1016, 0018; EX1017, 0010; EX1002, ¶¶70-75. The Vivelle® patch, for example,
`
`is a monolithic matrix-type transdermal estradiol delivery system that provides
`
`these nominal daily doses in “an active surface area of 7.25, 11.0, 14.5, 22.0, or
`
`29.0 cm2,” respectively. EX1008, 0012; EX1002, ¶¶71-73.
`
`To determine the dose of estradiol delivered by a patch, the amount of
`
`estradiol delivered per-unit-time and per-unit-area of the patch (i.e., flux) is
`
`measured. U.S. Patent No. 6,521,250 teaches a method of measuring flux in which
`
`a skin sample from a hairless mouse or from a human cadaver is placed in a Franz
`
`diffusion cell. An estradiol-containing patch is applied to the skin and the active
`
`substance release is measured at 37˚C.” EX1020 (Meconi), 7:6-10 -57, Table 2;
`
`EX1002, ¶¶76-77, 93; see also EX1004, 0208-09; EX1002, ¶¶39-43.
`
`Those in the art understood prior to 2008 that the patch size, dose, and flux
`
`of a patch for transdermal drug delivery are interdependent variables. EX1025 (van
`
`-17-
`
`
`
`
`
`der Bijl), 507; EX1002, ¶¶96. For example, if patch size is held constant, increased
`
`flux provides a proportional increase in the amount of drug delivered (dose). Id. If
`
`dose is held constant, increased flux allows for a proportional decrease in patch
`
`size. Id. It was well established in the art that smaller patches for a given dose were
`
`desirable because they reduce skin irritation, provide better patch adhesion,
`
`improve patient compliance, and reduce packaging costs. EX1012 (Fotinos),
`
`15:31-16:1; EX1013 (Bevan); EX1041 (Mantelle 2008), 408-9; EX1002, ¶¶66, 95-
`
`96, 98-102.
`
`Methods for increasing flux were known to those of ordinary skill in the art.
`
`For example, increasing polyacrylate content and including one or more
`
`penetration enhancers in the polymer matrix were each known to increase flux.
`
`EX1011, FIGS. 12, 16; EX1021 (Heiber), 10:1-14; EX1022 (Bucks), TABLE I-II,
`
`32; EX1039, 29-30; EX1002, ¶¶87-92, 95, 203, 242, 248. Kim teaches inclusion of
`
`penetration enhancers, such as oleyl alcohol and hydrophobic glycols, to improve
`
`drug permeation across skin thereby increasing flux. EX1010, 83; EX1002, ¶¶235.
`
`Kim also teaches that increasing the coat weight (thickness) of the adhesive
`
`polymer matrix of a monolithic, matrix-type patch increases flux. EX1010, 79, 82;
`
`EX1002, ¶84; see also EX1014, 287; EX1009. 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
`
`-18-
`
`
`
`
`
`adhesive matrix increased, the matrix also contributes to [the] occlusive effect[.]”
`
`EX1010, 82. As noted by Dr. Brain, while Figure 4 of Kim is misprinted as a
`
`duplicate of Figure 3, which is an unrelated graph on the adhesive force of
`
`pressure-sensitive adhesives, Kim expressly teaches that “[a]s the thickness of the
`
`matrix increased, the occlusive effect of the matrix increased, resulting in the
`
`increased flux[.]” EX1010, 82; EX1002, ¶¶76, 84.
`
`As explained by Dr. Brain, the positive effect of occlusion on drug flux
`
`observed by Kim was well-known in the art prior to 2008. EX1002, ¶¶85-88
`
`(discussing EX1026, 86, 89). In fact, Bronaugh teaches that “[o]f the various
`
`approaches employed to enhance the percutaneous absorption of drugs, occlusion
`
`(defined as the complete impairment of passive transepidermal water loss at the
`
`application site) is the simplest and most common method in use.” EX1026, 86, 89;
`
`see also EX1022 (of which Dr. Richard Guy, proponent of the Rule 132
`
`declaration during prosecution of the ’419 patent, is a co-author), 32; EX1004,
`
`0191 (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 (“[o]cclusion significantly
`
`(p<0.05) increased the percutaneous absorption of estradiol”); EX1002, ¶¶87-88.
`
`-19-
`
`
`
`
`
`Benson similarly notes that “hydration can be increased by occlusion,”
`
`characterizing water as “the most widely used and safest method to increase skin
`
`penetration of both hydrophilic and lipophilic permeants.” EX1039, 28; EX1002,
`
`¶90. As confirmed by Applicant, penetration enhancers (e.g., water) increase flux
`
`and are modeled in Fick’s 1st law by “D [drug’s diffusivity through skin]
`
`and/or…K [partition coefficient].” EX1004, 164; EX1002, ¶90. Benson also
`
`teaches supersaturating drug formulations result in increased flux. EX1039, 24
`
`(noting an “18-times saturated system was increased 18-fold across human
`
`membrane”); EX1002, ¶90. Thus, the prior art provided multiple methods for
`
`reliably increasing the flux of a transdermal drug delivery system.
`
`II. GROUNDS FOR STANDING
`
`Petitioner certifies under 37 C.F.R. § 42.104(a), that the ’419 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’419 patent on the grounds identified.
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. §42.8
`
`Real Parties-in-Interest (37 C.F.R. §42.8(b)(1)): Mylan Technologies, Inc.
`
`and Mylan Pharmaceuticals Inc., each a wholly owned subsidiary of Mylan Inc., an
`
`indirectly wholly-owned subsidiary of Mylan N.V., and Mylan N.V. are the real-
`
`parties-in-interest.
`
`-20-
`
`
`
`
`
`Related Matters (37 C.F.R. §42.8(b)(2)): Petitions for inter partes review of
`
`related U.S. Patent Nos. 9,730,900 (“the ’900 patent”) and 9,724,310 (“the ’310
`
`patent”) have been filed by the present Petitioner as IPR2018-00174 and IPR2018-
`
`00173, respectively. The ’419, ’310, and ’900 patents all claim the benefit of U.S.
`
`Application No. 12/216,811, filed on
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