UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`WARNER CHILCOTT COMPANY, LLC.,
`Patent Owner
`
`Case IPR2015-00682
`Patent 7,704,984
`
`PATENT OWNER PRELIMINARY RESPONSE
`PURSUANT TO 35 U.S.C. § 313 AND 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`DC: 5667161-12
`
`
`
`

`

`IPR2015-00682
`
`LIST OF EXHIBITS
`
`2003
`
`2004
`
`2005
`
`
`Document
`Exhibit
`2001 Opinion from Warner Chilcott Co., LLC v. Lupin Ltd. et al.,
`Civ. A. Nos. 11-05048, 12-2928 (D.N.J. Jan. 17, 2014)
`2002 Opinion from Warner Chilcott Co., LLC v. Lupin Ltd., et al,
`Nos. 2014-1267, -1273 (Fed. Cir. Oct. 22, 2014)
`Excerpts of Trial Transcripts from Warner Chilcott Co., LLC v.
`Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J. Oct.
`7-17, 2013)
`Speroff, L. & P.D. Darney, A Clinical Guide for Contraception
`(4th ed. 2005) (PTX 83 from Warner Chilcott Co., LLC v. Lupin
`Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Speroff, L. & Darney, P.D., A Clinical Guide for Contraception
`(3d ed. 2001) (PTX 82A from Warner Chilcott Co., LLC v.
`Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Prescribing Information for Lo Loestrin Fe
`van Heusden, A.M., Fauser, B.C.J.M., “Activity of the pituitary-
`ovarian axis in the pill-free interval during use of low-dose
`combined oral contraceptives,” Contraception, 1999; 59:237-
`243. (DTX 507 from Warner Chilcott Co., LLC v. Lupin Ltd. et
`al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Teichmann, A.T., et al., “The influence of the dose of ethinyl
`estradiol in oral contraceptives on follicle growth,” Gynecol.
`Endocrinol. 1995; 9:299-305. (DTX 477 Warner Chilcott Co.,
`LLC v. Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928
`(D.N.J.))
`2009 U.S. Patent 5,980,940 (JTX 16 from Warner Chilcott Co., LLC
`v. Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`2010 Kaunitz, A., Oral Contraceptive Estrogen Dose Considerations,
`58 Contraception 15S (1998) (PTX 48 from Warner Chilcott
`Co., LLC v. Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928
`(D.N.J.))
`2011 Darney, P., OC Practice Guidelines: Minimizing Side Effects,
`42 Int’l J. Fertility & Women’s Med. 158 (Suppl. 1 1997) (PTX
`21 from Warner Chilcott Co., LLC v. Lupin Ltd. et al., Civ. A.
`Nos. 11-05048, 12-2928 (D.N.J.)
`Thorneycroft, I. & Cariati, S., Ultra-Low-Dose Oral
`
`2006
`2007
`
`2008
`
`2012
`
`Page i
`
`

`

`IPR2015-00682
`
`Exhibit
`
`Document
`Contraceptives: Are They Right for Your Patient?,
`wvvw.medscape.com, July 3, 2001 (PTX 99 from Warner
`Chilcott Co., LLC v. Lupin Ltd. et al., Civ. A. Nos. 11-05048,
`12-2928 (D.N.J.))
`2013 Akerlund et al., Comparative Profiles of Reliability, Cycle
`Control and Side Effects of Two Oral Contraceptive
`Formulations Containing 150 mcg Desogestrel and Either 30 or
`20 mcg Ethinyl Estradiol, 100 Brit. J. Obstet. Gynecol. 832
`(1993) (PTX 1 from Warner Chilcott Co., LLC v. Lupin Ltd. et
`al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`2014 Marut, E., Oral Contraceptives; Who, Which, When, and Why,
`82 Postgraduate Medicine, 1987
`2015 U.S. Patent No. 4,292,315 (PTX 112 Warner Chilcott Co., LLC
`v. Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Serfaty, D., The 20 Microgram Ethinyl Estradiol Plus 150
`Microgram Desogestrel Pill Multicenter Study on 235 Women
`for 6 Months, 18 Contraception-fertilite sexualite 407 (1990)
`(PTX 78) from Warner Chilcott Co., LLC v. Lupin Ltd. et al.,
`Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Lammers et al., Double-blind comparative acceptability study
`with two combined oral contraceptives containing 20 μg
`ethinylestradiol plus desogestrel or norethisterone acetate, in
`Optimizing the estrogen dose in oral contraceptives 67-74
`(1992) (PTX 52 from Warner Chilcott Co., LLC v. Lupin Ltd. et
`al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Task Force on Oral Contraceptives, A randomized, double-blind
`study of six combined oral contraceptives, 25 Contraception 231
`(Mar. 1982) (PTX 97 from Warner Chilcott Co., LLC v. Lupin
`Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`2019 Bounds, et al., A Randomized Double-Blind Trial of Two Low
`Dose Combined Oral Contraceptives, 86 Brit. J. Obstetrics 325
`(1979) (PTX 10 from Warner Chilcott Co., LLC v. Lupin Ltd. et
`al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Szarewski, A. & Guillebaud, J., Contraception: A User’s
`Handbook (1998) (PTX 93 from Warner Chilcott Co., LLC v.
`Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`2021 U.S. Patent 4,921,843 (JTX 15 from Warner Chilcott Co., LLC
`v. Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`
`2020
`
`2016
`
`2017
`
`2018
`
`Page ii
`
`

`

`2024
`
`Document
`Excerpts from the Deposition Transcript of Kurt Barnhart, M.D.
`(7/30/2013) from Warner Chilcott Co., LLC v. Lupin Ltd. et al.,
`Civ. A. Nos. 11-05048, 12-2928 (D.N.J.)
`2023 Miscellaneous Exhibits introduced at trial by Lupin Ltd. and
`Amneal Pharmaceuticals in Warner Chilcott Co., LLC v. Lupin
`Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.)
`Sullivan et al., Effect of 21-day and 24-day oral contraceptive
`regimens containing gestodene (60 μg) and ethinyl estradiol (15
`μg) on ovarian activity, 72 Fertility & Sterility 115 (July 1999)
`(PTX 91 from Warner Chilcott Co., LLC v. Lupin Ltd. et al.,
`Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`2025 Gestodene Study Group 324, Cycle control, safety and efficacy
`of a 24-day regimen of gestodene 60 μg/ethinylestradiol 15 μg
`and a 21- day regimen of desogestrel 150 μg/ethinylestradiol 20
`μg, 4 Eur. J. Contraception & Reproductive Health Care 17
`(Suppl. 2 1999) (PTX 37 from Warner Chilcott Co., LLC v.
`Lupin Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Endrikat, J., et al., “Double-blind, multicenter comparison of
`efficacy, cycle control, and tolerability of a 23-day versus a 21-
`day low-dose oral contraceptive regimen containing 20 mcg
`ethinyl estradiol and 75 mcg gestodene,” Contraception, 2001;
`64:99-105. (DTX 520 from Warner Chilcott Co., LLC v. Lupin
`Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`Szarewski, A. & Guillebaud, J., Contraception: A User’s Guide
`(3d ed. 2004) (PTX 92 from Warner Chilcott Co., LLC v. Lupin
`Ltd. et al., Civ. A. Nos. 11-05048, 12-2928 (D.N.J.))
`2028 Complaint of Warner Chilcott Co., LLC. in Warner Chilcott Co.
`LLC v. Mylan, Inc. et al., Civ. No. 3:13-06560 (D.N.J.)
`2029 Answer and Counterclaims of Mylan in Warner Chilcott Co.
`LLC v. Mylan, Inc. et al., Civ. No. 3:13-06560 (D.N.J.)
`Scheduling Order in Warner Chilcott Co. LLC v. Mylan, Inc. et
`al., Civ. No. 3:13-06560 (D.N.J.)
`Thomas MA. Contraception. Conn’s Current Therapy, pp.
`1123-8, 2001.
`Thomas MA: Fertility Control and Contraception. Gynecology
`& Obstetrics, A Longitudinal Approach. Chapter III:185-207,
`1993.
`
`2026
`
`2027
`
`2030
`
`2031
`
`2032
`
`IPR2015-00682
`
`Exhibit
`2022
`
`
`
`Page iii
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`

`

`IPR2015-00682
`
`TABLE OF CONTENTS
`
`Page(s)
`
`I.
`
`II.
`
`Introduction ..................................................................................................... 1
`
`Background ..................................................................................................... 5
`
`A.
`
`B.
`
`C.
`
`The ’984 Patent and Lo Loestrin .......................................................... 5
`
`Prior Litigation Concerning the ’984 Patent ........................................ 7
`
`Petitioner’s Concurrent Obviousness Challenge to the ’984
`Patent .................................................................................................. 11
`
`D.
`
`Combination Oral Contraceptives ...................................................... 12
`
`III. Level of Ordinary Skill in the Art ................................................................ 15
`
`IV. Claim Construction Under “Broadest Reasonable Interpretation” .............. 15
`
`V.
`
`Petitioner Has Not Shown a Reasonable Likelihood That at Least One
`Claim of the ’984 Patent Is Unpatentable ..................................................... 15
`
`A. Ground 1: Petitioner Has Failed to Show That Claims 1-9 Are
`Unpatentable over the ’868 Publication and the ’050 Patent
`and/or the ’394 Patent in Further View of Sulak and the
`“General Knowledge in the Art” ........................................................ 15
`
`1.
`
`2.
`
`3.
`
`A POSA would not have reason to make a COC with 5-
`15 µg EE in light of concerns about an increased risk of
`amenorrhea (absence of withdrawal bleeding) ........................ 17
`
`Cycle control and efficacy concerns would also have
`prevented a POSA from selecting 5-15 µg EE in
`combination with NA or norethindrone ................................... 19
`
`A POSA would not have seen a reason to use the 24/2/2
`administration scheme of the ’984 patent ................................ 34
`
`B.
`
`Ground 2: Petitioner Has Failed to Show That Claims 1-9 Are
`Unpatentable over the ’381 Publication and the ’050 Patent
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`IPR2015-00682
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`and/or the ’394 Patent in Further View of the Sulak Reference
`and the “General Knowledge in the Art” ........................................... 42
`
`C.
`
`Ground 3: Petitioner Has Failed to Show That Claims 1-9 Are
`Unpatentable over the ’490 Patent in View of the ’940 Patent
`and in Further View of the PDR 56 and the “General
`Knowledge in the Art” ....................................................................... 45
`
`D.
`
`Claims 4, 6, and 8 would not have been obvious for the
`additional reason that they require use of 1 mg NA .......................... 50
`
`1.
`
`2.
`
`Grounds 1 and 2 are deficient .................................................. 52
`
`Ground 3 is deficient ................................................................ 54
`
`E.
`
`Objective Indicia Further Confirm the Non-Obviousness of the
`’984 Patent .......................................................................................... 55
`
`1.
`
`2.
`
`3.
`
`Unexpected results and FDA Approval ................................... 55
`
`Long-felt need .......................................................................... 56
`
`Commercial success ................................................................. 56
`
`VI. Conclusion .................................................................................................... 57
`
`
`
`Page v
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`

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`IPR2015-00682
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`ATD Corp. v. Lydall, Inc.,
`159 F.3d 534, 546 (Fed. Cir. 1998) .................................................................... 34
`
`Cisco Sys., Inc. v. Constellation Techs. LLC,
`IPR2014-01179, Paper 7 (PTAB Feb. 4, 2015) .................................................. 38
`
`Flir Sys., Inc. v. Canvs Corp.,
`IPR2014-00773, Paper 7 (PTAB Sept. 4, 2014) ................................................... 6
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 28
`
`Leo Pharm. Prods. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 56
`
`3-D Matrix, Ltd., v. Menicon Co., Ltd.,
`IPR2014-00398, Paper 11 (PTAB Aug. 1, 2014) ............................................... 42
`
`Medtronic, Inc. v. NuVasive, Inc.,
`IPR2013-00504, Paper 8 (PTAB Feb. 13, 2014) ................................................ 49
`
`Merial Ltd., v. Virbac,
`IPR2014-01279, Paper 13 (PTAB Jan. 22, 2015) .............................................. 34
`
`Mylan Pharm., Inc. v. Gilead Scis., Inc.,
`IPR2014-00886, Paper 15 (PTAB Dec. 17, 2014) ............................................. 29
`
`Phigenix, Inc. v. Genentech, Inc.,
`IPR2014-00842, Paper 10 (PTAB Dec. 9, 2014) ......................................... 29, 40
`
`Winner Int’l Royalty Corp. v. Wang,
`202 F.3d 1340 (Fed. Cir. 2000) .......................................................................... 28
`
`Statutes
`
`35 U.S.C. § 312(a)(3)-(4) ......................................................................................... 42
`
`35 U.S.C. § 316(e) ..................................................................................................... 5
`Page vi
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`IPR2015-00682
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`Other Authorities
`
`37 C.F.R. § 42.65(a) ................................................................................................. 38
`
`37 C.F.R. § 42.100(b) .............................................................................................. 15
`
`37 C.F.R. § 42.104(b) .............................................................................................. 49
`
`
`
`Page vii
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`

`

`IPR2015-00682
`
`I.
`
`Introduction
`
`Patent Owner Warner Chilcott Company LLC (“Patent Owner” or “Warner
`
`Chilcott”) submits the following preliminary response to the Petition filed by
`
`Mylan Pharmaceuticals Inc. (“Petitioner” or “Mylan”) on February 3, 2015,
`
`requesting inter partes review of claims 1-9 of U.S. Patent No. 7,704,984 (“the
`
`’984 patent”).
`
`Petitioner is the third generic challenger to raise an obviousness challenge to
`
`the ’984 patent‒‒the patent that covers Lo Loestrin, a combination oral
`
`contraceptive employing the lowest dose of estrogen in the history of marketed
`
`combination oral contraceptives. Two other parties previously raised obviousness
`
`challenges to the ’984 patent in federal district court and the Federal Circuit‒‒but
`
`failed‒‒and so now Mylan is trying a different strategy: to file a petition for inter
`
`partes review.
`
`But Petitioner’s change in venue does not and cannot cure the fatal flaws in
`
`its obviousness theory‒‒flaws that both the District Court and the Federal Circuit
`
`already identified in rejecting the obviousness challenges raised by previous
`
`challengers:
`
`o a person of ordinary skill in the art (“POSA”) would have no reason to
`couple‒‒and would not reasonably have expected success
`in
`
`coupling‒‒a low dose of 5-15 µg (or “mcg”) ethinyl estradiol (“EE”)
`
`1
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`IPR2015-00682
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`with
`
`the weak progestins norethindrone acetate
`
`(“NA”) or
`
`norethindrone, as required by the claims of the ’984 patent, given
`
`concerns about cycle control and efficacy; and
`
`o nothing would have
`administration scheme of (i) 24 days of norethindrone or NA plus EE
`
`led a POSA
`
`to
`
`the sequence-specific
`
`pills, (ii) followed by 2 days of EE-only pills, (iii) followed by 2 days
`
`of placebo dosing (“24/2/2”) claimed by the ’984 patent, as nothing in
`
`the art described, suggested, or provided any reason to arrive at such
`
`an administration scheme.
`
`As discussed more fully below, at the time of the ’984 patent, the prior art
`
`taught that there would be serious cycle control and efficacy concerns with using
`
`5-15 µg EE in conjunction with the weak first-generation progestins NA and
`
`norethindrone. The District Court and Federal Circuit previously so held in
`
`rejecting similar obviousness challenges to the claims of the ’984 patent, and
`
`nothing in the Petition demonstrates that those courts were mistaken. To the
`
`contrary, the undisputed factual record defeats any suggestion of a reasonable
`
`expectation of success.
`
`Moreover, nothing in the Petition identifies any teaching that would have led
`
`a POSA to the claimed administration scheme of the ’984 patent. Nowhere does
`
`Petitioner cite any prior art describing the claimed sequence-specific 24/2/2
`
`2
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`

`IPR2015-00682
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`administration scheme, or cite any prior art or other objective teaching that there
`
`would be an advantage to providing 2 days of estrogen-only tablets immediately
`
`before 2 days of placebo tablets as part of a 24/2/2 regimen. The closest Petitioner
`
`comes is in Ground III, when it cites the ’940 patent, but the prior art taught that if
`
`a POSA had been interested in making an oral contraceptive with 24 days of
`
`combination pills, two days of placebo pills, and 2 days of estrogen-only pills, the
`
`POSA should do so in the “combination→placebo→estrogen” order prescribed in
`
`the ’940 patent. Nothing in the art provided a reason for a POSA to reverse the
`
`order of the placebo and estrogen-only tablets to arrive at the order claimed in the
`
`’984 patent, and Petitioner cites to none. To the contrary, a POSA would have
`
`recognized that reversing the order of the placebo and estrogen-only tablets would
`
`eliminate the very benefit the ’940 patent describes as a basis for its invention‒‒
`
`using the days of estrogen-only dosing at the very end of the cycle to “produce[] in
`
`the subsequent cycle a reduced rate of intracyclic menstrual bleeding.” (Ex. 1009
`
`at 4:30-35.) Petitioner is instead reduced to making flawed, hindsight-driven,
`
`unsupported conclusory assertions that it would have been “logical” to ignore the
`
`prior art’s understanding of the biological implications of dose sequence and arrive
`
`at the reversed order specified in the ’984 patent.
`
`In addition, Petitioner’s post-hoc theory as to why a POSA supposedly
`
`would have arrived at the 24/2/2 administration scheme claimed by the ’984 patent
`
`3
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`

`IPR2015-00682
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`is itself a reason that all grounds of the Petition fail. Beyond subverting the very
`
`rationale the ’940 patent provides for placing estrogen-only tablets at the very end
`
`of the 28-day regimen, Petitioner’s argument regarding dose sequence conflicts
`
`with its own contentions regarding the dose of estrogen a POSA would have
`
`selected. Specifically, Petitioner contends that a POSA would have been led to
`
`choose the claimed 24/2/2 administration sequence “to reduce the well-known
`
`estrogen related side effects” but “still retain the desired artificial menstrual bleed
`
`to confirm that the female is not pregnant.” (Pet. at 3) (emphasis added). But the
`
`contention that a POSA wanted to “ensure the occurrence of the desired
`
`withdrawal bleed” in designing an oral contraceptive (Pet. at 3) is fundamentally
`
`incompatible with, and further undermines, Petitioner’s contention that a POSA
`
`would have selected a daily dose of estrogen of 5-15 µg EE, as required by the
`
`claims of the ’984 patent, because a POSA would have known that selecting such a
`
`low estrogen dose would increase the likelihood that a woman would miss her
`
`withdrawal bleed. Thus, Petitioner’s own argument would (at best) require the
`
`POSA to make a number of counter-intuitive leaps before arriving at the claimed
`
`invention. That being
`
`the case, Patent Owner respectfully submits
`
`that
`
`impermissible hindsight is the only bridge that links the cited art to Petitioner’s
`
`desired outcome.
`
`“[T]he petitioner shall have the burden of proving a proposition of
`
`4
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`

`

`IPR2015-00682
`
`unpatentability by a preponderance of the evidence.” 35 U.S.C. § 316(e). For at
`
`least the reasons set forth above, and as discussed more fully below, Petitioner has
`
`not shown a reasonable likelihood that any of the Grounds meet this burden with
`
`respect to any of the claims. Thus, Patent Owner requests that the Board deny inter
`
`partes review as to all grounds of the Petition.
`
`II. Background
`
`A. The ’984 Patent and Lo Loestrin
`The ’984 patent, entitled “Extended Estrogen Dosing Contraceptive
`
`Regimen,” issued on April 27, 2010. Roger M. Boissonneault is the named
`
`inventor of the ’984 patent. The application that led to the ’984 patent was filed on
`
`April 22, 2005.
`
`Lo Loestrin Fe® (“Lo Loestrin”) is the commercial embodiment of the
`
`claims of the ’984 patent. In the Lo Loestrin regimen, a combination of EE and NA
`
`are administered for 24 days, with EE provided at a daily dose of 10 micrograms
`
`(“µg” or “mcg”)—which is 0.010 milligrams (“mg”)—and NA provided in a daily
`
`dose of 1 mg. Those 24 days are then followed by two days of estrogen-only
`
`(unopposed estrogen) tablets containing a daily dose of 10 µg EE, and then
`
`followed by two days of placebo tablets containing 75 mg of ferrous fumarate (an
`
`iron supplement). (Ex. 2006 at 1.)
`
`Lo Loestrin remains the only marketed combination oral contraceptive
`
`5
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`

`

`IPR2015-00682
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`(“COC”) in the world with 10 µg of ethinyl estradiol (“EE”), and the only FDA-
`
`approved COC with less than 20 µg of EE. (Ex. 2003 at 671:24-672:8.)1 Before the
`
`introduction of Lo Loestrin, the lowest estrogen dose employed in the combination
`
`phase of any marketed COC in the United States was 20 µg EE. (Ex. 2003 at
`
`672:6-8, 984:6-985:2.) Lo Loestrin reduced that daily estrogen dose by 50%, but
`
`unexpectedly maintained sufficient contraceptive efficacy to obtain FDA approval.
`
`(Id. at 868:8-870:18.) As a result, Lo Loestrin fulfilled an unmet need for women
`
`who could not use higher EE-dose oral contraceptives because of adverse side
`
`effects related to estrogen dose, such as nausea and breast tenderness. (Id. at
`
`1
`Ex. 2003 contains excerpts of testimony taken during the October 2013 trial
`
`concerning the ’984 patent, including from Warner Chilcott experts Dr. Philip A.
`
`Darney (expert in gynecology and contraception), Dr. Risa Kagan (expert in
`
`clinical aspects of gynecologic practice and contraception management), Dr.
`
`Ronald A. Thisted (expert in applied statistical methods), and Raymond Sims
`
`(expert in commercial success analysis). Exhibit 2003 also contains excerpts of
`
`testimony of Dr. Kurt Barnhart, defendants’ expert in obstetrics and gynecology.
`
`Because all this testimony was given before the filing of the Petition and was not
`
`taken specifically for the purpose of the present proceeding, it is not “new,” and
`
`thus the Board can and should consider it. See Flir Sys., Inc. v. Canvs Corp.,
`
`IPR2014-00773, Paper 7 at 2 (PTAB Sept. 4, 2014).
`
`6
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`

`IPR2015-00682
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`989:14-990:9, 972:20-973:5, 987:2-988:1.)2 In light of its advantages, Lo Loestrin
`
`has achieved commercial success, enjoying over $250 million in net sales and 3
`
`million prescriptions in the first 27 months since launch alone. (Ex. 2003 at
`
`329:11–330:5, 334:14–335:10;3 Ex. 2001 at 41-42.)
`
`B.
`
`Prior Litigation Concerning the ’984 Patent
`
`Aware of the virtues of Lo Loestrin, two other parties (Lupin Ltd. and
`
`Amneal Pharmaceuticals) previously sought permission to sell generic equivalents
`
`of Lo Loestrin prior to the expiration of the ’984 patent, challenging the claims of
`
`the ’984 patent as obvious in Hatch-Waxman litigation that culminated in a 7-day
`
`bench trial in the District of New Jersey in October 2013. (Ex. 2001 at 1-9.)
`
`At trial, Lupin and Amneal advanced, and put into evidence, much of the
`
`same prior art references that Petitioner asserts in its Petition:
`
`o the ’394 patent (Ex. 1005), the ’050 patent (Ex. 1004), and the Sulak
`2000 article (Ex. 1006) asserted in Grounds 1 and 2 (see Ex. 2001 at
`
`38-39; Ex. 2023 pgs. 3-21);
`
`2
`This is prior testimony from Dr. Risa Kagan, Warner Chilcott’s expert in
`
`clinical aspects of gynecologic practice and contraception management in the
`
`October 2013 trial concerning the ’984 patent.
`
`3
`
`This is prior testimony from Raymond Sims, Warner Chilcott’s commercial
`
`success expert in the October 2013 trial concerning the ’984 patent.
`
`7
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`

`

`IPR2015-00682
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`o the ’490 and ’940 patents (Exs. 1008 and 1009, respectively), and
`Loestrin 1/20 regimen (also known as Loestrin 21 or Loestrin Fe)
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`asserted in Ground 3 (see Ex. 2001 at 20-21, 26); and
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`o the Guillebaud reference (Ex. 1016), the PDR entry for Micronor (Ex.
`1010), and the ’607 application (Ex. 1021) that Petitioner has lumped
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`in as part of the “General Knowledge In the Art.” (See Ex. 2023 pgs.
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`22-47.)
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`At trial, Lupin and Amneal did not advance the ’868 and ’381 applications,
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`as Petitioner does in Grounds 1 and 2, presumably because the ’490 patent that
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`those parties did advance at trial contained similar disclosures. Like the ’868 and
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`’381 publications, the ’490 patent describes an oral contraceptive with a “24/4”
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`administration scheme in which 24 days of a combination of estrogen and
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`progestin are followed by 4 days of estrogen-only tablets. (Ex. 1008 at 4:28-45;
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`Ex. 1003 at 7:18-25; Ex. 1007 at [0025].) The ’868 and ’381 applications also set
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`forth dosing ranges for estrogen and progestin that overlap with the ranges in the
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`’490 patent. (Ex. 1003 at 7:26-32; Ex. 1007 at [0025]; Ex. 1008 at 5:1-33.) And
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`like the ’490 patent, both the ’868 and ’381 application place special emphasis on
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`using levonorgestrel as the progestin. (Ex. 1003 at 7:35; Ex. 1007 at [0034]; Ex.
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`1008 at 5:39-41.)
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`After considering all of the evidence‒‒including the ’940 patent, the ’490
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`patent, and the ’394 patent relied upon by Petitioner here‒‒the District Court
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`rejected the defendants’ obviousness challenge on two primary, independent
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`grounds:
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`o the POSA would not have been motivated to combine, or reasonably
`expected success in combining, an estrogen dose below 20 µg EE
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`with NA or norethindrone (especially 1 mg NA or less), as required by
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`the claims of the ’984 patent; and
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`o the POSA would not have been motivated to arrive at the 24/2/2
`administration scheme, wherein the 2 days of EE-only dosing
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`precedes 2 days of placebo dosing, claimed by the ’984 patent.
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`The District Court found that, at the time of the ’984 patent, the prior art
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`taught against pairing the weak progestin NA with a low estrogen dose of less than
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`20 µg EE. (Ex. 2001 at 25-31.) This finding rested upon constituent findings that
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`the prior art recognized that lowering estrogen dose below 20 µg EE (1) generally
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`raised concerns about contraceptive efficacy and cycle control, and (2) specifically
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`raised concerns about trying to do so with NA, especially 1 mg of NA or less. (Id.
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`at 25-28, 30–31.) The District Court further found that, if a POSA had sought to
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`lower estrogen dose below 20 µg, that person would have been led to not use NA,
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`but a more potent progestin with a longer half-life. (Id. at 31–33.) The Court relied
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`in part upon Schering’s experience with Minesse, which was not approved in the
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`United States, but whose use of a low 15 µg EE dose was “ma[de] possible” by the
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`use of gestodene, a newer, more potent progestin with a longer half-life. (Id. at 32.)
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`The District Court separately found that a POSA would not have been led by
`
`the prior art to the administration scheme claimed by the ’984 patent, in which 24
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`days of a combination of estrogen and progestin is provided, followed by 2 days of
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`estrogen only, followed by blank placebo tablets. (Combination→EE→ placebo).
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`(Id. at 33–37.)
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`The District Court found that the ’940 patent (which Lupin and Amneal
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`relied upon heavily in arguing that the ’984 patent’s administration scheme would
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`have been obvious) specifically attributed the benefits of the ‘940 patent’s
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`invention to its different order of administration (Combination→placebo→EE)
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`than that claimed in the ‘984 patent. (Id. at 33.) Under the ’940 patent’s
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`administration scheme, estrogen-only tablets come at the very end of the 28-day
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`cycle, and therefore immediately precede combination tablets in the subsequent
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`cycle, as illustrated in this sequence:
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`Combination→Placebo→EE→Combination→ Placebo→EE. (Id. at 33–34.)
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`The District Court found that the prior art taught that placing estrogen-only
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`tablets immediately before the combination tablets of the subsequent cycle, as was
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`done in the ’940 patent, was beneficial because it allowed estrogen to “prime”
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`progesterone receptors, resulting in a better “cycle control,” or bleeding pattern.
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`(Id. at 34.) In contrast, the District Court found that the prior art did not teach that
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`one could get these benefits if one were to reverse the order of placebo and
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`estrogen-only tablets, i.e. placing estrogen-only tablets before the placebo tablets,
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`as in the claims of the ’984 patent. (Id. at 34–35.)
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`The District Court also rejected Defendants’ contention that other prior art
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`references, such as the ’490 and ’394 patents (Exs. 1008 and 1005), would have led
`
`a POSA to make the claims of the ’984 patent. (Ex. 2001 at 37-39.) And the court
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`further concluded that objective indicia of non-obviousness, including unexpected
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`results, satisfying a long-felt need, and commercial success further supported the
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`non-obviousness of the ’984 patent. (Id. at 39-42.)
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`On appeal, the Federal Circuit affirmed. (Ex. 2002 at 3.) In a decision dated
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`October 22, 2014, the Federal Circuit endorsed the reasoning of the District Court,
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`affirming the conclusion of non-obviousness with respect to all claims of the ’984
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`patent “on the basis of and for the reasons stated in the district court’s thorough
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`opinion.” (Id. at 3.)
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`Petitioner’s Concurrent Obviousness Challenge to the ’984 Patent
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`C.
`In addition to its Petition here, Petitioner is also challenging the ’984 patent
`
`as obvious in Hatch-Waxman litigation in the District of New Jersey. In May 2014,
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`Mylan answered and filed a counterclaim to Warner Chilcott’s complaint for patent
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`infringement, which alleges that Mylan has infringed the ’984 patent by virtue of
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`seeking to sell a generic equivalent of Lo Loestrin prior to the expiration of that
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`patent. (Exs. 2028, 2029.) In its answer and counterclaim, Mylan asserts that the
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`claims of the ’984 patent are invalid as obvious (Ex. 2029 at 13), and is generally
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`advancing that defense in the litigation. Expert discovery is scheduled to conclude
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`in August 2015. (Ex. 2030 at 3.)
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`D. Combination Oral Contraceptives
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`COCs contain two primary active ingredients: an estrogen and a progestin.
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`COCs prevent pregnancy primarily by inhibiting ovulation, i.e., by preventing a
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`woman from producing an egg. (See, e.g., Ex. 2032 at 195 (COCs “exert their
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`contraceptive effect primarily by inhibition of ovulation”).) Both the estrogen and
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`progestin component play a role in inhibiting ovulation. (Ex. 2001 at 10; Ex. 2032
`
`at 195.) Estrogen does so by stopping the release of follicle-stimulating hormone
`
`(“FSH”), which is the hormone released from the pituitary in the brain that causes
`
`the follicles in the ovaries to grow. (Ex. 2003 at 630:5–17; Ex. 1013 at 879.) In the
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`absence of sufficient amounts of FSH, follicles cannot reach a sufficient size to
`
`produce an egg. Progestin inhibits ovulation primarily by acting on the pituitary to
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`stop the release of luteinizing hormone. (Ex. 2003 at 630:5–25; Ex. 1013 at 879.)
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`Luteinizing hormone triggers the release of the egg from the follicle once the
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`follicle has developed and become dominant. (Ex. 2003 at 630:21–25.) In the
`
`absence of luteinizing hormone, the egg will not be released even if the follicle has
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`otherwise sufficiently developed. (Id.; see also Ex. 2001 at 10-11.)
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`When designing a COC, a POSA must consider not only contraceptive
`
`efficacy and safety, but also the tolerability of the regimen. (Ex. 2003 at 637:24–
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`641:11.) Because women will not take a COC that they cannot tolerate‒‒and
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`because an oral contraceptive cannot be effective if women do not take it‒‒a
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`contraceptive’s side effect profile has critical importance for the success and
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`overall efficacy of the regimen. (Id. at 639:7-20.)
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`In designing a COC, a POSA would need to consider a number of variables,
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`all of which affect the efficacy, safety, and tolerability of the regimen: (1) estrogen
`
`type; (2) estrogen dose; (3) progestin type; (4) progestin dose; (5) length of the
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`hormone-free interval (“HFI”); (6) length of the regimen; and (7) order of
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`administration of tablets. (Id. at 642:6–644:7; Ex. 2001 at 11.) These variables are
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`interdependent—i.e., a change to one variable can impact not only the performance
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`of the regimen as a whole, but also how the other variables perform individually.
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`(Ex. 2003 at 637:24–641:11, 802:6–803:11.)
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`Among such variables, estrogen dose has critical ramifications. An estrogen
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`dose that is too low may lead to increased follicular development and the
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`possibility of escape ovulation (release of a fertilizable egg), thereby threatening
`
`contraceptive efficacy. (Ex. 2003 at 697:16–703:13; Ex. 2001 at 12.) An estrogen
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`dose that is too low can also lead to poor “cycle control”—frequent unscheduled
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`vaginal bleeding or spotting on active pill-taking days. (Ex. 2003 at 673:25–
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`678:12.) Such unscheduled bleeding was known to be a major reason why many
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`women discontinued oral contraceptive use. (Ex. 2003 at 151:14–155:3; Ex. 2031
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`at 1127.) An estrogen dose that is too high can affect not only safety, but
`
`tolerability as well by, for example, causing nausea and breast tend