EXHIBIT 1019
`
`
`
`EXHIBIT 1019EXHIBIT 1019
`
`

`
`Contraceptive
`Technology
`
`Eighteenth Revised Edition
`
`Robert A. HatcJ.ler, MD, MPH
`James Trussell, PhD
`Felicia H. Stewart, MD
`Anita L. Nelson, MD
`Willard Cates Jr., MD, MPH
`Felicia Guest, MPH, CHES
`Deborah Kowal, MA, PA
`
`~'-
`
`ARDENT MEDIA, INC.
`NEW YORK
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`
`Copyright © 2004 by Contraceptive Technology Communications, Inc.
`All rights reserved. No part of this book may be reproduced in any manner
`whatever, including information storage, or retrieval, in whole or in part
`(except for brief quotations in critical articles or reviews), without written
`permission of the publisher, Ardent Media, Inc., Box 286, Cooper Station
`P.O., New York, NY 10276-0286 or fax (212) 861-0998.
`
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`
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`
`ISSN 0091-9721
`ISBN 0-9664902-2-3 (Paperback with CD-ROM)
`ISBN 0-9664902-3-1 (Hardcover Reference with CD-ROM)
`ISBN 0-9664902-5-8 (Hardcover Reference)
`ISBN 0-9664902-6-6 (Paperback)
`TRADEMARKS: All brand and product names are trademarks or registered
`trademarks of their respective companies. It has been attempted throughout
`this text to distinguish proprietary trademarks from generic or descriptive
`terms by following the capitalization style used by the manufacturer; how(cid:173)
`ever, the publisher cannot attest to the accuracy of this information. Use of a
`term in this text should not be regarded as affecting the validity of any
`trademark or service mark.
`·
`13 57 910 6 4 2
`Printed in the United States of America.
`The paper used in this publication meets the minimum requirements of
`American National Standard for Information Sciences - Permanence of
`Paper for Printed Library Materials, ANSI Z39.48-1984.
`
`DISCLAIMER
`The information contained herein is intended to be used by physicians and
`other qualified healthcare professionals. The information is not intended
`to be used for medical diagnosis or treatment by persons who are not qualified
`healthcare professionals. Such persons should not ·rely upon or use the
`information contained herein in place of a visit, call, or consultation with, or
`the advice of their personal physician or other qualified heal the are provider.
`Physicians and other qualified healthcare professionals should recognize
`that this book is to be used only as a reference aid, and that this book is
`not intended to be a substitute for their exercise of professional judgment.
`Since medical science is always cbanging, physicians and other qualified
`healthcare professionals users are advised to confirm the information
`contained herein with an independent source. The authors and contributors
`are not liable for errors and omissions.
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`
`Combined Hormonal
`Contraceptive Methods
`Robert A. Hatcher, MD, MPH
`Anita Nelson, MD
`
`• More than 100 million women throughout the world currently rely on
`oral contraceptives (OCs). In the United States, more than 80% of
`women born since 1945 have used OCs at some time in their lives,
`compared to 95% of French women and 4% of Japanese women. In
`Canada, 70% of pill users over the age of 35 have been taking OCs for
`more than 10 years.1
`• OCs effectively prevent pregnancy. Of 1,000 women taking pills per(cid:173)
`fectly, only 3 will become pregnant within a year. Of 1,000 typical
`users initiating OC use, 80 women (8%) will become pregnant in the first
`year of use. However, failure rates as high as 10% to 20% have been
`reported.2 Women on pills may find it reassuring to use a back-up
`contraceptive consistently.
`• Dual protection with both condoms and any combined hormonal con(cid:173)
`traceptive will provide some protection against infection as well as
`excellent protection against an unintended pregnancy. A woman who
`misses hormonal pills, or is late starting a new cycle of pills, should
`consider using a back-up contraceptive until she has taken 7 consecutive
`pills. Emergency contraceptive pills are also an option for any woman
`who has missed one or more pills.
`The newer combined hormonal methods-the monthly vaginal ring and
`weekly patches-were developed to combine the effectiveness and non(cid:173)
`contraceptive benefits of combined pills with longer acting delivery
`systems ill order to reduc~ the demands placed by daily administration
`of pills.
`
`•
`
`Forty years ago, "the pill" transformed family planning by providing
`women with an effective method to control their own fertility for the first
`time in history. Over the years, the doses of the sex steroids in oral
`contraceptive (OC) preparations have decreased, which increased both
`their safety and their acceptability. In addition, numerous noncontracep(cid:173)
`tive benefits have been identified with both short- and long-term OC use.
`
`CONTRACEPTIVE TECHNOLOGY
`
`CHAPTER 19 391
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`
`Newer hormonal methods-the once-a-month vaginal contraceptive ring
`and the once-a-week transdermal contraceptive patch-are now available
`and combine the obvious attractiveness of OCs with longer-acting deliv(cid:173)
`ery systems to reduce the demands imposed by daily administration.
`This chapter describes combined hormonal contraceptives: methods
`that contain both estrogen and progestin. Because all of these methods.
`share the same mechanisms of action, the chapter begins with a discus(cid:173)
`sion of how sex steroids influence the reproductive cycle. The effective(cid:173)
`ness and cost sections compare OCs, the patch, and the ring. Following
`these reviews, each combined hormonal method is presented in detail.
`
`M ECHANISMS OF ACTION
`
`·
`Combined hormonal contraceptives work primarily as a contra"
`ceptive, acting before fertilization. The progestins in all combined hormo(cid:173)
`nal contraceptives provide most of the birth control activity:
`• Thicken cervical mucus to prevent sperm penetration into the
`woman's upper genital tract
`• Block the luteinizing hormone (LH) surge and thus inhibit ovula(cid:173)
`tion. Although there are no precise statistics concerning the
`occurrence of "escape ovulation" in oral contraceptive users, the
`incidence in earlier higher dose pills was estimated in 1980 to be
`around 2%. 3 Breakthrough ovulation is probably higher in cur(cid:173)
`rent lower dose pills. In a study of 20 meg pills, progesterone
`levels indicative of luteinization and ovulation were found in 2 of
`24 women (8.3%).4
`Inhibit capacitation ofthe sperm, which limits the sperm's ability
`to fertilize the egg
`Slow tubal motility, which may delay sperm transport
`
`•
`
`•
`
`Some progestin effects additionally alter the environment that would be
`required for embryogenesis to proceed:
`• Disrupt transport of the fertilized ovum
`•
`Induce endometrial atrophy, change underlying vascular func(cid:173)
`tion and structure and alter the metalloproteinase content in the
`endometrium
`Estrog~n is included in combined hormonal methods primarily to
`provide better cycle control (see below), but it may also boost contracep(cid:173)
`tive efficacy. Pharmacologic doses of estrogen from combined hormonal
`contraceptives decrease follicle-stimulating hormone (FSH) release from
`the pituitary, which may aid in suppressing the LH surge and thus in
`blocking ovulation (contraception). Estrogen at high doses may induce
`localized edema in the endometrial lining, which, in turn, may reduce the
`probability of implantation (interception); however, the clinical signifi(cid:173)
`cance of this 'impact is not clear.
`
`392 COMBINED HoRMONAL CONTRACEPTIVE METHODS
`
`CONTRACEPTIVE TECHNOLOGY
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`
`HORMONES IN COMBINED HORMONAL
`CONTRACEPTIVES
`Estrogens
`Only two estrogenic compounds are used in hormonal contraceptives
`available in the United States: ethinyl estradiol (EE) and mestranol. The
`patch, ring, and virtually all modern OC formulations contain EE. Mestra(cid:173)
`nol, which must be metabolized into EE by the liver, is found only in a
`few 50 meg pills. (Because SO meg of mestranol is equivalent to 3S to 40
`meg of EE, avoid using 50 meg mestranol-containing pills when high(cid:173)
`dose estrogen pills are needed.) The patch and vaginal ring also release EE.
`Only the combined injection (Lunelle), which is no longer on the market,
`used a different estrogen (see Chapter 24, Future Methods).
`Doses of estrogen in active OCs vary from 20 to SO meg per day (see
`Figure 19-1 for a sample of pills). The transdermal contraceptive patch
`releases about 20 meg EE into circulation each day. The vaginal contra(cid:173)
`ceptive ring has serum levels of 15 mcg/cc of EE, or about half the
`circulating levels associated with that of a comparable 30 meg OC.5
`Progestins
`In order to maintain adequate serum concentrations of progestogenic
`activity for daily administration, an array of progestins was developed.
`There are currently nine different progestins available in OCs and three
`other progestins in the other combined hormonal systems. The power of
`a particular progestin results not only from its intrinsic potency, but also ·
`from the dose that is used. Each compound has a different potency and a
`different balance between proges~erone activity and any residual andro(cid:173)
`genicity.
`In OCs, the androgen-derived compounds include norethindrone,
`norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel,
`norethynodrel, desogestrel, and norgestimate. OCs containing the last
`two are sometimes called "third-generation pills." (Other androgen(cid:173)
`derived compounds, such as gestodene, are not available in the United
`States.) One new OC contains a new class of compound: drospirenone,
`derived from the antihypertensive compound spironolactone. Dros(cid:173)
`pirenone has both anti-androgenic and anti-mineralocorticoid activity.
`Doses of progestins in OCs vary from 0.15 to 1 mg (see Figure 19-1).
`The patch contains norelgestromin, the primary active metabolite of
`norgestimate, the progestin found in three OCs: Ortho-Cyclen, Ortho
`Tri-Cyclen, and Ortho Tri-Cyclen LO. About 1SO meg of norelgestromin is
`released into th.e circulatory system each day. The ring releases 120 meg a
`day of etonogestrel, the metabolite of the progestin desogestrel found in
`Cyclessa and Mircette OCs. Because the bioavailability of the progestins
`in the patch and the vaginal ring is higher than that of OC progestins, a
`lower dose can produce similar serum levels. Lower doses are effective.
`
`CONTRACEPTIVE TECHNOLOGY
`
`CHAPTER 19 393
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`
`Prog~lin (mg)
`
`Swyer
`(190l)
`
`0,]5
`
`Dorillng""r
`11905)
`Relative
`0.]5
`
`0.15-0.22
`
`0.375--0.75
`
`[}o§~Of
`Pmgt::§lln
`
`Name(sl
`of Pills
`
`Dos~or
`E!itrogen
`(meg)
`
`Ulrogcn (meg)
`
`Rei alive
`
`MfQOnl!lr
`Nor-QD
`
`Ovrelle.
`
`GreEnblatt
`(19&7)
`Re!alive
`
`0,15
`
`...
`
`1.0
`
`1.0
`
`3.0--7,5
`
`NotethlodtOfl~:o
`0.5/0.75/1.0
`
`Ncrethindr<:Jfl.e Nc1iny( l/l5
`1 .o
`Ortho 1/35
`Genora1/35
`N.E.E. 1/JS
`
`10
`
`11
`
`12
`
`n
`
`14
`
`15
`
`,.
`
`,.
`
`15
`
`lO
`
`0 2.0 1.5 1.0 0.5 0 5 4 3 2
`
`1
`
`Potency UniT§
`
`1.0 2.0
`
`Porenc:y UnllS
`
`Sources: Dorflinger (1 965); Greenblatt (1967}; Swyer (1962); Heinen (1971 ).
`
`Figure 19-1 Relative potency of est~ogens and progestins in selected oral contraceptives
`reflecting the debate about the strength of the progestins
`
`.·~
`
`394 COMBINED HORMONAL CONTRACEPTIVE METHODS
`
`CONTRACEPTIVE TECHNOLOGY
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`
`·EFFECTIVENESS
`.
`In general, combined OCs, patches, and vaginal rings belong in th~
`second tier of contraceptive effectiveness, having higher failure rates than
`IUDs, implants, and injections.
`
`Oral Contraceptives
`
`Among women who use OCs correctly and consistently, not missing
`any pills and following instructions perfectly, only about 3 in 1,000
`(0.3%) are expected to become pregnant within the first year. (See Table
`19-1.) The first-year failure rates among typical users as observed in real
`world use are estimated to be 8% (see Chapter 9, The Essentials of
`Contraception). This means that 1 woman in 12 will become pregnant in
`the first year of OC use. Among these typical users, pill-taking mistakes
`that increase the length of the hormone-free interval are particularly
`likely to lead to failures. The conventional 7-daypill-free interval may
`also play an important role in the pill's failures. Ultrasound studies have
`demonstrated that by the 7th placebo pill day, 23% of women can have
`ovarian follicles that measure at least 10 mm in diameter.6 If a woman
`misses pills early in her pack of pills, it may be much more difficult to
`suppress ovulati.on and protect against pregnancy during that cycle. Thus,
`OCs may be made more. effective by eliminating or shortening the pill(cid:173)
`free interval (see Starting The Pill section). Confusing this picture, how(cid:173)
`ever, is a recent small-scale study showing that initiation of pills early in
`the cycle did not reduce the risk of ovulation.7 Larger scale studies are
`underway to answer this question.
`
`Many pregnancies occur when women discontinue OCs, fail to begin
`another method of contraception and, therefore, have unprotected inter(cid:173)
`course. Studies show that 11 o/o of women discontinue their pills in the
`first month of use, and 19% of those who discontinue fail to adopt a new
`method.8 By 6 months, 28% of pill users have stopped the pill; by one
`year, that percentage approaches 33% to 50%.9 Quite disturbingly, 42%
`of women who discontinued OC use did so without consulting their
`clinicians. Because of these concerns, women starting the pill should also
`be given a second method they can implement on their own should they
`discontinue pill use before returning for follow-up. Instruct women in as
`much detail about their second method as you do their pills, and encour(cid:173)
`age them to practice using it. Also, provide new-start OC patients with a
`packet of or prescription for emergency contraception (Plan B) or, at a
`minimum, inform her about its availability.
`
`Recently, one retrospective study has suggested that heavier women may
`experience higher failure rates than do lighter women. 10 The greatest
`difference in failure rates was seen in the use of pills with less than 35 meg
`EE, with which heavier women were noted to have 4.5 (1.4- 14.4) times
`higher pregnancy rates (6.8% vs. 1.8%) than did lighter women. These
`
`CoNTRACEPTIVE TEcHNOLOGY
`
`CHAPTER 19 395
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`

`
`results have not yet been substantiated by any other studies. Consensus is
`that it is not prudent to prescribe higher dose pills based on these
`preliminary data because of the increased risk of thrombosis with high
`doses of estrogen.11 Heavier women who used extended cycles of OCs had
`no increase in pregnancy risk. 12
`
`Transdermal Patch and Contraceptive Ring
`
`The patch and the vaginal ring have not been in use long enough to
`permit precise measurements of typical-use failure rates. In comparative
`trials, the failure rates for patches, vaginal rings, and OCs were low13,14
`and roughly equivalent. Successful utilization rates were statistically
`higher with the longer acting agents than with the pills that were taken
`daily. Overall, women who used the patch or vaginal ring were more
`likely to use their methods correctly and consistently for 13 cycles than
`were OC users.l5,16 These observations suggest that, in routine practice,
`the newer long-acting delivery systems may be associated with lower
`typical-use pregnancy rates than are the pills. However, since this tanta(cid:173)
`lizing possibility has not yet been demonstrated, the authors have de(cid:173)
`cided to quote the same typical failure rates for the pill, the patch, and the
`vaginal ring (see Chapter 9, The Essentials of Contraception).
`
`One group of potential patch users deserves special counseling. Heavier
`women, weighing >198 lbs, comprised 3% of the study population but
`experienced 30% of all the pregnancies in the clinical trial. 17 This de(cid:173)
`crease in efficacy does not preclude use of the patch by heavier women
`but does suggest that these women may benefit from additional coun(cid:173)
`seling, 18 including recommending back-up contraception.
`
`Table 19-1 First-year probability of pregnancy* for women using combined hormonal
`contraceptives compared with other hormonal contraceptives
`
`% of Women Experiencing an
`Unintended Pregnancy Within the
`First Year of Use
`
`%of Women
`Continuing Use
`at One Year
`
`Method
`
`Typical Use
`
`Perfect Use
`
`Combined pill and minipill
`Evra Patch and Nuva Ring
`Depo-Provera
`IUD
`Paragard (Copper T)
`Mirena (LNG-IUS)
`
`8
`8**
`3
`
`0.8
`0.1
`
`0.3
`0.3
`0.3
`
`0.6
`0.1
`
`68
`68
`56
`
`78
`81
`
`* See Table 9-2 fur pregnancy year failure rates of all methods.
`** No data available; assumed to be same as combined oral contraceptives.
`Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected
`intercourse reduces the risk of pregnancy by at least 75%. (See Chapter 12 for more
`information.)
`
`396 COMBINED HORMONAL CONTRACEPTIVE MtrHODS
`
`CONTRACEPTIVE TECHNOLOGY
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
`
`

`
`COST
`
`Health department family planning programs in Washington State
`.have paid much less for OCs than for other hormonal contraceptives. In
`2001, they reported paying $1.35 per cycle of combined pills, just over
`. one third ofthe cost ofDepo-Provera. In Washington, the discounted cost
`• of ocs to health departments is about 1/20th of the price charged to a
`private pharmacy chain.19 The cost of the pills to women paying full
`price at pharmacies varies somewhat but is becoming higher all the time,
`ranging from $15 to $50 or even higher per cycle. Generic brands are
`typically less expensive. Usually, pills cost from $30 to $35 per cycle, one
`ring costs $40, and a pack of 3 patches (one cycle) costs $42. This means
`women paying full price pay $390 to $455 per year out of pocket for OCs,
`just over $500 for the ring and about $550 for the patch. Women whose
`. contraceptives are covered by insurance have to pay a co-pay each
`month. Purchase of OCs from the Internet, when 3 cycles are bought at a
`time, can reduce the price to under $20 per cycle with delivery charges
`extra. Some women travel to Mexico to purchase pills over-the-counter
`for as little as $3 to $5 per cycle.
`
`ORAL CoNTRACEPTIVES
`
`OCs are safe and effective for the vast majority of reproductive-aged
`women. They are the most extensively studied medications in the history
`of medicine. Over 80% of U.S. women born after 1945 have used the pill
`at some time.1 In the United States, OCs are available only by prescrip(cid:173)
`tion; in some other countries, they are available over the counter. The
`keys to successful and safe OC use are selection of appropriate OC candi(cid:173)
`dates, patient motivation, and effective counseling.
`Oral Contraceptive Formulations
`OCs are available in either monophasic or multiphasic packaging:
`• Monophasic formulations. Each active pill contains the same ·
`doses of the estrogen and progestin.
`• Multiphasic formulations. The amounts of hormones in the
`active pills can vary throughout the cycle.
`Biphasic pills have 2 different combinations of estrogen
`and progestin in the pills.
`Triphasic formulations have 3 different combinations. Some(cid:173)
`times the progestin content increases in stepwise progression
`during the cycle, but some other formulations may also alter
`the amounts of estrogen given during the cycle. One formu(cid:173)
`lation (Estrostep) holds the progestin dose constant and in(cid:173)
`creases the estrogen content in tablets late in the cycle.
`Most pill packs contain 21 active (hormone containing) pills with or
`without 7 placebo pills (21-pill packs versus 28-pill packs). However, one
`
`CONTRACEPTIVE TECHNOLOGY
`
`CHAPTER 19 397
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
`
`

`
`brand (Mircette) includes 21 active pills, 2 placebo pills and 5 pills withlo
`meg EE each. Another preparation (Seasonale) has 84 active pills followed
`by 7 placebo pills, which reduces the number of withdrawal bleeds to 4
`episodes a year. Under development are preparations containing 24 active
`pills .and 4 placebo pills per pack.
`
`ADVANTAGES AND INDICATIONS
`
`.
`Many women harbor profound misinformation about the safety
`and utility of OCs. A 2000 survey revealed that 41 o/o of those interviewed
`believed the pill was associated with significant health hazards. 20 How~
`ever, OCs have numerous attractive features:
`Genera/ Advantages
`I. Effectiveness. When taken correctly and consistently, OCs are
`very effective contraceptives that give women control over their
`own fertility.
`2. Safety. Through prudent selection of users {see below), OCs are
`safer for a woman's health than are pregnancy and delivery.
`Recent large-scale studies show that OC use does not increase the
`risk of death among non-smokers.21
`3; An option throughout the reproductive years. Healthy ·
`women can safely use OCs throughout their reproductive lives.
`Age itself is not a reason to avoid OCs. The noncontraceptive
`benefits of the pill meet the varying needs of women of all ages.
`Young women may benefit from reduction in severe dysmenor~
`rhea and acne, while at the other end reproductive life, peri~
`menopausal women may benefit from cycle control and hot flash
`reduction provided by OCs.
`4. Rapid reversil:,ility. On average, women who stop taking OCs
`have only a 2-week delay in return of ovulation. Some women
`(<3o/o) have a slower return to fertility-the so-called "post-pill
`amenorrhea"-that is diagnosed 6 months after stopping the
`pills. Women need to understand that OC use neither hastens
`nor delays the onset of menopause.
`Contraceptive health benefits
`1. Reduction of maternal deaths. The CDC calculated that there
`were 11.8 pregnancy-related deaths per 100,000 live births in
`the last decade of the 20th century, but that there was signifi(cid:173)
`cant under-reporting. 22 Embolism, hemorrhage, and pregnancy(cid:173)
`induced hypertension were the 3 leading causes of death.
`Considering that nearly half the pregnancies in this country are
`unintended, prevention of those pregnancies could significantly
`decrease maternal deaths.
`
`398 COMBINED HORMONAL CONTRACEPTIVE METHODS
`
`CoNTI?ACEPTIVE TECHNOLOGY
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 10
`
`

`
`.;---
`
`2. Reduction of ectopic pregnancies. OCs reduce the risk of ec(cid:173)
`topic pregnancy by over 90%;23~25 At least one in 80 pregnancies
`in the United States is an ectopic pregnancy, the leading cause of
`maternal death in the first trimester. The CDC reports that 25
`women died of ectopic pregnancy in 1992.
`
`Menstrually-related health benefits
`
`1. Decreased dysmenorrhea. OCs significantly decrease men(cid:173)
`strual cramps and pain. Although the original studies used high(cid:173)
`dose formulations, even low-dose formulations help when given
`in the conventional cyclic fashion. 26 OC use reduces the inci(cid:173)
`dence of all degrees of dysmenorrhea by 60%.27 Severe dysmenor(cid:173)
`rhea was reduced by almost 90%.28 In a randomized clinical trial,
`low-dose OC users reported fewer absences from school and work
`and used less pain relief medicine than placebo users. More
`significant relief of symptoms can be achieved by continuous or
`extended use, which eliminates withdrawal periods for prolonged
`periods of time.
`
`2. Decreased menstrual blood loss. OCs decrease the number of
`days of bleeding and the amount of blood women lose each cycle.
`In women with menorrhagia, high-dose OC use reduced blood
`loss by 53%.29 In more recent studies with low dose OCs (30 meg
`EE), menstrual blood loss and duration of flow were also de(cid:173)
`creased.30 Overall, a 38% to 49% reduction in menstrual blood
`loss was seen in another study with a 30 meg EE preparation. 31,32
`In addition, nearly 50% of women experience a reduction in
`duration of menstrual bleeding with OC use.33 Decreased ro~n­
`stntal blood loss reduces a woman's risk for iron deficiency ane(cid:173)
`mia. If women use any of the extended cycle options, the number
`of withdrawal bleeds decreases, enhancing these benefits even
`more.
`
`3. Reduction in menstrually-related PMS symptoms. OCs can
`reduce menstrually-related PMS symptoms such as mastalgia,
`bloating, cramping, and pain. Drospirenone-containing pills
`have also been shown to improve symptoms of water retention,
`negative affect, and increased appetite associated with men(cid:173)
`ses.34,35
`
`4. Decreased anovulatory bleeding. Low-dose OC use was associ(cid:173)
`ated with a more than 80% improvement in dysfunctional uter(cid:173)
`ine bleeding in a randomized, double blind, placebo-controlled
`study. 36
`
`5. Mittelschmerz relief. By preventing ovulation, OCs can elimi(cid:173)
`nate the midcycle pain some women experience with ovarian
`follicle swelling and oocyte extrusion.
`
`CONTRACEPTIVE TECHNOLOGY
`
`CHAPTER 19 399
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 11
`
`

`
`7.
`
`6. Fewer ovarian cyst problems. Because OCs suppress ovulation,
`they reduce the risk of hemorrhagic corpora luteal cysts, a condi(cid:173)
`tion which can require surgery. Because OCs decrease stimulation
`of the ovaries by FSH and LH, the incidence of other functional
`ovarian cysts among women using high -dose O~s was also re(cid:173)
`duced. Low-dose and multiphasic formulations may help reduce
`postovulatmy cysts;37
`38 however, they do not protect against
`•
`follicular cyst formation.39
`40
`,
`Improvement in menstrual migraines. Menstrual migraines
`are caused by estrogen withdrawal. Cyclic OC use may worsen
`the intensity of a woman's migraine during her menses; on the ·
`other hand, menstrual migraine symptoms may be prevented if
`she takes active pills every day continuously. (See the section on
`Headaches, in Managing Side Effects.)
`General. health benefits
`1. Endometrial and ovarian cancer risk reductions. When com(cid:173)
`pared with women who have never used OCs, OC users are 40%
`less likely to develop epithelial ovarian cancer.41 Ten years or
`more of use of all monophasic formulations reduces a woman's
`risk of developing such cancers by 80%.42 This protection lasts for
`up to two decades beyond the time the woman takes her last
`OC.42
`43 Studies that focus on the newer lower dose formulations
`,
`( <35 meg EE) have found similar protection levels43 · even in
`women genetically at higher risk for developing ovarian cancer •
`(BRCAl mutation cancers).43' 44 Formulations with high doses of
`progestins protected more than twice as well as OCs with a lower ·
`dose of progestins. 45 Women with a family history of ovarian
`cancer enjoy a greater benefit of ovarian cancer risk reduction
`tl!-an women with no family history.46 Women with first-degree
`relatives with ovarian cancer who use OCs for 4 years had a 90%
`reduction in ovarian cancer risk.47 One study found that iii(cid:173)
`creased duration of OC use did not reduce further the risk of ·
`ovarian cancer in BRCAl or BRCA2 mutation carriers and cau(cid:173)
`tioned against routine use of OCs for chemoprevention.48 On the.·
`other hand, current information has led some to suggest that OCs
`should be offered to women at high risk for ovarian cancer even.
`if contraceptive benefit is not required. 49
`OC use for at least 12 months reduces a woman's risk of devel(cid:173)
`oping endometrial cancer by about 40%. 50 That risk reduction is·
`increased to 80% in women who use OCs for at least a decadeY
`. This protection also endures for up to 20 years after OC dis con- .
`tin ua tion. 51
`2. Decreased risk of benign breast conditions. OC users are less
`likely to develop fibrocystic breast changes~ cysts, . or fibroadec
`noma and are less likely to experience progression of those breast
`
`400 COMBINED HORMONAL CONTRACEPTIVE METHODS
`
`CONTRACEPTIVE TECHNOLOGY
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 12
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`

`
`2 In one case-controlled study with over 500 women,
`conditions. 5
`the risk of benign breast conditions was lower in the OC users,
`and significantly less in women who started OC use before their
`first full-term pregnancy.53 Women who have hyperplasia with
`atypia are a notable exception; OC use does not confer any
`4
`protection to these women. 5
`
`3.
`
`Improvement of androgen sensitivity or androgen-excess
`conditions (e.g., polycystic ovary syndrome). In prospective,
`randomized, placebo-controlled, double-blind trials, women who
`use OCs have been shown to have a reduction in the numbers
`and size of acne lesions.55•56 Dutch surveys reported that OC use
`reduced the prevalence of acne by over two-thirds.57 Only 2
`formulations have received FDA approval for treatment of mild to
`moderate acne (OrthoTri-Cyclen and Estrostep), but other formu(cid:173)
`lations with little or no androgenicity and relatively high estro(cid:173)
`genicity increase sex hormone binding globulin (SHBG), which is
`understood to be the main mechanism for OC use in acne treat(cid:173)
`ment. Women with excessive facial or body hair (hirsutism) have
`59
`reduction in the hair shaft diameter with OC use.58
`•
`4. Reduced risk of hospitalization for gonorrheal PID. The risk
`of cervical gonorrhea infection spreading into the uterus ( endo(cid:173)
`metritis), fallopian tubes (salpingitis) or other pelvic organs (PID)
`is reduced. In studies conducted in the 1980s, when fewer women
`with PID were treated on an outpatient basis, the risk of hospitali(cid:173)
`zation for PID was reduced by SO% to 60% in current users after 12
`months of use. 61 The exact· mechanism of this protection is not
`known. It may be due to thickened cervical mucus blocking sperm
`penetration, atrophy of the endometrium (fewer days of bleed(cid:173)
`ing), and/or reduction of movement of pathogens into the tube.
`Similar reductions are not seen in the risk of chlamydia! PID. 60
`5. Suppression of endometriosis. Current or recent OC use is
`associated with a lower incidence of symptomatic endometriosis,
`especially among parous women (see Chapter 6, Menstrual Prob(cid:173)
`lems and Common Gynecologic Concems).62 The risk of en(cid:173)
`dometrioma was found to be significantly reduced in current OC
`users over age 25.63 OCs reduce menstrual flow and presumably
`decrease retrograde menses, which is generally believed to con(cid:173)
`tribute to endometriosis. Women who have endometriosis can be
`treated with extended or continuous use of strong progestogenic
`OCs to induce pseudo-decidualization of the endometriotic im(cid:173)
`plants and to reduce symptoms during use. 64 Such treatment is
`not curative, however; the implants undergo atrophy during treat(cid:173)
`ment but remain ready for reactivation when OCs are stopped. 65
`6. Decrease risk of iron deficiency anemia. By reducing men(cid:173)
`strual blood loss, women increase their hemoglobin and ferritin
`
`CoNTRACEPTIVE TECHNOLOGY
`
`CHAPTER. 19 401
`
`Petitioner Exhibit 1019
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 13
`
`

`
`levels.66 This benefit is especially important for women With
`sickle cell anemia or Von Willebrand's disease, women using
`anticoagulants or anticonvulsants, and women with fibroids or
`other causes of primary or secondary menorrhagia (see Chapter 6 ·
`Menstrual Problems and Common Gynecologic Concerns).
`'
`7. Treatment of hot flashes and other hormonal fluctuation
`symptoms in perimenopausal women. 67
`68 (See Chapter S on
`•
`Menopause for more discussion.)
`
`Other potential health benefits
`1. Reduced risk of developing