EXHIBIT 1024
`
`EXHIBIT 1024
`
`

`

`Volume !70, Number 5, Pan 2
`Am J Obstct Gynccol
`
`Stubblefield
`
`I 0. Upmalis D, Phillips A. Receptor binding and in vivo
`activities of the new progestins. Journal SOGC 1991; 13:
`35.
`11. Hoppen HO, Hammann P. The influence of structural
`modification on progesterone and androgen receptor
`binding of norethisterone: correlation with nuclear mag(cid:173)
`netic resonance signals. Acta Endocrinol 1987;115:406-
`12.
`12. Bergink EW, HamburgeT AD, de Jager E, et al. Binding of
`a contraceptive progest-ogen ORG 2969 and its metabo(cid:173)
`lites to receptor proteins and human sex hormone binding
`g lobulin. J Steroid Biochem 1981 ;14:175-83.
`13. Bergink EW, van Mccl F, Turpijn EW, et al. Binding of
`progestagens to receptor proteins in MCF-7 cells. J Ste(cid:173)
`roid Biochem 1983; 19: 1563-70.
`14. Phillips A, Demarest I\, Hahn DW, e~ al. Progestal.ionru
`and androgenic receptor binding affinities and in vivo
`activities of norgestimate and other progestins. Contra(cid:173)
`ception 1990;41 :399-410.
`15. Kloosterboer HJ, Vonk-Noordegraaf CA, Ttn·pijn EW. Se(cid:173)
`lectivity in progesterone and androgen receptor binding
`of progestogens used itt oral contraceptives. Contracep(cid:173)
`tion 1988;38:325-32.
`16. Phillips A, Hahn DW, Mc::Gttire JL. Preclinical evaluation of
`norgestimatt:, a progestin with minimal androgenic activ(cid:173)
`it.y. A:-.1 J Onsrrr CvNEC:OI. 1992;167:1191-6.
`
`17. McGuh·e JL, Phillips A, Hahn DW, et al. Pharmacologic
`and pham1acokinetic charactcritics of norgestimate and its
`metabolites. AMJ 01\s·m'r Gv:-:..:cm. 1990:163:2127-31.
`18. Hasenack HG, Bosch AMG, Kaar K. Serum levels of
`3-keto-dcsogesb·el after oral administration of de~ogeslrcl
`and 3-keto-desogesn-el. Contraception 1986;33:591-6.
`19. van der Vies j. De Visser J. Endocrinological studies with
`desogestrel. Anmeimittclforschung l 983;33: 231 -6.
`20. Phillips A, Hahn DW, Klimek S, ct al. A comparison of the
`potencies and activities of progestogens used in conn-a(cid:173)
`ceprives. Contraception I 98 7 ;3 6: 181 -92.
`21. McPhail MK. Tbe assay of progestin. J Physiol (Loncl)
`1934;83: 145-56.
`22. Hershberger LC, Shipley EG, Meyer RK Myotrophic
`activity of 19-nortcstosterone and otlter steroids deter(cid:173)
`mined by the modified levator ani method. Proc Soc Exp
`Bjol Med 1953;83:175-80.
`23. Bergink EW, Deckers CH, Kloosterboe1· HJ. lo: Halbe HW,
`H.ekers H, eds. Oral contraception into the 1990s: t.hc
`pnx:eedings of a symposium held at the 12Lh World
`Congress of Gynecology and Obstetrics, Rio de Janeiro,
`October l 988. Carnforth, England: Panhenon Publishing,
`1989:21-30.
`24. Speroff L, De Cherney A, Burkman R. EvaluaLion of a new
`genc1·ation of oral contraceptives. Obstet Gynecol 1993;
`81;103<!-47.
`
`Menstrual impact of contraception
`
`Phillip G. Stubblefield, MD
`Portland, Maine
`
`Persistent bleeding Is a common reason for the discontinuation of contraception. Standard terminology
`for describing bleeding patterns by reference pericx:l Is presented. Observed bleeding patterns with oral
`contraceptives, depot medroxyprogesterone acetate, the levonorgestrel subdermal implant, and
`intrauterine devices are described. Bleeding days are least with oral contraceptives that are highest In
`progestin and estrogen potency and dose, but the ratio of the two steroids is also Important. Published
`studies suggest that oral contraceptives containing new nonandrogenlc progestins have bleeding
`patterns as acceptable as older low estrogen formulations. Approaches to the evaluation and treatment of
`Intermenstrual bleeding with contraceptive methods are reviewed. Patient education on expected
`bleeding patterns Is essentral to compliance and continuation. (AM J OasrET GYNECOL 1994;170:1513-22.)
`
`Key wor ds: Contraception, mcnstmal cycle, breakthrough bleeding, oral contraception,
`intermenstrual bleeding
`
`Many contraceptive methods impact on the men(cid:173)
`strual cycle and may influence the pattern and amount
`of bleeding. Persistent bleeding is a common reason for
`
`Fnnn the Departnumt of Obstetrics and Gynecology. Maine Medical
`Crmler.
`RejJrint requests: Phillip G. St!lbblejieftl, MD, Maine Medical Cente1;
`22 B1·amh.all St., Portland, ME 04102.
`CojJJiight © 1994 lry Mosby-Yea?' Book, Inc.
`0002-9378!94 $3.00 + 0 6/0!53598
`
`the discontinuation of contraceptive methods and may
`therefore lead to unwanted pregnancy. A syndrome
`afflicting new pill users has been deso·ibed. The patient
`experiences nausea and as a result skips some pills and
`then has irregular bleeding, which leads her to stop
`taking the pills. 1 Contraceptives can have either of two
`effects on the menstrual cycle: ( 1) cyclic bleeding
`continues; oral contraceptives (OCs) as usually pre(cid:173)
`scribed (21 of 28 days) completely suppress the lvom-
`
`1513
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`1514 Stubblefield
`
`May 1991
`Am J Obstct Gynccol
`
`en's own ovarian cycle but substitute an artificial cycle
`because of withdrawal of the hormones on day 21.
`Intrauterine devices (IUDs) (with the exception of the
`levonorgestrcl-releasing device) do not suppress the
`ovarian cycle but may have impt·essive effects on the
`amount of bleeding. (2) The normal cycle is partially or
`completely suppressed, and the method does not nec(cid:173)
`essarily induce cyclic bleeding. This type of menstrual
`effect is seen with progestin-only OCs, the subdennal
`implants, iruectable steroids such as depot medroxypro(cid:173)
`gesterone acetate (DMPA), and the levonorgestrel(cid:173)
`releasing IUD, which contains enough of a potent
`progestin to inhibit ovulation in some women.
`With OCs there is a wide range in bleeding rates
`between the expected episodes of withdrawal bleeding,
`depending on the specific formulation. 2 There are dif(cid:173)
`ficulties in comparing pills. The terms "breakthrough
`bleeding" (BTB), defined as bleeding that occurs other
`than at the time of expected menstruation and suffi(cid:173)
`cient to require the usc of pads or tampons, and
`"spotting," defined as bleeding insufficient to require
`protection, are commonly agreed on. "Intermenstrual
`bleeding" includes both BTB and spotting. Generally,
`the patient is expected to record any bleeding or
`spotting daily and turn in her report monthly, which
`may lead to error when patients ful in data forms
`retrospectively. Unfortunately, as we try to compare OC
`trials by different groups, we find that definitions are
`not often given and no standard procedure is followed.
`For example, some workers report bleeding if a bleed(cid:173)
`ing episode occurs on 1 day, whereas others only count
`episodes occurring on 2 or more days in succession.
`The need to study contraceptive use in different cul(cid:173)
`tures introduces further complexity. Any amount of
`bleeding may be unacceptable in some cultures because
`a woman may be considered "unclean," not allowed to
`prepare food or participate in daily activities, and not
`allowed to have sexual intercourse. In general, pills with
`high doses of estrogen and progestin have the lowest
`rates of BTB, but these pills are much less commonly
`prescribed out of a concern to improve safety and
`prevent more serious side elTects. Producing OC for(cid:173)
`mulations that are lowest in dose and potency but have
`acceptable bleeding patterns is of great importance.
`This process would benefit by adoption of common
`methods and terminology.
`The World Health Organization working groups have
`made serious efforts to define a standard way of re(cid:173)
`porting bleeding that would be applicable to the study
`of all contraceptive methods. The "Reference Period
`Method" is recommended. Events occun·ing during a
`specific time period, typically 90 days, are recorded
`without distinction regarding where or whether they fit
`into a monthly cyde.a. 4 A "bleeding day" is a day on
`which bleeding occurs; a "bleeding episode" is one or
`
`more consecutive days during which bleeding occurs.
`Al1 "interval" is one or more consecutive days with no
`bleeding, and a "segment'' is a bleeding episode that
`follows an interval with no bleeding. The number of
`bleeding days, spotting days, episodes of bleeding, their
`average length, standard deviation of the length, range,
`minimum, and maximum are reported. Examples of
`BTB for two triphasic OCs reporting on the basis of
`both cycle and longer reference periods as recom·
`mended by the World Health Organization are given in
`Figs. 1 and 2."
`Determination of rates of intermenstrual bleeding
`between different OC formulations requires random(cid:173)
`ized, preferably blinded trials of two or more products
`compared in a standard fashion by unbiased observers.
`This is rarely done. One excellent example is a trial of
`three different 0.050 mg estrogen formulations re(cid:173)
`ported by Ravenholt et al.11 many years ago. The three
`OCs were repackaged so that neither patients nor
`investigators knew the formulation. Patients were con(cid:173)
`tacted daily, and a standard list of questions was admin(cid:173)
`istered. BTB was most common in initial cycles and
`decreased with time. Patients taking the OC of higher
`progestin potency, which contained dl-norgestrel, had
`lower rates of BTB. Patients receiving the OCs contain(cid:173)
`ing the less potent progestins norethindrone and nor(cid:173)
`ethindrone acetate began to bleed toward the end of
`the pill cycle while still taking the pill; those taking the
`more potent progestin, dl-norgestrel, did not begin
`bleeding until cycle day 22, after the OCs had been
`withdrawn (Figs. 3 and 4). The actual length of with(cid:173)
`drawal bleeding was the same for all three OCs. Cross(cid:173)
`ing over was an important feature of this study. Cross(cid:173)
`ing over ti·om the dl-norgestrel pill to either of the
`others resulted in renewed BTB.
`In another trial by independent investigators, Saleh
`et al.' randomly assigned patients to any of the three
`OC regimens: 1 mg of norethindrone (NET) plus 0.050
`mg of ethinyl estradiol (EE) (OCI); 1 mg of NET plus
`0.035 mg of EE (0C2); or 0.5 mg of NET plus 0.035
`mg of EE (OC3). The study was not blinded. 0C3,
`which had the least of both steroids, bad the highest
`rates of BTB-75% in t-ycle 1, decreasing to approxi(cid:173)
`mately 50% in cycle 8. OCl, the highest dose pill, had
`the least BTB, but OC2, with the same dose of NET but
`reduced estrogen, was similar and statistically not sepa(cid:173)
`rable (Fig. 5). Withdrawal bleeding occurred early in
`the cycle with OC3, the lowest close OC (Fig. 6). The
`investigators also measured blood levels of both ste(cid:173)
`roids and reported baseline and 1-hour slope values at
`day 21 of the cycle. Although blood levels were higher
`with the highe1· dose OCs, no correlation existed be(cid:173)
`tween these blood levels and bleeding patterns, and
`there were large variations between subjects in blood
`levels of steroids while receiving the same OC.
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`Volume 170, Number 5, Part 2
`Am] Obscet Gynecol
`
`Stubblefield 1515
`
`Proportion
`of days
`(mean)
`
`0.200
`
`0.150
`
`0.100
`
`0 .050
`
`0
`
`!iiB NET/EE
`0
`LNG/EE
`
`NS
`
`Bleeding
`
`Spotting
`
`Bleeding
`and/or spotting
`
`Fig. 1. Analysis by cycle (proportion ofaU days with bleeding or spotting ove•· 12 cycles). Comparison
`of two triphasic OCs. NET. Norethindrone; EE, ethinyl estradiol; LNG, levonorgestrel; NS, not
`significant. tp = 0.001; lP = 0.018. (From Schwa•·z BE, et nl. Int.) Fertii1992;S7:176-82.}
`
`t;r.im NET/EE
`0
`LNG/EE
`
`Mean
`length of
`episodes
`(days)
`
`Total
`days
`
`5
`
`4
`
`3
`
`2
`
`1
`
`0
`
`20
`
`15
`
`10
`
`5
`
`0
`3
`2
`,
`Consecutive 90-day reference periods
`
`Fig. 2. Analysis by reference period (bleeding and/or spotting over 3 consecutive 90-day reference
`periods). Comparison of L'IYO triphasic OCs. NE'J ; Norethindrone; EE, ethinyl estradiol; LNG,
`leva norgestrel. tfJ"' 0.001; tt1 = 0.013. (From Schwan. BE, et al. lnt] Fert.ill992;37:176-82.)
`
`In addition to dose and potency of the two sex
`~teroids, the ratio of the two may also impact bleeding.
`Lawson et al.~ studied seven different dosage combina(cid:173)
`tions of norgestimate and ethinyl estradiol in non-
`
`blinded study. Results are expressed in three-dimen(cid:173)
`sional .response surfaces (Figs. 7 to 9). In this study,
`spotting and BTB were combined. Bleeding was least
`frequent at the higher closes of either estrogen or
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`1516 Stubblefield
`
`May 19:11
`Am J Obstel Cynccol
`
`OA> of
`patients
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Avg. number of days for:
`Day 4·21 Day 21·28
`
`0.4
`- - NG 0.5 mg/EE 0.05 mg;
`---- Nt=T 1.0 mg!MES 0.05 mg; 1.5
`1.5
`- - NETA 1.0 mg/EE 0.05 mg;
`
`3.8
`3.8
`3.8
`
`Q L-.L-.1----li....-.,........JL....----J
`1 4 7
`14
`21
`28
`Day of contraceptive cycle
`
`Fig. 3. Cycle d~y of onset of vaginal bleeding with three diffeJ·em 0.050 mg OCs averaged for flrst
`three cycles. A double-blind crossover study of NG/EE, NET/MES, <md NETA/EE. NG, Norgcstrel;
`EE, ethinyl estradiol; NET, norethindrone; MES, mestranol; NETA, norethindrone acetate. (From
`Ravenholt RT, et al. Adv Plann Parent 1978;12:222-39.)
`
`75
`
`Cumulative
`%
`
`50
`
`25
`
`- - NG 0.5 mg/EE 0.05 mg
`• • •• NET 1.0 mg/MES 0.05 mg
`NETA 1.0 mg/EE 0.05 mg
`-
`
`o~--~--~~--~-----J~~~--~
`25
`27
`23
`26
`28
`24
`22
`Day of'contraceptive cycle
`
`Fig. 4. Percentage of patien ts wit!t withdrawal bleeding by cycle clay wit11 three diiTet·ent 0.050 mg
`OCs ave1-aged for first three cycles. (From Ravenholt RT, et al. Adv Plann Parent 1978;12:222-39.)
`
`progestin but remained acceptably low over a range of
`reduced doses of estrogen and progestin, provided
`similar ratios of estrogen to progestin were maintained
`(Fig. 7). This would lead to the expectation that one
`could decrease BTB by increasing either hormone.
`Nausea and vomiting were largely related to e::strogen
`dose and decreased as estrogen was decreased, inde-
`
`pendent of progestin dosage (Fig. 8). The prcgnam:y
`rate was highe::st at the lowesl doses of both hormones
`but was least at an in termediate dose and decreased as
`the proge::stin dose increased (Fig. 9).
`In introducing new formulations it is important to
`compare the effect on bleeding patterns in a random(cid:173)
`ized fashion to a standard. formulation with an ac-
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`

`Volume 170, Number 5, Part 2
`Am ] Obstct Gynecol
`
`Stubblefield 1517
`
`80
`
`70
`
`60
`
`% with 50
`1MB
`40
`
`30
`
`20
`
`10
`0
`
`_._ OC1
`-- oc2
`-
`ocs
`
`2
`
`3
`
`4
`Months
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Fig. 5. Intermenstrual bleeding (IMB) rates by month for three different norethindrone/cthinyl
`estradiol combination OCs. Cycle nine was excluded because of low numbers. OCJ, 1 mg of
`norethlndrone (NET) plus 0.050 mg of elhinyl estradiol (EE); OC2, 1 mg of NET plus 0.035 mg of
`EE; OC3, 0.!5 mg of NET plus 0.035 mg of EE. (From Saleh WA, et al. AM J OllSTliT GYNECOL
`1993;168:1740-7.)
`
`--11- OC1
`-to- OC2
`--- OC3
`
`100
`
`80
`
`60
`
`40
`
`20
`
`%with
`bleeding
`
`0
`
`o ·
`
`3
`
`6
`
`9
`
`12
`
`15
`Day
`
`16
`
`21
`
`24
`
`Fig. 6. Average daily bleeding r01tcs per cycle for three different norethindrone/ethinyl estradiol
`combination OCs. See Fig. 5 for regimen abbreviations. (FI'Om Saleh WA, et al. AM J Or~.~T GYNEC'..OL
`1993;168: 1740-7.)
`
`ceptable pattern. The trial comparing a combination
`OC containing the new progestin norgestimate and
`ethinyl estradiol with another low-dose OG containing
`dl-norgestrel-ethinyl estradiol provides an example.9
`The new OC was equal in preventing BTB and spotting
`(Fig. 10). Amenorrhea while taking OCs is also an
`important side effect, because it leads to patient con(cid:173)
`cern and possible OC discontinuation. Amenorrheic
`cycles were similar for the two OCs. Typically BTB
`and spotting are more common
`in
`initial cycles
`and diminish with time. This is well shown in a
`trial with one of the new progestins, desogestrel
`in combination with 30 1-Lg of ethinyl estradiol
`(Fig. 11).'0
`
`Tl1e progestin-only "mini-pills" affect the cycles
`much more than do the combination esn·ogen-proges(cid:173)
`tin OGs. With progestin-only pills, approximately 40%
`of women will have normal ovulatory cycles, 40% will
`have short cycles, probably with an inadequate luteal
`phase, and 20% will become amenorrheic.'' An ex(cid:173)
`ample of the effect of DMPA is given in Fig. 12. With
`the passage of time, 80% of continuing women develop
`amenorrhea. 12 A significant proportion have ex-cessive
`and prolonged bleeding 11 to 30 days out of the 3
`months between injections of DMPA, but this propor(cid:173)
`tion diminishes with time. With the levonorgestrel sub(cid:173)
`dermal implant various patterns at·e seen and range
`front normal cycles to frequent spotting and bleeding to
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`1518 Stubblefield
`
`May 1994
`Am j Obstet Gynecol
`
`%BTB
`and
`spotting
`
`31.78
`29.24
`26.69
`24.15
`21 .61
`19.06
`16.52
`13.98
`11.43
`8.89
`·~
`·~6' ~
`
`Progestin
`
`·V'o
`
`·c..?s-
`.,0
`
`Estrogen
`
`.,6'
`
`·s-o
`
`Fig. 7. Response surface for spotting and BTB combined. (From Lawson YS, et al. AM J Ousn;;r
`GYNECOL 1979;134:315-20.)
`
`29.12
`
`23.34
`
`17.55
`
`11.77
`
`°/() Gl·
`disturbance
`
`Progestin
`
`Estrogen
`
`Fig. 8. Response surlace for gastrointestinal (GI) disturbances. (From Lawson YS, et al. A\l J O&IET
`GYNECOL 1979; 134:315-20.)
`
`complete amenorrhea. I ! Of 100 women starting with
`the implants in one study, only 60 completed 5 years.'"
`Forty requested early removaL Twenty-five women quit
`to become pregnant. Of the remaining 15, 12 had
`removal for menstrual disturbances, nine for prolonged
`
`bleeding, two for frequent bleeding ep isodes, and one
`for amenorrhea. Only two patients discontinued for
`other medical reasons: one for weight loss and one for
`hair loss.'''
`Bleeding experience with lwo copp et· IUDs over a
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`

`Volume 170, Number 5. l'arL 2
`Atn J Olmet Gynccol
`
`Stubblefleld 1519
`
`~
`
`Progestin
`
`6.55
`
`4.52 Pregnancy
`rate/100
`women
`
`2.50
`
`.47
`
`Estrogen
`
`Fig. 9. Response surface for 7 -month pregnancy rates. (From Lawson YS, et al. ~~ J QIJSTET GYNECOL
`1979;1!14:315-20.)
`
`25 ~--------------------------
`
`20
`
`15
`
`%of
`patients
`
`11.2 10.6
`
`IIDJ NGM/EE
`~ NG/EE
`
`1-6
`
`7-12
`
`Cycle
`
`13-24
`
`Fig. I 0. Bleeding and spotting with nm·gestimate/ethinyl estradiol compared with norgestreVcthinyl
`cstmdiol in a randomized uial. NGM, No•·gcstimate; EE, ethinyl estradiol; NG, norgestrel. (From
`Corson SL. Acta Obstcl Gynecol Scand [Suppl) 1 990; 152:25-!11. Copyright 1990, Munksgaard
`Intcmational Publishers Ltd., Copcnhngcn, Denmark.)
`
`7 -year period is given in Table I. As can be seen, many
`of these women stopped contraception with the IUD
`because of pain and/or bleeding, 22% by the end of 7
`years with the TCu 380A.'r. Bleeding with IUDs typically
`results in heavy menses rather than in between bleed(cid:173)
`ing. In one small study, women experiencing menor(cid:173)
`rhagia while wearing T IUDs agreed to x-ray hysrero-
`
`salpingography.·~ Most of these women had embed(cid:173)
`ment of the arm of the T or a marked deformation of
`the shape of the IUD that suggested it was the interac(cid:173)
`tion between the IUD and the wall of the uterus that
`accounted in a physical way for the excessive bleeding.
`Menorrhagia, bleeding, and spotting between menses
`in IUD wearers suggests endometritis. These women
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`

`

`1520 Stubblefield
`
`May 1994
`Am J Obstel Cyne<:ol
`
`~ ~----------------------------------~
`
`20
`
`15
`
`10
`
`%
`
`Treatment group
`~ Starters
`• Switchers
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`9 10 11 12 13 14 15 16
`6
`Cycle
`
`Fig. II. Intermenstrual bleed ing with monophasic desogcstrel, 0.150 mglcthinyl cmadiol, 0.030 mg,
`through 16 months. (From Walling M. A multicenter eJlicacy and safety study of an oral contracept.ive
`containing 150 meg desogestrel and 30 meg ethinyl estradiol. Contraception 1992;46:313-26, by
`permi~sion of ButteiWorth-Heinemann.)
`
`100
`
`%
`
`Days
`~miD 11-30
`fim 8-10
`~ 1-7
`
`• o
`
`0 '----... Lia .......
`3
`9
`15
`
`21
`
`45
`27 33 39
`Time (Months)
`
`51
`
`57 63 69
`
`Fig. 12. Women with bleeding or spotting while taking DMPA, 150 mg, for 3 momhs. (From
`Schwallie, PC, Assenw JR. Contraceptive use efficacy study utilizing medroxyprogesterone acetate
`administered as <m injection once every 90 days. Fertil Steril 1973;24:331-9. Reproduced with
`permission of lhe publisher, 1be American Fcnilily Society.)
`
`Table I. Seven-year data for TCu220C and
`TCu380A IUDs
`
`should be
`infection.
`
`tested for gononhea and chlamydia]
`
`TCu220A
`
`TCu380A
`
`Woman-months
`Total medical removals
`Pain or bleeding
`Other medical
`
`66,343
`22.6•
`19.8
`3.5
`
`67,885
`25.8
`22.7
`4.1
`
`From WI-JO Spcciall'rogram in Human Reproduction. Con(cid:173)
`traception 1990; 42:141-57, by permission of Butterworth(cid:173)
`Heinemann,
`*Rate per 100 women/yt·.
`
`Treatment of BTB and spotting
`Speroff el al. 17 proposed that patients receiving OCs
`with persistent BTB can be treated with 7-day courses
`of estrogen, either ethinyl estradiol, 0.020 mg, or con(cid:173)
`jugated equine estrogens, 2.5 mg/day. Many practitio(cid:173)
`ners believe this tJ·eatment works, although no random(cid:173)
`ized trials have been conducted. The same treatment
`can be used for bothersome bleeding with the implant
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
`
`

`

`Volume 170, Number 5, Pan 2
`Am J Obstet Gynccol
`
`Stubblefield 1521
`
`Table II. Drug management of breakthrough
`bleeding with Norplant
`
`I Day.~ n + S* I No. tn:atme711S
`
`Regimm
`
`Levonorgesu·el
`0.03 mg twice daily for
`20 clays
`Ethinyl estr-ddiol
`0.05 mg cl~ily for
`20 days
`Ibuprofen
`800 mg three times
`daily for 5 da}'S
`Placebo
`One daily fo1· 20 days
`
`101
`
`77
`
`94
`
`129
`
`2.2
`
`2.2
`
`2.7
`
`3.1
`
`From Diaz S, Croxatto HB, Pave£ M, et al. Clinical assess(cid:173)
`ment of treatme nts for prolonged bleeding in users of Nor(cid:173)
`plant implants. Contl'aception 1990;42:97-1 09, by permission
`of Butterworth-Heinemann.
`*Days of bleeding plus days of spotting.
`
`and with DMPA. An alternative during early months
`with DMPA is to give the next injections sooner than 3
`months. ' 01is appears to result in tl1e patient entering
`tl1e amenorrhea phase sooner, although again d1ere
`appear to have been no randomized trials. There is a
`published trial of medication to reduce bleeding with
`levonorgestrcl implants.'d Women who were j ust begin(cid:173)
`ning Norplant were randomly given any of four oral
`medications: levonorgestrcl, 0.030 mg twice daily; ethi(cid:173)
`nyl estradiol, 0.050 mg daily for 20 days; ibuprofen, 800
`mg tlwec times daily for 5 days; or placebo, once daily
`for 20 days. When the patients experienced bleeding
`episodes lon~er than 8 consecutive clays, they were
`instructed to take their pres<.Tibed medication daily for
`2l days. The three active agents produced fewer bleed(cid:173)
`ing days and fewer episodes of treatment than did
`placebo (Table H). Finally, it must be observed that
`abnormal uterine bleeding is not always caused by the
`contraceptive method under sludy. Women may de(cid:173)
`velop any of several pathologic conditions independent
`of the contraceptive method (I'able Ill). Some of Lhese,
`such as ectopic pregnancy, may be life-threatening.
`When a woman develops abnormal bleeding after many
`months on a hormonal contraceptive, it is worth re(cid:173)
`evaluating whether something else may be going on. A
`recent example from my practice is a woman who began
`to experience heavy and prolonged menses afler years
`of use of one the higher dose OCs. Abnormal bleeding
`continued off OCs, and a vaginal p robe ultrasound
`examination eventually revealed a large intracavitary
`submucous leiomyoma. Hysteroscopic removal of the
`myoma resulted in return to a normal bleeding pattern.
`Excessive bleeding with IUDs has been treated with
`nonsteroidal antiinflamn1atory drugs, and anti.fibrin(cid:173)
`olytic agents.""
`The role of good pallent education on the mensLntal
`impact of contraceptive methods cannot be overcmpha-
`
`Table III. Pathologic causes of
`intermenstrual bleeding
`
`Trauma-vaginal laceration
`Cerviol lesion
`Cervical polyp
`Cervical cance1·
`Endometrial lesion
`Endometritis (chlamydia or gonorrhea)
`Submucosal leiomyoma
`Endometrial polyp
`Endometrial hypeo·plasia
`Endometrial cancer
`Fallopian tube cancel'
`Pregnancy
`Normal inttauterine
`Abnot·mal intrauterine
`Ectopic
`
`sized. One study compared bleeding patterns with ste(cid:173)
`roid-releasing vaginal rings, OMPA, combination OCs,
`and progestin-only OCs and related tl1e bleeding pat(cid:173)
`terns to patient continuation with the met.hod. Stu·pris(cid:173)
`ingly, although disruption of me menstrual cycle was
`least with combination OCs, patients taking OCs were
`least likely to accept their irregular bleeding."' Patients
`on the other methods were less likely man OC users to
`stop contraception because of bleeding, perhaps be(cid:173)
`cause the OC users had not been sufficiently educated
`to expect abnormal bleeding.
`
`Conclusion
`Clinical trials of new OCs should use standard termi(cid:173)
`nology and definitions and ideally should analyze
`bleeding data with the reference petiod method. New
`nonandrogenic progestins combined with low estrogen
`doses appear to have bleeding patterns that are as
`acceptable as older low estrogen formulations. When
`BTB occurs de novo in a patient who has experien-ced
`normal cycles while taking OCs, other causes should be
`considered. Persistent BTB can be managed with short
`courses of estrogen for OC users. Estrogen, progestin,
`or nonsteroidal antiinflammatory agents can be used in
`patients with BTB who use lcvonorgestrel implants.
`Good patient education on bleeding patterns is essen(cid:173)
`tial to compliance and continuation with contraception.
`
`REFERENCES
`1. l'ouer LS. Oral contraceptive compliance and its role in
`the ell'ectivencss nf the method. In: Crammer JA, Spi lker
`B. eds. Patient compliance in medical practice and clinic<~!
`trials. New York: Raven Press, 1991:195-207.
`2. Dickey RP. Managing contraceptive pill patients, 5th ed.
`Durant, Oklahoma; Crentive lnfomatics, 1987.
`3. Snowden R. The statistical analysis Clf menstmal bleeding
`patterns . .J nioSt)C Sci 1977;9: 107-20.
`4. Belscy EM, Farley TMM. The analysis of menstrual bleed(cid:173)
`ing p atterns; a review. Contraception 1988;38:129-57.
`5. Scltwarz BE, Pierce C. Walden C, Knopp RH. Randomized
`comparHtivc study of cycle control with triphasic oral
`contraceptives co11talning norethindrone or
`levonor-
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
`
`

`

`1522 Stubblefield
`
`M<1y 1994
`Am j Obstet Gynecol
`
`gestrcl: frequency and duration of b leeding events. Clin
`Prac Sexuality 1992;8:25-30.
`6. Ravenholt RT, Kessel E, Spiedel], et al. A comparison of
`symptoms associated with
`the use of
`three oral
`contraceptives: a double blind a·ossover study of Ovral,
`Norinyl and Norkmin. Adv Plann Parent !978;12:222-39.
`7. Saleh WA, Burkman RT, Zarur HA, et al. A randomized
`trial of three oral conu·aceptives: comparison of bleeding
`patterns by contraceptive types and steroid levels. A\! J
`OIISTET GYNECOL 1993;168:1740-7.
`8. LawsonJ S, Yliano SF., Pasquale SA, et al. Optimum dosage
`of an oral contraceptive. Aw J OnSTF.T GvNECOL 1979;134:
`315-20.
`9. Corson SL. Efficacy and clinical profile of a new
`oral contraceptive containing norgestimate: U.S. clinical
`trials. Acta Obstet Gynecol Scand (Suppl) 1990;152:
`25-31.
`l 0. Walling M. A multicenter efficacy and safety study of nn
`oral contraceptive containing 150 meg desogestrel and 30
`meg cthinyl estradiol. Contraception 1992;16:313-26.
`11. Speroff L, Damey P. A clinical guide for contraception.
`Baltimore: Williams and Wilkins, 1992:127.
`12. Schwallie PC, Assenza JR. Contraceptive use efficacy study
`utilizing medroxyprogesterone acetate administered as an
`intramuscular injection once every 90 days. Ferlil Steril
`1973;24:331 -9.
`13. Sivin I, Sanchez FA, Diaz S, et al. Three-year experience
`
`witb Norplant subdermal contracepti~n. Fertil Steril 1983;
`39:799-808.
`14. Singh K, Viegas OA, Fong YF, Ratnam SS. Acceptability of
`Norplant implants for fertility regulation in Singapore.
`Contraception 1992;45:39-4 7.
`15. WH:O Special Program in Human Reproduction. Contra(cid:173)
`ception 1990;42:141-57.
`16. Pizan·o E, Schl:lenstedt G, Mehech G, et al. Uterine cavity
`a nd the location or IUDs following administration of
`meclofenamic acid to menorrhagic women. Contraception
`1989;40:413-23.
`17. SperoffL, Glass RH, Kase NG. Clinical gynecologic endo(cid:173)
`crinology and infertility, 4lh ed. Baltimore: Williams and
`Wilkins, 1989:487.
`18. Diaz S, Croxatto HB, Pavez M, et al. Clinical assessment of
`treatments for prolonged bleeding in users of Norplant
`implants. Contraception 1990;42:97-109.
`19. Roy S, Shaw ST Jr. Role of prostaglandin in IUD associ(cid:173)
`ated uterine bleeding-effect of a prostaglandin synthesis
`inhibitor (ibuprofen). Obstct Gynecol 1981 ;58: 101 -6.
`20. Tauber PF, Kloppel A, Goodpasture jC, et a!. Reduced
`menstrual blood loss by release of an antifibrinolytic agent
`intrauterine conu·aceptive devices. AM J OnsTF.T
`from
`GYNECOL 1981;140:322-8.
`21. Delsey EM. The association between vaginal bleeding
`patte1·ns and reasons for discontinuation or contraceptive
`use. C',ontraception 1988;38:207-24.
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 10
`
`

`

`SUPPLEMENT TO
`
`May 1994
`in two parts, part 2
`volume 170, n11mber 5
`
`of OBSTETRICS
`AND GYNECOLOGY
`
`Copyright @ 1994 by Mosby-Year Book, Inc.
`
`PREVENTING UNINTENDED PREGNANCY:
`THE ROLE OF HORMONAL CONTRACEPTIVES
`
`· Bethesda, Maryland
`April 27-28, 1993
`
`Steering Committee and Guest Editors
`Gabriel Bialy, PhD
`Florence Haseltine, PhD, MD
`Nancy J. Alexander, PhD
`Michael Burnhill, MD, DMSc
`
`Sponsored by the
`NATIONAL INSTITUTE OF CHILD HEALTH
`AND HUMAN DEVELOPMENT
`
`In cooperation with the
`ASSOCIATION OF REPRODUCTIVE
`HEALTH PROFESSIONALS
`
`Supported by an educational grant from
`ORTHO PHARMACEUTICAL CORPORATION
`
`Published by
`
`MOSBY-YEAR BOOK, INC.
`
`St. Louis, Missouri 63146-3318
`
`ISSN 0002-9378
`
`Petitioner Exhibit 1024
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 11
`
`

`

`American Journal at Obstetrics and Gynecology
`Founded in 1920
`
`Copyright@ 1994 by Mosby- Year Book, Inc.
`
`PREVENTING UNINTENDED PREGNANCY:
`THE ROLE OF HORMONAL CONTRACEPTIVES
`
`Introduction
`Gabriel Bjaly, PhD, Florence Haseltine, PhD, MD, Nancy J. Alexander, PhD, and
`Michael Burnhill, MD, DMSc
`Bethesda, Maryland, and New Brunswick, New Jersey
`
`PREVENTING UNINTENDED PREGNANCY:
`THE ROLE OF HORMONAL CONTRACEPTIVES
`
`May Part 2
`1994
`
`1483
`
`1485
`
`1489
`
`1495
`
`1499
`
`Epidemiology of unintended pregnancy and contraceptive use
`Jacqueline Darroch Forrest, PhD
`New York , New York
`
`Decreasing periods of contraceptive nonuse and misuse will help lower the rate of unintended
`pregnancy in the United States.
`
`The morbidity and mortality of pregnancy: Still risky business
`David A. Grimes, MD
`San Francisco, California
`
`Risk of maternal morbidity and mortality in pregnancy exceeds that associated with
`contraception, abortion, and sterilization and is greatest in minorities and unmarried and
`uneducated women.
`
`Obstacles to use of hormonal contraception
`Louise B. Tyrer, M D
`Incline Village, Nevada
`
`Identifying women at risk for unintended pregnancy resulting from inappropriate or
`inadequate contraception is important in reducing the high rate reported in the United States.
`
`New knowledge in the physiology of hormonal contraceptives
`Rogerio A. Lobo, MD, and Frank Z. Stancyzk, PhD
`Los Angeles, California
`
`The pbys~ology and mechanisms of action of most orally and parenterally administered
`hormonal contraceptives are reviewed, including a discussion of the role of
`gonadotropin-releasing hormone agonist& and antagonists and antiprogestins.
`
`Vol. 170, No. 5, Part 2, Muy 1994. The American journal of Obsteh·lcs and Gynecology (ISSN 0002-9378) is published month