EXHIBIT 1007
`
`
`
`EXHIBIT 1007EXHIBIT 1007
`
`

`
`llllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`us 20030139381Al
`
`(19) United States
`(12) Patent Application Publication
`Bell et al.
`
`(10) Pub. No.: US 2003/0139381 A1
`Jul. 24, 2003
`(43) Pub. Date:
`
`(54) O RA L CONTRACEJYfi VES TO PREVENT
`PREGNANCY AND DfMINISH
`PREMENSTRUAL SYMJYfOMATOLOG Y
`
`(75)
`
`Inventors: Robert G . Bell, Palm Harbor, FL (US);
`Carole Ben-Maimon, Merion, PA (US);
`Beata Iskold, Livingston, NJ (US)
`
`Correspondence Address:
`STERNE, KESSLER, GO LDST EIN & FO X
`PLLC
`UOO NE W YORK AVENUE, N.W.
`WASHINGTON, DC 20005 (US)
`
`(73)
`
`Assignee: Barr Laboratories, Inc.
`
`(21)
`
`Appl. No.:
`
`10/309,313
`
`(22) Filed:
`
`Dec. 4, 2002
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/335,807, filed on Dec.
`5, 2001.
`
`Publication C lassification
`
`Int. C l.7
`(51)
`(52) U.S. C l .
`
`........................ A61K 31/56; A61K 31/137
`............................................ 514/170; 514/649
`
`(57)
`
`ABSTRACT
`
`This invention relates to a method of preventing pregnancy
`and treating PMS including PMDD. More particularly, Lbe
`invention relates to a method, which involves administering
`one of several combination oral contraceptive regimens io
`combination with a.n antidepressant and a kit containing ibe
`same.
`
`Petitioner Exhibit 1007
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`
`US 2003/0139381 A1
`
`Jul. 24, 2003
`
`1
`
`ORAL CONTRACEPTIVES TO PREVENT
`PREGNANCY AND DIMINISH PREMENSTRUAL
`SYMPTOMATOLOGY
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001) This application claims the benefit of U.S. Provi(cid:173)
`sional Application No. 60/335,807, filed Dec. 5, 2001, the
`disclosure of which is hereby incorporated herein by refer(cid:173)
`ence.
`
`BACKGROUND OF THE INVENTION
`
`[0002] 1. Field of the invention
`
`[0003) This invention relates to ora.l contraceptives that
`prevent pregnancy and diminish or eliminate premenstrual
`symptomatolog-y, including PMS and PMDD, and to a
`method of preveming pregnancy and diminishing or elimi(cid:173)
`nating premenstrual symptomatology, including PMS and
`PMDD.
`
`[0004) 2 . Background Art
`
`[0005) The human menstrua.! cycle involves a repetitive
`sequence of hormonal changes that result in episodic uterine
`bleeding. Normally, each menstrual cycle bas a mean inter(cid:173)
`val of 21 to 35 days, conventionally beginning witb the first
`day of menstrual flow and ending on the day before the next
`onset of bleeding. Duration of the menstrual flow is usually
`2 to 6 days with loss of 20 to 60 ml of blood.
`
`[0006) Tbe menstrual cycle is divided into follicular and
`lutea.l phases, each corresponding to changes occurring in
`tbe ovary. These phases may also be described as prolifera(cid:173)
`tive or secretory, corresponding to changes observed in the
`uterine endometrium. Variations in the length of the cycle
`are usually due to alterations in the (ollicular phase, because
`the luteal phase length remains relatively constant at12 to 16
`days.
`
`[0007) During the follicu lar phase, several primary fol(cid:173)
`licles are recruited for further growth and development.
`Granulosa cells in primary follicles posses follicle stimulat(cid:173)
`ing hormone (FSH) and estradiol receptors. Upon FSH
`stimulation, granulosa cells produce aromatase. This
`enzyme converts the androgens androstenedione and test(cid:173)
`osterone, made in response to luteinizing hormone (LH) by
`thecal cells, to estrone and estradiol, respectively. Granulosa
`cells respond to estradiol by undergoing mitosis to increase
`the number of granulosa cells and estradiol production. By
`day 7 of the cycle, one enlarging primary follicle is selected
`by unknown processes to be the follicle that will release the
`oocyte at ovulation.
`
`[0008] The midcycle rise in plasma estradiol stimulates
`the large midcycle LH surge. This midcycle Lll surge
`triggers resumption of meiosis within the oocyte and lutein(cid:173)
`ization of the granulosa cells within the preovulatory fol(cid:173)
`licle. Immediately before ovu lation, tbe outer follicular wall
`begins to dissolve and an oocyte is released approximately
`24 to 36 hours from tbe onset of the UI surge.
`
`[0009) After ovulation, granu losa cells and the surround(cid:173)
`ing theca cells enlarge, accumulate lipid, and become trans(cid:173)
`formed into lutein cells. 1l1is begins the luteal phase of tbe
`menstrua.! cycle. These cells form a new vascularized struc(cid:173)
`ture called the corpus luteum, which secretes estradiol and
`
`progesterone. LH maintains the corpus luteum during tbe
`luteal phase and, acting via the adenyl cyclase system,
`stimulates progesterone production. If pregnancy does not
`occur, lutein cells degenerate, and dimioisbed hormone
`secretion precedes menstruation. Menstruation is immedi(cid:173)
`ately followed by the onset of another menstrual cycle.
`
`[0010] Because endometrial proliferation serves to pre(cid:173)
`pare the uterus for an impending pregnancy, manipulation of
`hormones and of the uterine environment can provide con(cid:173)
`traception. For example, estrogens are known to decrease
`FSH secretion by feedback inhibition. Under certain circum(cid:173)
`stances, estrogens can also inhibit LH secretion, once again
`by negative feedback. Under normal circumstances, tbe
`spike of circulating estrogen found just prior to ovu lation
`induces the surge of gonadotropic hormones that occurs just
`prior to and results in ovulation. High doses of estrogen
`immediately post-coitally also can prevent conception prob(cid:173)
`ably due to interference with implanta tion.
`
`[0011] Progestins can also provide contraception. Endog(cid:173)
`enous progesterone after estrogen is responsible for tbe
`progestational changes of the endometrium and the cyclic
`changes of cells and tissue in the cervix and the vagina.
`Administration of progestin makes the cervical mucus thick,
`tenacious and cellular which is believed to impede sperma(cid:173)
`tozoal transport. Administration of progestin also inhibits
`LH secretion and blocks ovulation in huma ns.
`
`[0012) The most prevalent form of oral contraception is a
`pill that combines both an estrogen and a progestin, a
`so-called combined oral contraceptive preparation. Alterna(cid:173)
`tively, there are contraceptive preparations that comprise
`progestin only. However, the progestin-only preparations
`have a more varied spectrum of side effects than do the
`combined preparations, especially more breakthrough
`bleeding. As a result, the combined p reparations are the
`preferred ora.l contraceptives in use today (Sheth et al.,
`Contraception 25:243 (1982)).
`[0013)
`In establishing an estrogen-progestin regimen for
`ora l contraceptives, two principal issues must be confronted.
`First, efficacy must be maintained and second, there must be
`avoidance of further erosion in the control of endometrial
`bleeding. ln general, even the lowest dose oral contraceptive
`products commercially available have demonstrated efficacy
`but the overall instances of bleeding control problems have
`increased as the doses were reduced, as manifested both in
`breakthrough bleeding (untimely How or spotting) or with(cid:173)
`drawal amenorrhea during the "pill free" week (expected
`menses).
`[0014) During the luteal phase of the menstrual cycle, as
`many as 75% of women with regular menstnaal cycles
`experience some symptoms of premenstrua.! syndrome
`(PMS), a recurring, cyclical disorder involving behavioral,
`emotional, social and physica.l symploms (Steiner et a!.,
`Annu. Ret~ Med. 48:447-455 (1997)). Behavioral, emotional
`and social symptoms include, but arc not limited to, irrita(cid:173)
`b ility, mood swings, depression, hostility and social with(cid:173)
`drawa.l. Physica.l symptoms include, but arc not limited to,
`bloating, breast tenderness, myalgia, migraines or headaches
`and fatigue. True PMS only occurs during the luteal phase
`of the menstrual cycle, with a symptom-free period during
`the follicular phase. The etiology of PMS is still unknown.
`[0015) A subgroup of women with PMS, about 2-9%,
`exbibit symptoms that are primarily related to a severe mood
`
`Petitioner Exhibit 1007
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`
`US 2003/0139381 Al
`
`Jul. 24, 2003
`
`2
`
`disorder. In these women, the diagnosis of Premenstrual
`Dysphoric Disorder (PMDD), which is defi ned in the Fourth
`edition of the Diagnostic and Statistical Manual of Mental
`Disorders (DSM-IV) can be applied. According to the DSM(cid:173)
`W, a woman with PMDD must have at least five premen(cid:173)
`strual symptoms during the luteal phase, with at least one of
`the symptoms being an emotional or ·'core" symptom. T he
`core symptoms must be irritability, anger, mood swings,
`tension or depression (and interfere with daily activities),
`and must be confirmed by a prospective daily rating for at
`least two cycles. Three to five percent of women with PMS
`report to have PMDD.
`
`(0016) There is also a subgroup of women who experience
`severe PMS, which accounts for about 20% of the PMS
`population. These women experience severe emotional
`symptoms that do not fall under the strict criteria of PMDD
`as defined in DSM-!V but require medical allention.
`
`[0017] Symptoms of PMDD may begin at any age after
`menarche, but the average age at onset appears to be around
`26 years and several researchers found that symptoms, such
`as estrogen withdrawal symptoms, associated with the pre(cid:173)
`menstrual phase gradually become wo rse, and perhaps more
`protracted, over Lime. It bas been suggested that worsening
`could occur because of the recurring increases and decreases
`in ovarian hormones. This is supported by data from other
`cultures: when menstruation is infrequent, premenstrual
`symptoms are rare. It is also supported by data as.sociating
`low parity with the risk of PMDD. Low parity yields a
`greater number of hormonal cycles, and, thus, a woman has
`more exposure to and withdrawal from massive amounts of
`progesterone. Further, several studies find lower rates of
`premenstrual symptoms among users of oral contraceptives,
`again suggesting that briefer exposure to peaks and troughs
`of endogenous progesterone is protective against PMDD
`(Yonkers, K., .!. C!in. Psychiatry S8(Suppl. 14):4-13
`(1997)).
`
`(0018] Suppression of ovulation has been an important
`rationale for the use of hormonal treatments for PMS. One
`method of inltibiting ovulation is by using oral contracep(cid:173)
`tives (OCs). Combination oral contraceptives inhibit ovula(cid:173)
`tion by suppressing gonadotropins, follicle stimulating hor(cid:173)
`mone (FSH) and luteinizing hormone (LH). To date, only
`two controlled studies of the oral contraceptive treatment of
`PMS have been published. The results indicate that combi(cid:173)
`nation oral contraceptives eJiectively reduce physical symp(cid:173)
`toms (especially breast pain and bloating), but the response
`on the relief of psychological symptoms bas been less clear.
`
`[0019) Therapeutic interventions for women who meet the
`criteria for PMDD include selective serotonin reuptake
`inhibitors (SSRI), tricyclic antidepressants and anxiolytics,
`as well as the antidepressant alprazolam (XANAX®). These
`interventions have demonstrated efficacy wi th minimal side
`effects. Recent investigations of SSRI have also demon(cid:173)
`strated success at low doses.
`
`(0020] An tidepressants that are active at serotonin recep(cid:173)
`tors include clomipramine (ANAFRANIL®), Ouoxetine
`(PROZAC®),
`paroxetine
`(PA.XlL®),
`sertraline
`(ZOLOFT®), nefazodone (SERZONE®),
`fenfiuramine
`(PONDI MIN®) and venlafaxine (EFFEXOR®).
`
`(0021] The only approved product today for the treatment
`of PMDD
`is
`tbe SSRI
`fiuoxetine bydrocbloride
`
`(SARAFEM®). The effectiveness of fiuoxetinc for the treat(cid:173)
`ment of PMDD was established in four randomized, pla(cid:173)
`cebo-controlled trials. Fluoxetine at a daily dose of either 20
`mg or 60 mg proved to be superior to placebo in reducing
`symptoms (Steiner et a!., New Engl. J Med. 332:1529-34
`(1995)). However, the combination of oral contraceptive and
`Ouoxetine was not examined, as women who were taking
`oral contraceptives were excluded from the trial.
`
`It is the object of the present invention to provide
`(0022]
`estrogen-progestin combinations and/or regimens for oral
`contraceptive use, including estrogen-progestin combina(cid:173)
`tions and/or regimens that contain an antidepressant, to
`concurrently diminish or eliminate premenstrual symptoms
`(PMS) including PMDD. Two regimens are proposed, the
`so-called 28-day regimen and the 91-day regimen. The
`28-day regimen will allow women the option of maintaining
`tbe customary 13 menstrual cycles per year while diminish(cid:173)
`ing or alleviating premenstrual symptoms (PMS) including
`PMDD. The 91 -day regimen will allow women the option
`of maintaining only 4 menstrual cycles per year while
`dimioislting or alleviating premenstrual symptoms (PMS)
`including PMDD. Thus, the 91 -day regimen enhances
`compliance by involving fewer stop/start transitions per yea r
`and also results in less blood loss, and hypo thetically, will
`diminish premenstrual symptoms, including PMDD. Having
`fewer menstrual intervals can also enhance lifestyles and
`convenience. This and otber objects of the invention will
`become apparent to those skilled in the art from the follow(cid:173)
`ing detailed description.
`
`BRIEF SUMMARY OF Til E INVENTION
`
`[0023] This invention relates to female oral contraceptives
`that will prevent pregnancy and treat PMS including PMDD.
`This invention further rela tes to a method of preventing
`pregnancy and treating PMS including PMDD, by avoiding
`complete withdrawal of estrogen at the end of the treatment
`period, or between treatment periods, by administering oral
`contraceptives. Premenstrual symptoms are rare when men(cid:173)
`struation is infrequent. Further, users of oral contracep tives
`have lower rates of premenstrual symptoms, again suggest(cid:173)
`ing that briefer exposure to peaks and troughs of endogenous
`progesterone is protective against PMD D. More particularly,
`the invention relates to a method of preventing pregnancy,
`which involves administering one of two combination oral
`contraceptive regimens. Additio nally, l he invention relates
`to a method of preventing pregnancy, which involves admin(cid:173)
`istering one of two combination ora I contraceptive regimens
`that contain an antidepressant.
`
`DETAlLEO DESCRIPTION OF THE
`INVENTION
`
`(0024] The invention relates to oral contraceptives that
`will prevent pregnancy and dinJioish or eliminate PMS
`including PMOD. Methods of using these oral contracep(cid:173)
`tives to prevent pregnancy and diminish or eliminate PMS
`including PMDD are also provided. More particularly, the
`methods involve administering one of several combination
`oral contraceptive regimens. Impo rtan tly, these regimens do
`not contain pill-free or placebo intervals.
`
`[0025] Ooe embodiment of the invention is the so-called
`twenty-eight day regimen thai allows women the option o(
`maintaining 13 menstrual cycles per year. Io accordance
`
`Petitioner Exhibit 1007
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`
`US 2003/0139381 Al
`
`Jul. 24,2003
`
`3
`
`with the present invention, a women in need of contracep(cid:173)
`tion and treatment ofPMS including PMDO, is administered
`a combined dosage form of estrogen and progestin, prefer(cid:173)
`ably monophasicly, for 21 to 26 consecutive clays, preferably
`about 22-25 days, followed by administration of low-dose
`estrogen for 2 to 10 days, preferably about 3-7 days, more
`preferably about 2-7 days, in which the daily amounts of
`estrogen and progestin arc equivalent to about 5-50 pg of
`ethinyl estradio l and about 0.025 to lO mg, preferably about
`0.05 to 1.5 mg, of levonorgestrel, respectively.
`
`(0026]
`In a preferred embodiment, women will be admin(cid:173)
`istered an oral contraceptive on days 1 through 21 of the
`menstrual cycle containing 150 pg levonorgestrel and 30 pg
`ethinyl estradiol, followed by a dosage form on days 22-28
`of the cycle, which contains 30pg ethinyl estradiol. Atypical
`administration schedule is illustra ted in Table 1. Thus, in a
`28 -day regimen schedule, there are about 13 treatment and
`menstrual cycles per year.
`
`TABLE 1
`
`Administration schedule for a 28-dny regimen
`
`Days
`
`1-21
`
`22-28
`
`Hom1one
`
`Antidepressant
`
`150 I'S lcvonorgestrel and
`30 ftg ethinyl estradiol
`30 !tg ethinyl estradiol
`
`none
`
`none
`
`In another embodiment of the invention, a women
`[0027]
`in need of contraception and treatment of PMS including
`PMDD, is administered a combined dosage form of estrogen
`and progestin, preferably mooophasicly, for 21 to 26 con(cid:173)
`secutive days, preferably about 22-25 days, followed by
`adm inistration of low-dose estrogen for 2 to 10 days, pref(cid:173)
`erably about 3-7 days, more preferably about 2 -7 days, in
`combination with the antidepressant Ouoxctine hydrochlo(cid:173)
`ride, in which the daily amoun ts of estrogen and progestin
`are equivalent to about5-50ftg of etbinyl estradiol and abou t
`0.025 to 10 mg, preferably abo ut 0.05 to 1.5 mg, of
`levonorgestrel, respectively, and the Ouoxetioe hydrochlo(cid:173)
`ride is in an amount of about 5-120 mg. Oral contraceptives
`with initial doses of l:luoxetine at either 5 mg or 10 mg/clay
`can be started to avoid any activating side eliects that may
`lead to noncompliance. The dose can tben be increased as
`needed. Fluoxetine can also be given intermittently during
`the late lutea.l phase, which is typically 1-2 weeks before
`menses. Ln addition, a one-time or once-weekly dose of
`about 90 mg of fluoxetine can be administered.
`
`[0028]
`In a preferred embodiment, women will be admin(cid:173)
`istered an oral contraceptive on days i through 21 of tbe
`menstrual cycle containing 150 ,ug levonorgestrel and 30 pg
`etbioyl estradiol, followed by a dosage form on days 22-28
`of the cycle, which contains 20 mg fluoxetine hydrochloride
`and 30 pg ethinyl estradiol. A typical administration sched(cid:173)
`ule is illustrated in Table 2. Thus, in a 28 -day regimen
`schedule, there are about 13 treatment and menstrual cycles
`per year.
`
`TABLE 2
`
`Administration schedule for a 28-dav regimen with no antidepressant
`
`Days
`
`1-21
`
`22-28
`
`Hormone
`
`Antidepressant
`
`JSO JIS levonorgestrel and none
`30 /IS ethinyl estradiol
`30 Jt£ ethinyl estradiol
`
`20 mg l:luoxetine hydrochloride
`daily OR
`a one-lcme dose of 90 mg
`lluoxeti11c hydrochloride OR
`a once-week! y dose of 90 mg
`ftuoxetine hydrochloride
`
`[0029) An addi tional embodiment of the invention is a
`long-term regimen that allows women nbc option of limiti ng
`their menstrua l periods to about four ti mes per year. In
`accordance with the present invention, a women in need of
`contraception and trea tment of PMS i ncluding PMDO, is
`administered a combined dosage form of estrogen and
`progestin, preferably monophasicly, fo.r 60 to 110 consecu(cid:173)
`tive days, preferably about 81 to 89 days, followed by
`administration of estrogen for 2 to 10 days, preferably abou t
`5 to 8 days, in which the daily amounts of estrogen and
`progestin are equivalent to about 5-50 pg of cthinyl estradiol
`and about 0.025 to 10 mg, preferably about 0.05 to 1.5 mg,
`of levonorgestrcl, respectively.
`(0030)
`ln a preferred embodiment, the 91 -day regimen,
`women will be administered an oral cootraceptive on days 1
`through 84 of the menstrual cycle containing 150 J.tg
`levonorgestrel and 30 ,ug ethinyl estradiol, followed by a
`dosage form on days 85-91 of tbc cycle, which contains 30
`pg etbinyl estradiol. A typical administration schedule is
`illustrated in Table 3. Thus, in a 91 -day regimen, there are
`only four treatment and menstrual cycles per year.
`
`TABLE 3
`
`Admini~tmtion schedule for a 9·1·day .regimen
`
`Days
`
`J-84
`
`85-91
`
`Hom1ooe
`
`Antidepressant
`
`150 /IS levooorgestrel and
`30 /IS eth inyl estradiol
`30 I'S eth inyl estradiol
`
`none
`
`none
`
`In an additional embodiment of the invention, a
`[0031]
`women in need of contraception and trea tment of PMS
`including PMDO, is administered a combined dosage form
`of estrogen and progestin, preferably monopbasicly, for 60
`to 110 consecutive days, preferably about 81 to 89 days,
`followed by administration of low-close estrogen and Ouox(cid:173)
`etine hydrochlo ride for 2 to 10 days, p referably about 5 to
`8 days, in which the daily amounts of estrogen and progestin
`are equivalent to about5-50pg of etbinyl estradiol and about
`0.025 to 10 mg, preferably about 0 .05 to 1.5 mg, of
`levooorgestrel, respectively, and the t1uoxetine hydrochlo(cid:173)
`ride is in an amount of about 5-120 mg .. Oral contraceptives
`witb initial doses of Huoxetine at either 5 mg o r 10 mg/day
`can be started to avoid any activating side effects that may
`lead to noncompliance. Tbe dose can then be increased as
`needed. Fluoxetine can also be given intemJittenlly duri ng
`the late luteal phase, which is typically 1-2 weeks before
`menses. In addition, a one-time or once-weekly dose of
`about 90 rug of Ouoxetine can be administered.
`
`Petitioner Exhibit 1007
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`
`US 2003/0139381 Al
`
`Jul. 24,2003
`
`4
`
`In a preferred embodiment, women will be admin(cid:173)
`[0032)
`istered an oral contraceptive on days J through 84 of the
`menstrual cycle containing 150 pg levonorgestrel and 30 pg
`cthinyl estradiol, followed by a dosage form on days 85-91
`of the cycle, which contains 30 ,ug etbinyl estradiol and 20
`mo
`lluoxetine hydrochloride. A typical administration
`schedule is illustrated in Table 4. Thus, in a 91 -day regimen,
`there arc only four treatment and menstrual cycles per year.
`
`TABLE 4
`
`Administration schedule for a 9"l·dav regimen with an antidepre.~sant
`
`Days
`
`1-84
`
`85- 91
`
`Hormone
`
`Antidepressant
`
`150 JIS levonorgeslrel and none
`30 Jig ethinyl estradiol
`30 Jig etbinyl estradiol
`
`20 mg ftuoxetine hydrochloride
`daily OR
`a one-time dose of 90 mg
`fluoxetine hydrochloride OR
`a onoe-weekl y dose of 90 mg
`fluoxetine hydrochloride
`
`[0033) The estrogens which may be employed as a com(cid:173)
`ponent in tbe regimens of this invention may be any of those
`conventionally avail able. Typically, the estrogen may be
`selected from the group comprising synthetic and natural
`estrogens, including steroidal and nonsteroidal estrogens.
`The synthetic estrogens may be selected from, for example,
`ethinyl estradiol, ethynodiol diacetate, mestranol and
`quinestranol. Particularly of interest are 17a-etbinyl est r~­
`diol and esters and ethers thereof. The preferred estrogen tS
`17a-etbioyl estradiol. The natural estrogens may include, for
`example, conjugated equine estrogens, esterified estrogens,
`17B-estradiol, estradiol valerate, estrone, piperazine estrone
`sulphate, estriol, estriol succinate and polyestrol phosphate.
`
`[0034) The progestin component may be any progestation(cid:173)
`ally active compound. T hus, the progestin may be selected
`from progesterone and its derivatives such as, for example,
`17-hydroxy progesterone esters, 19-nor-17-hydroxy proges(cid:173)
`terone esters, 17a-ethioyltestosterone and derivatives
`thereof, 17a-ethinyl-19-nor-testosterone and derivatives
`thereof, norethindrone, norethindrone acetate, ethynodiol
`diacetate, dydrogesterone, medroxy-progesterone acetate,
`lynoestrenol,
`fuingestanol
`norethynodrel, allylestrenol,
`acetate, medrogestone, norgestrienone, dimetbiderome,
`ethisterone, cyproterone acetate, levonorgestrel, dl-norg(cid:173)
`estrcl,
`d-17a-acetoxy-13B-ethyl-17a-ethinyl-gon-4-en-3-
`onc oxime, cyproterone acetate, gestodene, desogestrcl and
`norgestimate. The preferred progestin is levonorgestrel.
`
`[0035) The weight ratio of the active ingredients, e.g.,
`etbinyl estradiol and levonorgestrel, is at least 1:45 and
`preferably at least 1:50. The preferable amount of ethinyl_
`estradiol is about 10-50 ,ug and the preferable amount o[
`lcvonorgestrcl is about 0.15-1.5 mg. Other estrogens vary in
`potency from ethinyl estradiol. For example, 30 pg of
`ethinyl estradiol is roughly equivalent to 60 ,ug o~ mestran?l
`or 2 g of 17B-estradiol. Likewise, other progestms vary •.n
`potency from levonorgestrel. Thus, 1 mg of levonorgestrelts
`roughly equivalent to about 3.5 mg of norethindrone acetate,
`or 1 mg of desogestrel and 3-k~todesogestrel or about _0.7
`mg of gestodene. The values gwen above are fo r ethmyl
`estradiol and levonorgestrel and if a diiiereDL estrogen or
`progestin is employed, an adjustment in the amount based on
`
`the relative potency should be made. The correlations in
`potency between the various estrogens and progcstins are
`known. See for example European Patent Application No.O
`253 607, which is hereby incorporated in its entirety by
`reference hereto.
`
`[0036) The preferred antidepressant is fluoxetine hydro(cid:173)
`chloride although other antidepressants can be employed.
`For example, tbe antidepressants alprazolam (XANAX®),
`clomipramine (ANAFRANlL®), paroxetinc (PAXJL®),
`sertraline (ZOLOFT®), oefazodone (SERZONE®), feoflu (cid:173)
`raminc (PONOIMlN®) and vcnlafaxin.e (EFFEXOR®) can
`also be used. The daily amounts of these antidepressants can
`vary, depending on the antidepressant "Used, from 0.75 to 2
`mg, 10 to 20 mg or 50 to 100 mg.
`
`[0037) Each of the described regimens will prevent preg(cid:173)
`nancy and additionally diminish or eliminate debilitating
`premenstrual symptomatology.
`
`[0038] Other useable estrogens include the esters of estra(cid:173)
`diol, estrone and ethinyl estradiol such as the acetate, sulfate,
`valerate or benzoate, conjugated equine estrogens, agnostic
`anti-estrogens, and selective estrogen .receptor moduJators.
`The formulations of the invention may be administered
`orally, preferably in tablet form, parenterally, sublingually,
`transdermally, intravaginally, intranasally or buccally. The
`method of administration depends on the types of estrogens
`and progestins used in the formulation, as well as ~be
`amounts per unit dosage. Most estrogens are orally acttve
`and that route of administration is therefore preferred. Meth(cid:173)
`ods for transdermal administration including the associated
`methods for manu factu.riog such systems are well known in
`the art. In this connection, reference may be had to U.S. Pat.
`Nos. 4,752,478, 4,685,911, 4,438,139 and 4,291,014, which
`are hereby incorporated in their entirety by reference hereto.
`
`[0039] Pharmaceutical fo rmulations or preparations_ con(cid:173)
`taining the formulations of the invention and a SUitable
`carrier can be solid dosage forms which includes tablets,
`dragecs, capsules, cachets, pellets, pills, powders or gran(cid:173)
`ules; topical dosage forms which include solutions, powders,
`fluid emulsions, fluid suspensions, semi-solids, ointments,
`pastes, creams, gels or jellies, foams and controlled release
`depot entities; transdermals, vaginal rings, buccal formula(cid:173)
`tions; and parenteral dosage forms which includes solutions,
`suspensions, emulsions or dry powder comprising an effec(cid:173)
`tive amount of estrogen, progestin and antidepressant as
`taught in this invention.
`
`It is known in the art that active ingredients can be
`[0040)
`contained in such formulations in addition to pharmaceuti (cid:173)
`cally acceptable dlluents, fillers, disiotegraots, binders,
`lubricants, surfactaots, hydrophobic vehicles, water soluble
`vehicles, emulsifiers, buffers, humectants, moisturizers,
`solubilizers, preservatives and the lilke. The means and
`methods for administration arc known in the art and an
`artisan cao refer to various pharmacologic references for
`guidance. For example, '·Modem Pharmaceutics", Banker &
`Rhodes, Marcel Dekker, Inc. (1979); ''Goodman & Gilman's
`The Pharmaceutical Basis of Therapeutics", 6th Edition,
`MacMillan Publishing Co., New York (1980), or Reming(cid:173)
`ton's Pharmaceutical Sciences, Osol, A ., ed., Mack Publish(cid:173)
`ing Company, Easton, Pa. (1980) can be consulted.
`
`[0041) Generally speaking, the formulations are prepared
`according to conventionally known procedures io accor-
`
`Petitioner Exhibit 1007
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`
`US 2003/0139381 Al
`
`Jul. 24, 2003
`
`5
`
`dance with the method of administration. Thus, the active
`ingrcdi.cnts are prepared according to known methods in a
`pharmaceutically acceptable form for administration. These
`ingredients, in their required quantities are combined with
`the appropriate pharmaceutical carriers such as additives,
`vehicles and/or flavor ameliorating substances. These sub(cid:173)
`stances may be referred to as diluents, binders and lub ri(cid:173)
`cants. Gums, starches and sugars arc also common terms.
`Typical of these types of substances or excipients are phar(cid:173)
`maceutical grades of mannitol, lactose starch, magnesium
`stearate, sodium saccharin, talcum, cellulose, glucose,
`sucrose, magnesium carbonate and the like. The active
`ingredient(s) may comprise from about 0.01% by weight to
`about 99.99% by weight of the total formulation and the
`remainder comprises the pharmaceutically acceptable car(cid:173)
`rier. The percentage of active ingredient(s) may vary acco rd(cid:173)
`ing to the de livery system or method of administration a nd
`is chosen in accordance with conventional methods known
`in tbe art.
`
`In the oral form of the formulation, the contracep(cid:173)
`[0042]
`tive preparations are preferably produced in the form of a kit
`or package, with the daily dosages arranged for proper
`sequential admini'itration. Thus, in another aspect, the
`present invention also provides a pharmaceutical package
`w hich contains combination-type contraceptives in m ultiple
`dosage units in a synchronized, fixed sequence, wherein the
`sequence or arrangemen t of the dosage units corresponds to
`the stages of daily administration.
`
`[0043] For example, the pharmaceutical formulations may
`be provided in kit form containing for the 28 -day regimen
`at least about 18, and preferably at least about 21 tablets, and
`up to 26 tablets, intended for ingestion on successive days.
`Preferably administration is daily for at least 21 days using
`tablets containing both the estrogen and the progestin a nd
`then for at least 7 days using tablets containing only estro(cid:173)
`gen. In another preferred e mbodiment, administration is
`daily lor at least 21 days using tablets containing both the
`estrogen and the progestin and tbcn for at least 7 days using
`tablets containing bolb estrogen and a n antidepressant, e.g.,
`fiuoxetine hydrochloride. For the long-term regimen, tbe
`pharmaceutical formu lation may be provided in kit form
`containing at least about 60, and preferably at least about 81
`to 89 tablets, and up to 110 tablets, intended for ingestion on
`successive days. Preferably administration is daily for at
`least 84 days usi ng tablets containing both the estrogen and
`tbc progestin and tben for at least 7 days using tablets witb
`only estrogen. In another preferred embodiment, adminis(cid:173)
`tration is daily for at least 84 days using tablets containing
`both tbe estrogen and the progestin and then for at least 7
`days using tablets with both estrogen and an antidepressant,
`e.g., fiuoxetine bydrochloride.
`
`[0044] Efficacy of the 28 -day and 91 -day regimens on
`premenstrual symptomatology arc measured by psychomet(cid:173)
`ric scales that include self-administered Visual Analogue
`Scales (VAS) and a prospective daily symptoms chart or
`diary to evaluate psychological and somatic symptoms.
`Total score of the psychological and somatic symptoms is
`computed. The VAS measures tension, irritability, dyspho(cid:173)
`ria, sleeping and eating patlerns, headache, bloating, pain
`and breast tenderness and weigh t gain symptoms.
`
`In order to further ill ustrate the present invention,
`[0045]
`specific examples are set forth below. It will be appreciated,
`
`however, that these examples are illustrative only and are no t
`intended to limit the scope of the invention.
`
`EXAMPLES
`
`Example 1
`
`[0046] Multicenter Randomized Phase III C linical Trial to
`Evaluate Two Continuous Oral Contraceptive Regimens in
`Women Diagnosed with Premenstrual Syndrome (PMS) and
`Premenstrual Dyspboric Disorder (PMUD)
`
`[0047] Clinical Design and Summary
`
`In a multicenter, randomized, clinical trial the
`[0048]
`efficacy and safety of three combination oral contraceptives
`regimens in the prevention of pregnancy in sexually active