EXHIBIT 1003
`
`EXHIBIT 1003
`
`

`

`PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 97/41868
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`A61K 31/565 II (A61K 31/565, 31:565)
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publicatio n Date:
`
`13 November 1997 (13.11.97)
`
`(21) International Application Number:
`
`PCT/ US97/07074
`
`(22) International Filing Dute:
`
`28 April 1997 (28.04.97)
`
`(30) Priority Data:
`08/647,078
`
`8 May 1996 (08.05.96)
`
`us
`
`(81) Dcsignuted States: AL, AU, BA, 88, BG, BR, CA. CN, CU,
`CZ. EE, GE, HU, IL,IS, JP, KP, KR, LC, LK, LR, LT. LV,
`MG, MK, MN, MX, NO, NZ, PL, RO, SG, Sl, S K, TR, TT,
`UA, UZ, VN, ARTPO patent (GH, KE, LS, MW, SD, SZ,
`UG), Eurasian patent (AM, AZ, BY, KG. KZ, MD, RU, TJ,
`TM), European patent (AT, BE, CH, DE, DK, ES, Fl, FR.
`GB, GR, IE, IT, L U, MC, NL, PT, SE), OAPI patent (BF,
`BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant: AMERICAN HOME PRODUCTS CORPORA-
`TION [US/US]; Five Giralda Farms, Madison, NJ 07940- Published
`With international search report.
`0874 (US).
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`Jay;
`
`230 Country Lane,
`
`GAST, Michael,
`(72) Inventor:
`Phoenixville, PA 19460 (US).
`
`(74) Agents: ALICE, Ronald, W.; American Home Products Cor(cid:173)
`poration, Patent Law Dept. - 28, One Campus Drive, Par(cid:173)
`sippany, NJ 07054 (US) et al.
`
`(54) Title: ORAL CONTRACEPTIVE
`
`(57) Abstract
`
`This invention provides a method of contraception which comprises administering to a female of childbearing age for 28 days per
`menstrual cycle a combination of a progestin at a daily dosage equivalent to 40-125 11g levonorgestrel and an estrogen at a daily dosage
`equivalent to 10-15 ttg ethinyl estradiol for 23-25 days beginning on day I of the menstrual cycle, followed by administering an estrogen
`at a daily dosage equivalent to 5- 15 J.l& ethinyl estradiol for 3-5 days.
`
`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`Codes used to identify States party to the Per on the front pages of pamphlets publishing international applications under the Per.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`Cll
`Cl
`CM
`CN
`cu
`cz
`OF.
`OK
`EE
`
`Albania
`Amu:nia
`Ausrria
`Ausrralia
`Azerbaijan
`Bosnia and Hen.egovina
`Barbados
`Belgium
`Burkina l'aso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switu:riAnd
`C61e d'lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`estonia
`
`£S
`Fl
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`LL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`Ll
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`Unilcd Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`llaly
`Japan
`Kenya
`Kyrgyt.Sian
`Democratic People's
`Republic of Korea
`Republic of Korea
`KaT.aksran
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`Ml.
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`so
`SE
`SG
`
`l.esocho
`l.irhuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Tile former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mex ico
`Niger
`Ncrherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Ruuian Federation
`Sudan
`Sweden
`Singapore
`
`Sl
`SK
`SN
`sz
`TO
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swuiland
`Cnad
`Togo
`Tajikisran
`Tlirkmenistan
`Tlirkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`UzbekiS!an
`VietNam
`Yugoslavia
`Zimbabwe
`
`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`W097/41868
`
`PCT/US97/07074
`
`- 1 -
`ORAL CONTRACEPTIVE
`
`BACKGROUND OF TilE INVENTION
`The vast majority of oral contraceptives consist of a combination of a progestin
`and estrogen that are administered concurrently for 21 days followed either by a 7 day
`pill free interval or by the administration of a placebo for 7 days in each 28 day cycle.
`The most important aspects of a successful oral contraceptive product are effective
`contraception, good cycle control (absence of spotting and breakthrough bleeding and
`occurrence of withdrawal bleeding), and minimal side effects. Combination oral
`contraceptives have traditionally acted by suppression of gonadotropins. In addition, it
`appears that the progestin component is primarily responsible for contraceptive efficacy
`through inhibition of ovulation, and other peripheral effects which include changes in
`the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the
`endometrium (which reduce the likelihood of implantation). The estrogenic component
`intensifies the anovulatory effect of the progestin, and is also important for maintaining
`cycle control.
`Since the introduction of oral contraceptives (OCs) over a quaner-century ago,
`research has been directed toward developing preparations that minimize the potential
`for side effects while maintaining efficacy and normal menstrual patterns. The first-
`generation OCs contained more progestin and estrogen than was necessary to prevent
`conception. Adverse hemostatic and metabolic changes, clinical problems, and side
`effects were associated with these high-dose preparations. In 1978, the World Health
`Organization (WHO) recommended that the focus of OC research should be the
`development of products containing the lowest possible dose levels of estrogen and
`progestin.
`The first reductions in steroid content in a combination pill were focused on
`estrogen because it, rather than progestin, was thought to be related to the most serious
`side effects. Reduction in progestin content followed, as evidence mounted that
`lowering progestin intake might lower the risk of cardiovascular complications such as
`stroke and ischemic heart disease. [Kay CR, Am J Obstet Gynecol 142:762 (1982)1.
`However, this evidence was not as clear as that implicating estrogen in thromboembolic
`disorders. [Inman WHW, Br Med J 2:203 (1970); Stolley PD, Am J Epidemiol
`102:197 (1975)]. The need for a balance between esrrogens and progestins to minimize
`adverse effects on carbohydrate metabolism and on lipid and lipoprotein levels was also
`recognized. [Bradley DD, N Eng! J Med 299:17 (1978); Wynn V, Lancet 1:1045
`(1979)]. Researchers then found that the synergistic action between progestin and
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`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
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`

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`wo 97141868
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`
`estrogen in a balanced ratio successfully inhibited ovulation at low levels of both
`
`components.
`into
`Research
`the
`low-dose progestins was advanced significantly by
`development of norgestrel (Ng) and levonorgestrel (LNg). Levonorgestrel is the
`biologically active moiety of racemic norgestrel. It is strongly progestational, has no
`inherent estrogenic activity, is amiestrogenic, and possesses good biologic activity.
`
`T he contraceptive effects of levonorgestrel are manifested throughout the hypothalamic(cid:173)
`pituitary-gonadal-target organ axis.
`Ethiny l estradiol (EE) is the estrogen most frequently used in combination OCs.
`In attempts to fulfill the WHO objective, the dosage of EE in marketed OC formu lations
`
`has been steadily reduced from that found in earlier OCs. Thromboembolic mortality
`decreased when the amount of synthetic estrogen in OC formulations was reduced from
`100 jlg to 50 f..lg. Subsequently, a significant reduction in fatal myocardial infarctions
`was reported for women using OCs with 30 ~g of EE rather than 50 J...Lg of EE. I Meade
`TW, Br Med J 280:1157 (1980)).
`In keeping with the goal of reducing the total steroidal dosage, while
`maintaining contraceptive efficacy, good cycle control, and minimizing side effects,
`numerous regimens have been developed in which the progestin/estrogen combination
`
`is administered either as a fixed dosage combination (monophasic) or as biphasic or
`triphasic regimens in which the dosage of the combination is varied either once or twice
`throughout the menstrual cycle. In these regimens, the progestin/estrogen combination
`is typically administered for 21 days followed by either a 7 -day pill free period or the
`administration of a non-contraceptive placebo (or iron supplement) for 7 days. In these
`
`regimens, 3-ketodesogestrel (3-KDSG), desogestrel (DSG), levonorgestrel (LNg) ,
`gestodene (GT D), norgesrrel (NG), and norethindrone (NE) are typically used as the
`progestin w hile ethinyl estradiol (EE); 17~-estradiol, and mestranol are typically the
`estrogenic components.
`
`Several examples of attempts at reducing the total steroidal dosage are provided
`
`below.
`
`Erlich (German Patent DE 4,104,385 Cl and U.S. Patent 5,280,023) discloses
`sequential contraceptive regimens consisting of the administration of an estrogen which
`effects a disturbance of follicle stimulation, followed by the administration of a
`combination of a progestin/estrogen in a dose at least adequate to inhibit ovulation.
`T he regimen is administered for a total of 28 days per cycle.
`It is preferred that the
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`estrogen is administered for 5- 14 days per cycle and the progestin/estrogen combination
`
`is administered for 23-14 days per cycle, so that the total administration is for 28 days
`per cycle. Specific regimens include (a) 4 mg estradiol for 7 days followed by 21 days
`
`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
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`

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`W097/41868
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`PCTIUS97/07074
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`- 3 -
`of the combination of 1 mg norethisterone acetate and 4 mg estradiol; (b) 2 mg estradiol
`valerate for 7 days followed by 21 days of the combination of 2 mg chlormadinone
`acetate and 4 mg estradiol valerate; and (c) 20 )lg EE followed by 18 days of the
`combination of 150 )lg LNg and 20 )lg EE. Regimen (c) in Erlich provides a total
`steroidal load of 2.7 mg of LNg and 560 )lg EE per 28 day cycle.
`Lachnit (PCT Publication WO 95/26730) discloses bridged regimens consisting
`of the administration of a combination of a progestin/estrogen combination (50- 125 )lg
`LNg and 10 - 40 )lg EE) for the first 23-24 days of the menstrual cycle followed by the
`administration of an estrogen (2 - 40 )lg EE) for 4-10 days for a total administration of
`at least 28 days per cycle. The use of I 00 - 300 )lg drospirenone and 10 - 40 )lg EE as
`the 23-24 day progestin/estrogen combination is disclosed. Lachnit also discloses a
`triphasic plus bridging regimen (4-9 days, 4-9 days, 9-13 days, and 28 days for the
`three phases and estrogen phase, respectively) in which a combination of 50 )lg LNg
`and 20 )lg EE are administered in the first phase, a combination of 75 )lg LNg and 25
`)lg EE are administered in the second phase, a combination of 100 J.J.g LNg and 20 )lg
`EE are administered in the third phase, and I 0 )lg EE is administered in the estrogen
`phase. Other progestins disclosed include GTD, DSG, 3-KDSG, DRSP, cyproterone
`acetate, norgestimate, and norethisterone.
`Moore (DE 4313926 A 1) discloses bridged triphasic regimens consisting of the
`administration of a combination of 10- 50 Jl.g LNg and 5 - 20 )lg EE from days 1-7 of
`the menstrual cycle; of 50 - 75 )lg LNg and 5 - 20 )lg EE from days 8-14 of the
`menstrual cycle; of 75 - 125 )lg LNg and 5 - 20 )lg EE from days 15-21 of the
`menstrual cycle; and 5- 20 )lg EE from days 22-28 of the menstrual cycle.
`
`Spona (PCT Publication WO 95/17194) discloses contraceptive regimens which
`consist of the administration of a combinaton of a progestin (50- 75 )lg GTD, 75 - 125
`)lg LNg, 60- 150 )lg DSG, 60- 150 )lg 3-K.DSG, 100 - 300 )lg DRSP, 100- 200 )lg
`cyproterone acetate, 200- 300 jlg norgestimate, or >350 - 750 Jlg norethisterone) and
`an estrogen ( 15 - 20 jlg EE or 2 - 6 mg 171}-estradiol) for 23-24 days per cycle.
`
`Upton (EP Patent Specification 253,607 B 1) teaches the use of low dose
`progestin/estrogen combinations for combined hormone replacement therapy and
`contraception in climacteric women. Climacteric women are defined in Upton as pre(cid:173)
`menopausal women around 40 years of age whose hormone levels are waning. The
`climacteric woman still ovulates (albeit may have irregular ovulation), but she still
`experiences many of the symptoms of the hypoestrogenic menopausal woman, such as
`insomnia, hot flushes, and irritability. Upton teaches the administration of a 23-26 day
`monophasic regimen of progestin/estrogen followed by a pill free or placebo interval of
`2-5 days; with 24 days of progestin/estrogen administration followed by a 4-day pill
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`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
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`- 4-
`
`free or placebo administration being preferred. Upton teaches the use of a progestin
`selected from 25 - 100 )lg LNg, 10- 70 )lg GTD, 25 - 100 )lg DSG, 25 - 100 )lg 3-
`KDSG, and 85 - 350 J.Lg NE used in combination with an estrogen selected from 500 -
`2000 )lg 17 ~-estradiol, 8 - 30 )lg EE, and 15 - 60 )lg mestranol. Based on relative
`potencies, Upton teaches that a dose of 75 )lg LNg is equivalent to 35 J.Lg of GTD, 75
`)lg of 3-K.DSG or DSG, and 250 )lg NE and that a dose of 1000 )lg of 17~-estrailiol is
`equivalent to a dose of 15 )lg EE and 30 J.Lg mestranol. Upton also teaches that NG
`may be substituted for LNg, but at twice the dose .
`Sanoretto (Clinica e Terapeutica 3: 399 (1974)) discloses a monophasic
`contraceptive regimen consisting of the administration of a combination 100 )lg LNg
`and 20 J.Lg EE for 21 days.
`
`Lachnit-Fixson (U.S. Patent 3,969,502) discloses biphasic progestin/estrogen
`combination regimens in which a combination of 50-125 J.Lg LNg and 25-35 J.Lg EE are
`administered for 10-12 days in the first phase and 100-350 )lg LNg and 30-50 )lg EE
`are administered for 10-12 days in the second phase. Placebo is administered for 5-7
`days following the administration of the contraceptive steroid regimen.
`Lachnit-Fixson
`(U.S.
`Patent 3,957 ,982) discloses
`triphasic 21-day
`progestin/estrogen regimens in which a combination of 40-90 )lg LNg and 20-50 )lg EE
`is administered for 4-6 days in the first phase, 50-125 )lg LNg and 30-50 )lg EE is
`administered for 4-6 days in the second phase, and 100-250 )lg LNg and 25-50 J.Lg EE
`is administered for 9-11 days in the third phase. It is preferred that the first, second,
`and third phases are 6, 5, and 10 days, respectively.
`Bennick (U.S. Patent 5,418,228) discloses triphasic regimens which consist of
`the administration of a combination progestin/estrogen in a 6-8 day phase, a second 6-8
`day phase, and a third 6-8 day phase, with it being preferred that the three contraceptive
`steroid phases be 7 days each. Bennick discloses that the first contraceptive steroid
`phase consists of a progestin at a daily dosage equivalent to 75 - 150 )lg DSG and an
`estrogen at a daily dosage equivalent to 20 - 25 11g EE; the second contraceptive
`steroid phase consists of a progestin at a daily dosage equivalent to 75 - 125 )lg DSG
`and an estrogen at a daily dosage equivalent to 20 11g EE; and the third contraceptive
`steroid phase consists of a progestin at a daily dosage equivalent to 75 - 100 )lg DSG
`and an estrogen at a daily dosage equivalent to 20 J.Lg EE. Placebo is administered for 7
`days following the 21-day contraceptive steroid period. Bennick discloses that the
`progestin may be 3-KDSG, DSG, LNg, or GTD.
`Bergink (U.S. Patent 5,262,408) discloses a 24 day triphasic combination
`regimen in which the first 7-9 day phase consists of the administration of a progestin at
`a daily dosage equivalent to 100 J.Lg DSG and an estrogen at a daily dosage equivalent to
`
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`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
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`

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`PCTIUS97/07074
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`- 5 -
`
`25 ~g EE, the second 7-9 day phase consists of the administration of a progestin at a
`daily dosage equivalent to 125 ~g DSG and an estrogen at a daily dosage equivalent to
`20 J,l.g EE, and the third 7-9 day phase consists of the administration of a progestin at a
`daily dosage equivalent to 50 J..Lg DSG and an estrogen at a daily dosage equivalent to
`20 J.!g EE. It is preferred that the three phases be 8 days each. Following the 24 day
`contraceptive steroid administration, a placebo may be administered for 4 days, the 4
`day interval may be pill free, or a progestin at a dosage equivalent to 25-35 ~g DSG
`may be administered.
`Boissonneault (U.S. Patent 4,962,098) discloses triphasic progestin/estrogen
`combinations in which the amount of the estrogenic component is increased stepwise
`over the three phases. Contraceptive steroid combinations are taken for 4-7 days during
`the first phase (5 days being preferred); for 5-8 days during the second phase (7 days
`preferred); and for 7-12 days during the third phase (9 days being preferred).
`Following the administration of 21-days of the contraceptive steroid combination,
`placebo is taken for 7 days. For all three phases, 0.5-1.5 mg of norethindrone acetate
`is used in the progestin, with 1 mg being preferred. 10-30 J,.Lg EE is used in the first
`phase, 20-40 J,l.g in the second, and 30-50 ~gin the third phase.
`Pasquale (U.S. Patent 4,921.843) discloses combination progestin/estrOgen
`contraceptive regimens which contain 0.5 to 1 mg of progestin and an estrogen having a
`dose equivalent to 10-40 J,l.g of EE. NE, LNg, D-17~-acetoxy-13~-ethyl-17cx-ethinyl­
`gon-4-en- 3-one oxime, and 19-nor-17 -hydroxy progesterone ester are disclosed as
`progestins, with NE being preferred. Specifically disclosed regimens include a
`uniphasic regimen (2 days of placebo, 5 days of 20 J,l.g EE, and 21 days of a
`combination of 500 J,l.g NE and 35 j.lg EE); a uniphasic regimen (2 days of placebo, 5
`days of 40 ~gEE, and 21 days of a combination of 500 J..Lg NE and 35 j.lg EE); and a
`triphasic regimen (2 days of placebo; 5 days of 20-40 J,l.g EE; 7 days of a combination
`of 500 J.!g NE and 35 J,l.g EE; 7 days of a combination of 750 J,l.g NE and 35 ~g EE; and
`7 days of a combination of I mg NE and 35 ~g EE).
`triphasic progestin/estrogen
`Pasquale (U.S. Patent 4,628,051) discloses
`combination regimens in which contraceptive steroid is administered for 21 days.
`Contraceptive steroid combinations are taken for 5-8 days during the first phase (7 days
`being preferred); for 7-11 days during the second phase (7 days preferred); and for 3-7
`days during the third phase (7 days being preferred). In all three phases, an estrogen at
`a daily dosage equivalent to 20-50 J..Lg EE is administered in combination with a
`progestin having a daily dosage equivalent to 65-750 J,l.g NE in the first phase,
`0.25-1.0 mg NE in the second phase, and 0.35-2.0 mg NE in the third phase. A
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`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
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`5
`
`specific triphasic regimen discloses the administration of 35 jlg EE in each of the three
`7-day phases in combination with 0.5 mg, 0.75 mg, and 1.0 mg in the first, second,
`and third phases, respectively. A second specific triphasic regimen discloses the
`administration of 35 jlg EE in each of the three 7-day phases in combination with
`50 jlg, 75 jlg, and 100 jlg in the first, second, and third phases, respectively. A third
`specific triphasic regimen discloses the administration of 35 jlg EE in each of the three
`7-day phases in combination with 25 jlg, 35 J.Lg. and 50 J.Lg in the first, second, and
`third phases, respectively.
`21 -day
`triphasic
`Patent 4,621,079) discloses
`Lachnit-Fixson
`(U.S.
`progestin/estrogen combination regimens in which a combination of 40-70 jlg GTD and
`20-35 jlg EE is administered for 4-6 days in the first phase; 50-100 J.Lg GID and
`30-50 J.Lg EE is administered for 4-6 days in the second phase; and 80-120 jlg GID
`and 20-50 J.Lg EE is administered for 9-11 days in the third phase. Placebo is
`administered for 7 days following the 21-day contraceptive steroid regimen.
`Pasquale (U.S. Patent 4,530,839) discloses triphasic 21-day progestin/estrogen
`combination regimens in which a dose of 20-50 J.Lg EE is administered in all three
`phases in combination with a contraceptively effective daily dose of progestin in the
`first phase, 1.5-2 times that dose of progestin in the second phase, and 2-2.5 times the
`first phase dose of progestin in the third phase. Each of the three phases is 7 days long.
`20 A specific regimen discloses 20-50 jlg EE in combination with 500 J.Lg LNg, 750 J.Lg
`LNg, and 1 mg LNg during each of the three 7-day phases, respectively.
`Edgren (U.S. Patent 4,390 ,531) discloses triphasic 21-day progestin/estrogen
`combination regimens in which a dose of 20-40 jlg EE (or another estrogen in an
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`equivalent dosage) is administered in all three phases in combination with 0.3-0.8 mg
`25 NE (or another progestin in an equivalent dosage) for 5-8 days in the first phase, twice
`the dose of NE for 7- 11 days in the second phase, and the dose of NE being the same
`as in the first phase for 3-7 days in the third phase. It is preferred that each of the three
`phases is 7 days. Placebo is administered for 6-8 days following administration of the
`contraceptive steroid combination. A specific regimen discloses a first phase of 7 days
`of 0.5 mg NE in combination with 35 jlg EE, a second 7 day phase of 1.0 mg NE in
`combination with 35 J.Lg EE, and a third 7 day phase of 0.5 mg NE in combination with
`35 jlg EE.
`Oenel (EP 628,312 A 1) discloses combination contraceptive combinations
`a biogenic estrogen (estradiol,
`containing the combination of three components:
`estrone, or estriol), a synthetic estrogen (EE or mestranol), and a progestin (LN g,
`desogestrel, progesterone, norethisterone acetate, DSGT, chlormadinone acetate,
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`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
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`wo 97/41868
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`
`is
`the combination
`In one embodiment,
`gestodene, or cyproterone acetate).
`administered for 21 days followed by the administration of placebo (or pill free) or an
`estrogen on days 22-28 of the cycle.
`Oettel (EP 696,454 A2) discloses a three phase contraceptive regimen in which
`the first phase consists of the administration for 3-4 days of a composition containing at
`least one biogenic estrogen; the second phase consists of the administration for 20-22
`days of at least one biogenic estrogen and at least one progestin (progesterone, DGST,
`desogestrel, 3-KDSG, GTD, LNg, norgestimate, notethisterone, norethisterone acetate,
`dehydrogestrone, chloromadinone acetate, cyproterone acetate, medroxyprogesterone
`acetate, or megestrol acetate); and the third phase consists of the administration for 3-4
`days of a composition containing at least biogenic one estrogen.
`
`5
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`15
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`20
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`DESCRIPTION OF TilE INVENTION
`This invention provides a bridged monophasic combination progestin/estrogen
`oral contraceptive regimen for females of child-bearing age that provides effective
`contraception, good cycle control, and minimal side effects while greatly reducing the
`total contraceptive steroid administered (particularly the estrogenic component) per 28-
`day cycle. To achieve the substantial reduction in the total contraceptive steroid
`administered per cycle while maintaining good cycle control,
`the
`low dose
`progestin/estrogen combination is administered for 23-25-days per cycle followed by
`the remaining 3-5 days of the cycle.
`the administration of an estrogen for
`Administration of the contraceptive progestin/estrogen combination is begun on the first
`day of menses (day I ), and continued for 23-25 consecutive days. Following the 23-
`25-day administration period, an estrogen is administered for 3-5 days to assist in
`25 maintaining good cycle control. The total administration during each cycle is 28 days.
`More particularly, this invention provides a method of contraception which
`comprises administering to a female of child bearing age a combination of a progestin
`at a daily dosage equivalent in progestational activity to 40-125 Jlg levonorgestrel and
`an estrogen at a daily dosage equivalent in estrogenic activity to I 0-15 Jlg ethinyl
`estradiol for 23-25 days beginning on day I of the menstrual cycle. Following the 23-
`25-day period, an estrogen at a daily dosage equivalent to 5-15 Jlg ethinyl estradiol is
`administered for 3-5 days. The total administration during each cycle is 28 days.
`Preferred progestins include, but are not limited to levonorgestrel, norgestrel,
`desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, and
`norgestimate.
`It is more preferred that the progestin is Jevonorgestrel. When
`levonorgestrel is used as the progestin, it is preferred that the daily dosage of
`levonorgestrel is 40-1 00 Jlg.
`
`30
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`35
`
`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
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`PCT/US97/07074
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`Preferred estrogens include, but are not limited to ethinyl estradiol; 17~­
`estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol; with
`ethinyl estradiol being more preferred. When ethinyl estradiol is used as the estrogen
`during the first 23-25 days of the cycle, it is preferred that the daily dosage of ethinyl
`estradiol is 10-15 jlg, with 15 ).J.g being more preferred. When ethinyl estradiol is used
`
`as the estrogen during the last 3-5 days of the cycle, it is preferred that the daily dosage
`of ethinyl estradiol is 5-15 jlg, with 15 jlg being more preferred. When 17~-estradiol is
`
`used as the estrogen during the last 3-5 days of the cycle, it is preferred that the daily
`dosage of 17P-estradiol is 1-3jlg. Preferred salts of estrone include, but are not limited
`
`to the sodium and piperate salt. When conjugated estrogens, USP are used as the
`estrogen, it is preferred that the daily dosage is 0.3-5 mg, with a daily dose of 1.25 mg
`conjugated estrogens, USP being equivalent to a daily dose of 15 jlg ethinyl estradiol.
`It is preferred that the progestin/estrogen combination be administered for 24
`days beginning on day 1 of the menstrual cycle, and following this 24-day period, it is
`preferred that the estrogen be administered for 4 days.
`The following daily dosages of a combination of levonorgestrel and ethinyl
`estradiol are preferred for contraception when administered for 23-25 consecutive days
`beginning on the first day of menses, followed by the administration of ethinyl estradiol
`for 3-5 days. The total administration during each cycle is 28 days. It is preferred that
`the dose of ethinyl estradiol during the 3-5 day period be the same as the dose of ethinyl
`estradiol that was administered during the 24 day period, or lower.
`
`PREFERRED DAlLY DOSAGES
`Last ~-5 Cycle Days
`First 23-25 Cycle Days
`Levonorgestrel
`Ethin:tl Estradiol
`Ethin:tl Estradiol
`5-15 jlg
`100 jlg
`15j.1.g
`5-15 jlg
`15j.lg
`90 jlg
`5-15 j.lg
`75jlg
`15j.!g
`5-15 ).J.g
`60 ).J.g
`15jlg
`5- 15 j.lg
`50 jlg
`15 ).J.g
`5-15 ).J.g
`15 ).J.g
`40 jlg
`5-10 ).J.g
`10 jlg
`100 jlg
`5-10 ).J.g
`10 jlg
`90 jlg
`10 jlg
`5-10 ).J.g
`75jlg
`10 jlg
`5-10 ).J.g
`60).J.g
`5-10 ).J.g
`10 j.lg
`50).J.g
`5-10 j.lg
`10 j.lg
`40 jlg
`
`Regimen
`A
`B
`c
`D
`E
`F
`G
`H
`
`J
`K
`L
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 10
`
`

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`W097141868
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`PCT/US97/07074
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`5
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`10
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`The following daily dosages of a combination of levonorgestrel and ethinyl
`estradiol are more preferred for contraception when administered for 24 consecutive
`days beginning on the first day of menses, followed by the administration of ethinyl
`estradiol for 4 days. The total administration during each cycle is 28 days. Of the
`regimens listed below, Regimens M-0 are more preferred, with Regimen M being most
`preferred.
`
`MORE PREFERRED DAILY DOSAGES
`Last 4 C~cle Days
`First 24 C~cle Da~s
`Levonorgestrel
`Ethin~l Estradiol
`Ethin~l Estradiol
`15 Jlg
`75 ~g
`15 Jlg
`15 Jlg
`15 Jlg
`90~g
`15 ~g
`15 ~g
`100 ~g
`10 ~g
`10 Jlg
`50~g
`15 Jlg
`15 ~g
`60~g
`IO~g
`IO~g
`15 Jlg
`15 Jlg
`
`40~g
`
`75~g
`
`Regjmen
`M
`N
`0
`p
`
`Q
`R
`s
`
`For administration during the first 23-25 days of the menstrUal cycle, it is
`preferred that the combination progestin/estrogen contraceptive be administered in unit
`dosage form i.e., tablet or pill, with each unit providing the entire daily dosage. It is
`preferred that the progestin and estrogen are admixed together in the same dosage unit.
`Such dosage units can be prepared by conventional methodology that is well known to
`one skilled in the an.
`In each dosage unit, the contraceptivcly active progestin and
`estrogen are combined with excipients, vehicles, pharmaceutically acceptable carriers,
`and colorants. For example, the following illustrates an acceptable composition of a
`contraceptive progestin/estrogen combination of this invention.
`
`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 11
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`W097/41868
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`PCT/US97107074
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`EXAMPLE 1
`
`Levonorgestrel, 75J..Lg
`Ethinyl estradiol, 15 J..Lg
`Microcrystaline Cellulose
`Lactose, NF, Spray Dried
`Polacrillin Potassium, NF
`Magnesium Stearate
`Opadry Pink
`Polyethylene Glycol , 1500, Flakes
`Water, Purified, USP
`Wax E (Pharma)
`
`For administration during the last 3-5 days of the menstrual cycle, it is preferred
`that the estrogen be administered in unit dosage form i.e., tablet or pill, with each unit
`providing the entire daily dosage. Such dosage units can be prepared by conventional
`ln each dosage unit, the
`methodology that is well known to one skilled in the art.
`estrogen is combined with excipients, vehicles, pharmaceutically acceptable caniers,
`illustrates an acceptable estrogen
`and colorants.
`For example,
`the following
`composition of this invention.
`
`EXAMPLE2
`
`Ethinyl estradiol, 15 J..Lg
`
`Microcrystaline Cellulose
`Lactose, NF, Spray Dried
`Polacrillin Potassium, NF
`Magnesium Stearate
`Opadry Pink
`Polyethylene Glycol, 1500, Flakes
`Water, Purified, USP
`Wax E (Pharma)
`
`5
`
`10
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`15
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`20
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`25
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`30
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`35
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`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 12
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`

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`W097/41868
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`PCTIUS97/07074
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`- 11 -
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`This invention also provides a contraceptive kit adapted for daily oral
`administration which comprises a total of 28 separate dosage units. In this kit, 23-25
`dosage units each consisting of a combination of progestin at a daily dosage equivalent
`in progestational activity to 40-125 Jlg levonorgestrel and an estrogen at a daily dosage
`equivalent in estrogenic activity to 10-15 J.lg ethinyl estradiol. The remaining 3-5
`dosage units contain an estrogen at a daily dosage equivalent in estrogenic activity to
`5-l5f.Lg ethinyl estradiol. The daily dosage arrangements are preferably arranged in a
`blister pack or in a dial pack type tablet dispenser. Specific referred progestins and
`estrogens and the specifically preferred dosages of each combination dosage unit are
`described above.
`
`5
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`10
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`Petitioner Exhibit 1003
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 13
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`

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`wo 97/41868
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`PCT/US97/07074
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`WHAT IS CLAIMED IS:
`
`- 12-
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`A method of contraception which comprises administering to a female of
`1 .
`child bearing age a combination of a progestin at a daily dosage equivalent in
`progestational activity to 40-125 jlg levonorgestrel and an estrogen at a daily
`dosage equivalent in estrogenic activity to 10-15 jlg ethinyl estradiol for 23-25
`days per menstrual cycle beginning on day 1 of the menstrual cycle; wherein the
`same dosage of the progestin and estrogen combination is administered in each of
`the 23-25 days, followed by the administration of an estrogen at a daily dosage
`equivalent in estrogenic activity to 5-15 jlg ethinyl estradiol for 3-5 days; wherein
`
`the same dosage of the estrogen is administered in each of the 3-5 days; such that
`the number of days of administration of the progestin and estrogen combination
`plus the number of days of administration of estrogen is equal to 28 per menstrual
`cycle.
`
`The method according to claim 1, wherein the progestin is select