United States Patent (l9J
`Spona et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111 111111111111
`US005980940A
`[11] Patent Number:
`(45) Date of Patent:
`
`5,980,940
`*Nov. 9, 1999
`
`[54] PHARMAC EUTICAL C OMBINATlON
`PREPARATION FOR HORMONAL
`CONTRACEI•TLON
`
`5,583,129 12/1996 Spona .
`5,633,242
`5/ 1997 Oeuel et al. .
`5,756.490 5/1998 Lachoit ct al ..
`
`l75J
`
`Inven to rs: .Jiirgen Spona, Vienna, Austria; Bernd
`Oiisterbe rg, Berlin, Germany
`
`[73] Assignee: Schedng AG, Berl in, Germany
`
`[ * l Notice:
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21] Appl. No.:
`
`08/930, 630
`
`(22] PCTFiled:
`
`Apr. 4, 1996
`
`(86] PCT No.:
`
`§ 371 Date:
`
`PCT/EP96/01529
`Jan. 27, 1998
`
`§ 102(e) Date:
`
`.}an. 27, 1998
`
`[87] PCT Pub. No.: W096/32114
`
`PCT Pub. Date: O ct. 17, 1996
`
`(30]
`
`Foreign Application Priority Data
`
`Apr. 8, 1995
`
`[DE] Germany ........................... 195 13 662
`
`Int. C l.6
`............ .... ... ..•. .... A61K 31/ 57; A61K 31/56
`[51 ]
`(52] U.S. C l. .......................... 424/464; 514/ 177; 514/178;
`514/ 170; 51 4/182; 514/843; 514/173
`(58] F ield of Sear ch ..................................... 424/465, 464;
`514/ 177, 178, 170, 182,843, 173
`
`[56]
`
`References C ited
`
`U.S. PATENT DOCUMENTS
`
`3,502,772
`4,921,843
`5,280,023
`
`3/1970
`tjzcrman .
`5/ 1990 Pasquale .
`t/ 1994 Ehrl ich el al. .
`
`Primmy Examiner-Thurman K. Page
`Assistant Examiner~rian K. Seidlecb
`Allomey, Agent, or Firm-Millen, White, Zelano &
`Branigan
`
`[57]
`
`ABST RACT
`
`Tbe invent ion provides a pharmaceutical combination
`preparation with two hormone components in a packaging
`unit and intended for time-sequential oral administration,
`comprising a number of da ily dosage units physically sepa(cid:173)
`rate and individually removable in the packaging unit,
`whereby as a hormonal ac6ve ingrediem a first hormone
`component contains in combination an estrogen preparation
`and in at least a dosage that is sufficient to inhibit ovttlation
`a gestagen preparation, and as a hormonal active ingredie nt
`the second hormone component contains only an estrogen
`preparation, whereby the first hom10ne component com(cid:173)
`prises 23 or 24 da ily u.nits and the second hom10ne com(cid:173)
`ponent comprises 4, 3 or 2 daily units, and between these
`two hormone components, 2 or 1 active ingredient-free daily
`units are present or 2 or 1 blank pill days are indicated, and
`the total number of hormone daily units and the active
`ingredient-free daily units o r tbc bla11k pill days is equal to
`the total number of days of the desired cycle, but at least 28
`days in length. T his combination preparation is usefu.l for
`female birth control, and allows for an estrogen content that
`is as low as possible in each individual dosage unit and also
`bas a low total hormone content per administration cycle,
`with high contraceptive reliability, low incidence of follicu(cid:173)
`lar development, and satisfactory cycle control, w ith reliable
`avoidance of inlracyclic menstrual bleeding as well as of
`undesirable side-effects.
`
`10 C laims, No Dra wings
`
`Joint Trial Exhibit
`
`JTX-016
`
`LUPL0_0019656
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2009, Pg. 1
`
`

`
`5,980,940
`
`1
`PHARMACEUTlCAL COM BINATlON
`PREPARATlON FOR HORMONAL
`CONTRACEPflON
`
`This application is a 371 of PCf/ EP96/01529, filed on 5
`Apr. 4, 1996.
`
`DESCRIPTION
`
`This invention relates to a pharmaceutical combination
`preparation with two hormone components which are manu- 10
`facturcd physically separately in a packaging unit aLJCI arc
`intended for o ral administration that is sequential in time and
`which consist in each case of a number of physically
`separate and individually removable daily dosage units
`placed in the packaging unit, whereby as a hormonal active 15
`ingredient a first hormone component contains in combina(cid:173)
`tion an estrogen preparation and, in a dosage that is sufficient
`at least to inhibit ovulation, a gestagen preparation in eithe r
`one-stage o r multi-stage structuring and as a hormonal
`active ingredient the second hormone component contains 20
`only an estrogen preparation, whereby the first hormone
`component comprises 23 or 24 daily units and the second
`hormone component comprises 4, 3 o r 2 daily units; and
`between these two hormone components, 2 o r 1 active
`ingredient-free daily units (placebos) arc present or 2 or 1 25
`blank pill days are indicated, and the total number of
`hormone daily units and the active ingredient-free daily
`units or the blank pill days is equal to the total number of
`days of the desired cycle, but at least 28-days in length, and
`a corresponding packing that contains this combination 30
`preparation.
`Oral contraceptives in the form o f combination prepara(cid:173)
`tions have been known as so-called one-phase preparations
`since 1960. These preparations consist of 21 active
`ingredient-containing dosage units and 7 active ingredient- 35
`free tablets or coated tablets. The daily dosage unit consists
`of an estrogen and a gestagen. In one-phase preparatioos, the
`dose of the active substance that is to be administered daily
`is equally high in each dosage unit. If the dose of the active
`components that is to be administered daily is different in the 40
`individual dosage units in individual sections over the
`administration cycle, these are so-called multi-phase prepa(cid:173)
`rations. Triquilar® can be cited as an especially well-known
`representative (DE-A 23 65 103).
`It was possible to reduce the daily gestagen dosage 45
`continuously through the development of new, more effec(cid:173)
`tive gestagens than those contained in the first oral contra(cid:173)
`ceptives. It was also possible to lower the daily estrogen
`dosage, although in most cases etbinylestradiol is still con-
`tained as an estrogen in hormonal contraceptives.
`Because of the development of new, improved oral
`contraceptives, the foUowing three points were (and are)
`emphasized:
`(1) Contraceptive reliability,
`(2) good cycle control, i.e., low incidence of intracyclic
`menstrual bleeding and
`(3) a minimum of uodesirable side-effects are to be
`ensured.
`Contraceptive reliability is mainly provided by the 60
`gestageo component. The amount of its daily dosage corre(cid:173)
`sponds in each case to at least the maximum dose that is
`considered necessary for the gestagcn in question to inhibit
`ovulation. Tbe ethinylcstradiol that is used in most cases as
`an estrogen in combination preparations is supposed to 65
`increase the ovulation-inhibiting effect of the gestagen and
`mainly to ensure cycle stability. The daily dose in the case
`
`50
`
`55
`
`2
`of ethioylestradiol administered alone, which must be used
`to inhibit ovulation, is 100 pg.
`Combination preparations with the most recent generation
`of gestagens are, e.g., the one-phase preparation Femovan
`(DE-PS 2546062) or Marvelon (DE-OS 2361120). Milv(cid:173)
`ane® can be mentioned (EP-0 148 724) as an example of a
`muHi-pbase preparation whose dosage units contain a
`gestagen of the most recent generation, namely gcstodene.
`In the case of these three-phase preparations, in most cases
`4-6 coated tablets are administered in the .first phase, in
`which each coated tablet contains an amount of estrogen in
`a low dose and a gestageo in a low dose. In the second phase
`of 4-6 coah;d tablets, each dosage unit contains an estrogen
`at a dose that is equal o r slightly raised, increased to a
`maximum up to 2-folcl, aod a gestagen at a dose that is equal
`or slightly raised, iocreased to a maximum up to 1.5-fold.ln
`a third phase of 9-11 units, each coated tablet contains an
`estrogen at a dose that is equal or is again lowered, reduced
`to a maximum of the initial value, and a gestagen at a dose
`that is further raised, increased to a maximum of 3 times the
`initial value. Then come 7 pill-free clays.
`Recently, multi-phase combination preparations were also
`proposed whic h can provide an extended, i.e., up to 24-day,
`intake of active ingredient-containing dosage units in a
`28-day cycle. In this case, the daily gcstagen-dosage amount
`either increases from the first through the second to the third
`phase (EP-AO 491 415), or it decreases (EP-A 0 491 438).
`lb complete the 28-day cycle, in tbe first case 4 blank pill
`days, 4 placebos, or else 4 exclusively gestagen-containing
`dosage units follow, o r in the second case 4 to 7 blank pill
`days or 4 to 7 placebos follow.
`The purpose of the development of new o ral contracep(cid:173)
`tives with a reduced daily hormone dose was to minimize the
`side-effects that are described in epidemiological studies.
`Recent epidemiological data point to such a trend toward
`better compatibility o( low-dosed preparations witb respect
`to cardiovascular side-effects. [Thorogood M ., Oral Contra(cid:173)
`ceptives and Cardiovascular Disease: An Epidemiologic
`Overview; Pbarmacoepidemiology and Drug Safety, Vol. 2:
`3-16 (1993); Gerstman, B. B.; Piper, J. M.; Tomita, D. K.;
`Ferguson, W. J.; Stadel, B. V.; Lundin, F. E.; Oral Contra(cid:173)
`ceptive Estrogen Dose and the Risk of Deep Venous Thro m(cid:173)
`boembolic Disease, Am J E, Vol. 133, No. 1, 32-36 (1991);
`Lidegaard 0, Oral Contraception and Risk of a Cerebral
`Thromboembolic Attack ResuUs of a Case-Control Study:
`BMJ Vol. 306, 956-63 (1993); Vessey, M.; Mant, D.; Smith,
`A; Yeates, D., Oral Contraceptives and Venous Throm(cid:173)
`boembolism: Findings in a Large Prospective Study; BMJ,
`Vol. 292, (1986); Misbell, D. R., Oral Contraception: Past,
`Present and Future Perspectives; lot J Fertile, 36 Suppl.,
`7-18 (1991)).
`A correlation between the amoun t of the daily estrogen
`dose and the frequency of cardiovascular complications is
`assumed.
`Tbc preparation with the lowest-dosed amount of estrogen
`at this time is marketed as Mercilon® and contains 20 ,ug of
`ethinylestradiol in combination with 150,ugofdcsogestrel in
`each daily dosage unit over 21 days, followed by a 7-day
`pill-free interval. The cycle control of this preparation is
`somewhat less good than that of preparations with a higher
`estrogen dose. The observation, confirmed in several
`studies, of slighter ovarian suppression for the preparation
`that contains 20 pg of ethinylestradiol represents another
`clinically important problem. Obviously, for many women
`this very low estrogen dose can result in the maturation of
`follicles, as bas been detected in ultrasound studies or
`hormone studies [Lunell, N. 0.; Carlstrom, K.; Zador, G.,
`
`LUPL0_0019657
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2009, Pg. 2
`
`

`
`5,980,940
`
`10
`
`20
`
`3
`Ovu latioo lnbibitioo with a Combioed Oral Cootraceptive
`Cootaioing 20 pg of Etbinylestradiol and 250 ,ug of
`Lcvonorgestrel; Acta Obstet Gynecol Scand Suppl. 88:
`17- 21 (1979); Mall-Haefeli, M.; Weroer-Zodrow, 1.; Huber,
`P. R., Kliniscbe Erfabrungeo mit Mercilon unci Marvelon
`uoter besooderer Berucksichtiguog der Ovar-Fuoktioo
`[Clioical Experimeots with Merciloo aod Marvelon with
`Special Consideratioo of Ovarian Function]; Geburtsb. und
`Frauenbeilk. [Childbirth and Gynecology) , 51, 35-38,
`Georg Thieme Verlag, S tuttgart-New York (1991); Strobel,
`E., Behandlung mi t oralen Kontrazeptiva [Treatment wit h
`Oral Contraceptives); Fortscbr. Med. 110 Jg. No. 20 (1992);
`Leuer to Editor, Contraception 45: 5 l 9-52l (1 992);
`Teichmann, A T.; Brill, K., Can Dose Reduction of Etbi(cid:173)
`nylestradiol in OCs Jeopardize Ovarian Suppression and 15
`Cycle Control? Abstract Book, VTlltb World Congress on
`Human Reproduction, Bali, Iodooesia (1993)).
`Other preparatioos have beeo described which contain an
`estrogenic and a gestagenic active ingredient and which
`generally are administered over 21 days in constant amounts
`in each individual dosage unit, in which the intake of this
`dosage un it that contains an estrogenic and gestagenic active
`ingrerlient precedes the intake of exclusively estrogen(cid:173)
`containing dosage units (fjzerman, U.S. Pat. No. 3,502,772:
`Pasquale, U.S. Pat. No. 4,921,843; Kuhl et a!., EP-A 0 499
`348). lo the case of these preparatioos, the patient begins 25
`laking dosage units that cootain only ooe estrogenic active
`ingredient, spedfically at a dosage that lies below the
`ovulation-inhibiting dose of the estrogenic component,
`which can lead to follicular development, e ither as early as
`on lhe first cycle day (Kubl) or at the earliest on the secood 30
`cycle day (Pasquale). Follicular development is though t to
`be responsible for breakthrough ovulations (Chowdhury et
`al., "Escape" Ovulatioo io Womeo Due to the Missiog of
`Low-Dose Combinatioo Oral Contraceptive Pills,
`Cootraceptioo, 22: 241-247, 1980; Molloy, B. G. et al., 35
`" Missed Pill" Conception: Fact or Fiction? Brit. Med. J. 290,
`]474-1475, 1985). Contraceptive protection is th us jeopar(cid:173)
`dized. The risk of pregoaocy is therefore high, especially io
`the case of intake errors below the 20 11g etbioylestradiol
`preparations.
`'fbe object of Ibis invention is to make available a 40
`combination preparation with an estrogen content that is as
`low as possible in each iodividual dosage unit but also wi th
`a low total hormone conteot per administration cycle,
`whereby with high contraceptive reliability, au incidence of
`follicular developmeo t that is as low as possible aod satis- 45
`factory cycle cootrol with reliable avoidaoce of iotracyclic
`menstrual bleeding such as breakthrough bleediog and
`"spottings" as well as as lillie amenorrhea as possible are to
`be achieved and undesirable side-effects arc to be avoided.
`Ibis object is achieved by the provision of the above- so
`iodicated two-phase combioation preparation, in which
`between the first aod the second hormone component, 2 or
`1 active ing:redieot-free daily units (placebos) are preseot or
`2 or 1 blank pill days are indicated.
`lo the first phase, beginning with the first day of the cycle, 55
`a dosage unit tha t contains an estrogen in combioation wi th
`a gestageoic compooeot is admioistered daily over 23 or 24
`days. Subsequeot to these 23 or 24 daily dosage units, 2 or
`1 active ingredient-free daily units are administered or 2 or
`1 blank pill days are indicated. After that is the second phase,
`in w hich an estrogen is admi nistered over 4, 3 or 2 days over 60
`the remainiog period in the cycle, which preferably com(cid:173)
`prises 28 days.
`fn this case, the first phase which contains both estrogen
`and gestageo cao also be structured io multiple stages io a
`way that is familiar to one skilled io the art.
`When the combination preparation according to the
`invention is taken, the recruitment of the dominant follicle,
`
`4
`which io the spontaoeous cycle occurs during the first 6 days
`of the menstrual cycle, is already efficiently suppressed in
`the first admioistration cycle. Thus, with the combination
`preparation of this inventioo, follicular development can be
`suppressed as early as in the first intake cycle, and thus
`breakthrough ovulatioos can be avoided, thereby increasing
`contraceptive reliability.
`This is of emioeot importance mainly io the case of iotake
`errors, oamely especially with hormonal contraceptives with
`low daily ethinylestradiol dose amounts. Since, in the case
`of 25% of women who take the pill, intake errors (skipping
`dosage units or exteoding the interval betweeo the daily
`intake of two dosage units to more than 24 hours) are known
`(Finlay, f. G.; Scott, M. B. G.: Patterns of Contraceptive
`Pill-taking in an loner City Practice. Br. Med. J. 1986, 293:
`601- 602), the combination preparation according to the
`iovention, if it is used as an ovuJation-inhibiting agent,
`increases coolraceptive reliability. This is true especially io
`the case of lowest-dosed preparations.
`The increase in the number of dosage units that cootain
`both estrogeo aod gestagen above the usual number of 21
`days to 23 or 24 days produces an effective shortening of the
`plll-free interval, in which the selection of follicles occurs
`with cooventional combination preparations as in a normal
`menstrual cycle, and thus fo llicular developmeot results and
`increased eodogenic estrogeo is formed. These follicles lead
`to breakthrough ovulations, as already stated above. These
`breakthrough ovulations occur to an increased extent espe(cid:173)
`cially in the case of intake errors.
`T he subsequent administration of 2 or 1 hormone-free
`daily units or inclusion of 2 or 1 blank pill days as well as
`the subsequent phase, in which dosage units that cootaio
`only one estrogenic component as a horn10nal aclive ingre(cid:173)
`dient are admioistered daily over 4, 3 or 2 days, eosures
`withdrawal bleeding aod produces io the subsequent admio(cid:173)
`istration cycle a reduced rate of intracyclic menstrual bleed(cid:173)
`ing compared with conveotional, low-dosed preparations.
`According to a preferred embodiment of the inven tion,
`the estrogen of the first hormone component is selected from
`the group of compounds
`17P-estradiol,
`etbinylestradiol and
`17B-estradiol valerate
`and the gestagen is selected from tbe group of compounds
`gestodene,
`levonorgeslrel,
`desogestrel,
`3-ketodesogestrel,
`drospirooeoooe,
`cyproterone acetate,
`norgestimate aod
`noretbisterone and
`the estrogen of the second hormone component is selected
`from the group of compounds
`17P-estradiol,
`etbinylestradiol aocl
`17B-estradiol valerate.
`According to another preferred variant of Ibis invention,
`the estrogen of the first hormone component io each daily
`dosage unit is container! io a dose of
`1.0 to 6.0 mg of .1 7~-estradiol,
`O.Dl5 to 0.025 mg of ethinylestradiol,
`J .0 to 4.0 mg of 17~-estradiol valerate
`65 and the gestagen in each daily dosage unit is contained in a
`dose of
`0.05 to 0.075 mg of gestodene,
`
`LUPL0_0019658
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`Mylan v. Warner Chilcott IPR2015-00682
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`

`
`5,980,940
`
`5
`0.05 to 0.125 rug of levonorgestrel,
`0.06 to 0.15 rug of desogestrel,
`0.06 to 0.15 rug of 3-ketodesogestrel,
`1.0 to 3.0 mg of drospironenone,
`1.0 to 2.0 mg of cyproterone acetate,
`0.2 mg to 0.3 rug of norgestimate,
`0.35 to 0.75 mg of norethisterooe.
`The second hormone component contains the estrogen in
`each daily dosage uni t preferably in an amount of
`1.0 to 6.0 mg of 1 7~-estradiol,
`0.002 to 0.04 mg of ethinylestradiol,
`1.0 to 4.0 rng of 17~-est radiol valerate.
`According to an especially preferred embodiment, the 15
`second hormone component in each daily dosage unit
`contains, as estrogen, ethinylestradiol in an amoun t of 0.01
`to O.DlS mg.
`A preparation according to this invention contains a total
`of preferably 28 hormone daily units.
`As an estrogen for both the first and the second hormone 20
`component, primarily ethinylestradiol is considered.
`Of the above-mentioned gestagens for the second hor(cid:173)
`mone component, geslodene is to be emphasized; also
`levonorgestrel is preferred.
`17~-est radiol valerate, which can be contained as estro- 25
`gen both in the first and in the second hormone component,
`is mentioned only as a possible representative of IIJ.is 17~ ­
`estradiol ester; other such homologous esters can also be
`used as estrogenic components within the scope of this
`invention.
`1l1e following examples are used to ex"Plain this invention
`in more detail:
`
`30
`
`EXAMPLES
`
`Day
`Composition
`Day
`Composition
`Day
`Composition
`Day
`Composition
`
`]
`
`c c
`8
`9
`c c
`15 16
`c c
`22 23
`c c
`c c
`c c
`c c
`
`_,
`4
`c c
`JO Jl
`c c
`J7
`JS
`c c
`24 25
`c
`I'
`p
`p
`c p
`r E
`
`5
`6
`c c
`12 J3
`c c
`19 20
`c c
`26 27
`p E
`E E
`E E
`E E
`
`7
`c
`14
`c
`21
`c
`28
`E Example J
`E Example 2
`E Example 3
`E Example 4
`
`Day ~ Day of the menstrual cycle, day l is the first day of bleeding
`C • combination of estrogen and gestagen (• filllt hormone component)
`E • estrogen (• second hormone component)
`t' = placebo or indications of a blank pill day.
`
`'l11e dosage units arc formu lated conventionally using
`estrogen-/gestagen- and exclusively estrogen-containing
`tablets, pills, coated tablets, etc. of known adjuvants for
`production.
`The active ingredient-free daily units are formu lated
`exclusively from tbese adjuvants. Instead of 2 or 1 active
`ingredient-free daily units, indications can also be contained
`in the combination preparation according to the invention
`that signal (to the user) that the intake of the first hormone
`component is to be followed by a two- or one-day pause
`without the intake of each dosage uni t before proceeding
`with the second hormone component wi tb the four-, three- or
`two-day intake.
`"ll1e combination preparation according to the invention is
`used in female contraception by administering the daily
`dosage units of the first hormone component over 23 or 24
`days, beginning on day one of the menstrual cycle (first day
`of menstrual bleeding), a subsequent two- or one-day hor-
`
`6
`mone pause, followed by 4, 3 or 2 daily dosage units that
`contain exclusively an estrogen (E), during a total of at least
`28 days in the administrat ion cycle. With this combination
`preparation, pronounced ovarian suppression without fre(cid:173)
`quent follicle stimulation, as welJ as excellent cycle control
`in the case of low dai ly estrogen dosage, low total amounts
`of estrogen, and low total amounts of hormone per admin(cid:173)
`istration cycle can be achieved.
`The advan tages of this combination prepa ration
`10 (ovulation-inhibiting agent) according to the invention that
`is administered over generally 28 days compared to the
`previously described preparations, especially those with a
`daily ethinylestradiol dose of less than 30 ,ug and those with
`a prolonged pill-free interval, can be characterized as fol(cid:173)
`lows:
`l. A significantly lower frequency of follicu lar development
`in the user. 1l1is means a lower risk of breakthrough
`ovulation and thus greater contraceptive reliability, espe(cid:173)
`cially in the case of intake errors.
`2. The recruitment o[ the dominant follicle is suppressed as
`early as in the fi rst cycle by extending the intake of the
`combinat:ion to 23 or 24 days.
`3. The intake of 4, 3 or 2 daily estrogen dosage units each
`in connection with the administration of the 23- or 24-day
`combination dosage and the two- or one-day pause resulis
`in considerably improved cycle control and a lower
`incidence of side-effects, such as headaches, within the
`framework of the premenstrual syndrome.
`4. Other c lin.ical symptoms that are attributable to greatly
`fluctuating endogenic estrogen levels, such as, for
`example, breast tenseness, are reduced also clearly owing
`to the considerably greater ovarian suppression.
`5. Better cycle control, specifically from the first intake
`cycle, results. Reliable breaktbrough bleeding is ensured
`by the 1- or 2-day intake pause in connection wi th the
`administration of 23- or 24-day combination dosage and
`before the intake of 4, 3 or 2 daily estrogen dosage units
`each, and thus the rate of amenorrhea is reduced.
`6. Improved cycle control and the very low incidence of
`amenorrhea results in higher compliance.
`The formula tion of an estrogen and a gestagen for the
`production of a combination preparation according to the
`invention is carried out completely analogously to the way
`already known for conventional oral contraceptives with a
`21-day intake period of the active ingredients, such as, for
`example, Femovan® (ethinylestradio Vgestodene) or Micr(cid:173)
`ogynon® (ethinylestradiol/levonorgestrel). lne formulation
`of the dosage units that contain only estrogen can also be
`carried out quite analogously to the way known for already
`obtained estrogen-containing agents that arc intended for
`so oral use, for example, Progynon C®.
`A packing that contains a combination preparation
`according io the invention is also built up analogously to
`packings for al ready known oral contraceptives tha t are on
`the market, with tbe difference that, instead of the usual 21
`55 dosage units that contain active components, now 23 or 24
`such dosage units, which are indicated by 2 or L active
`ingredient-free daily units or 2 or 1 blank pill days, and
`another 4, 3 or 2 dosage units that contain only estrogen are
`present. As a packaging form for the combination prepara(cid:173)
`tion according to the invention, generally a conventional
`60 blister pack is used, but other packaging forms that arc
`known for tbis purpose are also conceivable.
`To determine equivalent-action amounts of ethinylestra(cid:173)
`diol and 17~-estradiol, on the one hand, and variotL<;
`gestagens such as gestodene, levonorgestrel, desogestrel and
`65 3-ketodesogestrel, on the other band, reference is made to
`the indications given in EP-A-0 253 607. Other details [or
`determining dose equivalents of various gestageoic active
`
`35
`
`40
`
`45
`
`LUPL0_0019659
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2009, Pg. 4
`
`

`
`5,980,940
`
`8
`0.015 to 0.025 mg of ethinylestradiol or
`1.0 to 4.0 rug of 17~-estracliol va.lerate;
`and the gestagcn in each daily dosage unit is present in a
`dose of
`0.05 to 0.075 mg of gestodene,
`0.05 to 0. 125 mg or levonorgestrel,
`0.06 to 0.15 mg of desogestrel,
`0.06 to 0.15 mg of 3-ketodesogestrel,
`1.0 to 3.0 mg of drospironenone,
`1.0 to 2.0 mg of cyproterone acetate,
`0.2 mg to 0.3 mg of norgestimate or
`0.35 to 0.75 mg of norethisterone.
`4. A combination preparation of claim 2, wherein the
`second hormone component in each daily dosage unit is
`present in an amount of
`1.0 to 6.0 mg of 17~-estradiol,
`0.002 to 0.04 mg of elhioylestradiol or
`1.0 to 4.0 mg of 17~-estradiol valerate.
`5. A combination preparation of claim 4, wherein the
`second hormone component in each daily dosage unit con(cid:173)
`tains ethinylestradiol in an amount of 0.0 1 to 0.015 mg.
`6. A combination preparation of claim 1, wherein the total
`number of hormone clai.ly units and the active ingredient-free
`daily units or blank pill clays is 28.
`7. A method of inducing a contraceptive effect for female
`birth control, comprising administering a sequential daily
`dosage unit of a pharmaceutical combination preparation of
`claim 1, in the sequence set forth.
`8. A method of claim 7, wherein each individual dosage
`unit bas a very low effective estrogen content and a very low
`effective total hormone content per administration cycle, and
`whereby the low effective estrogen content and low total
`hormone content provides higb contraceptive reliability, low
`incidence of fo llicular development, and satisfactory cycle
`control, with reliable avoidance of intracyclic menstrual
`bleeding and undesirable side-effects.
`9. A method of claimS, wherein the low effective estrogen
`content of the .first hormone component in each daily dosage
`unit comprises
`1.0 lo 6.0 mg of 17~-estradiol,
`O.Q15 to 0.025 mg of ethinylestradiol or
`L.O to 4.0 mg of 17~-estradiol valerate;
`45 and the low eJiective gestagen content comprises
`0.05 to 0.075 mg of gestodene,
`0.05 to 0.125 mg of levonorgestrel,
`0.06 to 0.15 rug of desogestrel,
`0.06 to 0.15 mg of 3-ketodesogestrel,
`1 .0 to 3.0 mg of clrospironenone,
`1.0 to 2.0 mg of cyproterone acetate,
`0.2 mg to 0.3 mg of norgestimate or
`0.35 to 0.75 mg of norethisterone; and
`ss the low ctiective estrogen content of the second hormone
`component comprises
`1.0 to 6.0 mg of 17f3-estradiol,
`0.002 to 0.04 mg of ethioylestradiol or
`1.0 to 4.0 mg of 17~-estradiol valerate.
`10. A pharmaceutical combination preparation of claim 1,
`whereby bigh contraceptive reliabiliiy, low incidence of
`follicular development, and satisfactory cycle control, with
`reliable avoidance of intraeyclic menstrual bleeding and
`undesirable side-effects are provided.
`
`35
`
`40
`
`so
`
`7
`ingredients are found in, for example, "Probleme der Dos(cid:173)
`isfiodung: Sexualhormooe [Problems of Dose Finding: Sex
`Hormones]"; F. Neumann et al., in '"Arzneimittelforsebung
`(Pharmaceutical Agem Research]" (Drug Research) 27, 2a,
`296-318 (1977) as well as in "AktueiJe Eotwicklungeo in 5
`der hormonalen Kontrazeption (Current Developments in
`Hormonal Contraception]" : H. Kubl
`in
`''Gyoii.kologe
`[Gynecologist]" 25: 231-240 (1992).
`We cla·im:
`l. A pharmaceutical combination preparation with two 10
`hormone components that are manufactured physically
`separately in a packaging unit and that are intended fo r
`time-sequemial oral administration, comprising
`a number of daily dosage units of a first and a second
`hormone component that arc placed physically sepa- 15
`rately and individually removable in the packaging
`unit, wherein
`said first hormone component comprises, in
`combination, an estrogen preparation and a dosage
`effective to inhibit ovu lation of a gestagen 20
`preparation, in either a one-stage or multi-stage
`structure; and
`said second hormone component consisting essentiaJJy
`of an estrogen preparation, whereby
`the first hormone component comprises 23 or 24 daily 25
`units and
`U1e second hormone component comprises 4, 3 or 2 daily
`units, and
`between these two hormone components, 2 or 1 active
`ingredieot-free daily units are present or 2 or 1 blank 30
`pill days are indicated, and
`the total number of hormone daily units is equal to the
`total number of days of the desired cycle, but at least 28
`clays in length, and
`whereby the low etl'ective estrogen content and low total
`hormone content provides high contraceptive reliability, low
`incidence of follicular development, and satisfactory cycle
`control, with reliable avoidance of intracyclic menstrual
`bleeding and undesirable side-effects.
`2. A combination preparation according of claim 1,
`wherein the estrogen of the first hormone component is
`selected from the group consisting of
`17~-estradiol ,
`ethinylestradiol and
`17~-estradiol valerate
`and the gestagen is selected from the group consisting of
`gestoclene,
`levonorgestrel,
`desogesrrel,
`3-ketodesogestrel,
`drospironenone,
`cyproterone acetate,
`norgeslimate and
`norethisterone and
`the estrogen of the second hormone component is selected
`from the group consisting of
`1 7~-est radiol ,
`ethinylestradiol and
`17~-estradiol valerate.
`3. A combination preparation of claim 2, wherein the
`estrogen of the first hormone component in each daily
`dosage uni t is present in a dose of
`1.0 to 6.0 mg of 1 7~-estradiol,
`
`60
`
`65
`
`* * * * *
`
`LUPL0_0019660
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2009, Pg. 5
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DA TED
`INVENTOR($)
`
`: 5,980,940
`: November 9, J999
`: Jurgen Spona: Bernd Dusterberg
`
`Page I of l
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`Colunm 7. claim 1.
`L ine 32, insert the term "active ingredient-free daily units. and/or blank piiJ days" after
`"the total number of hormone daily units,".
`
`Signed and SeaJed this
`
`Ninth Day of October, 200 l
`
`Arrtsr:
`
`Am:sring Offil'er
`
`NICHOLAS ? . GODICI
`Acting Director of t/11: Unittd Stares Par em and Tnulmwrk Oj]iu
`
`LUPL0_0019661
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2009, Pg. 6