EXHIBIT 1009
`
`EXHIBIT 1009
`
`

`

`United States Patent [19J
`Spona et al.
`
`(54) PHARMACEUTICAL COMBINATION
`PREPARATION FOR HORMONAL
`CONTRACEPTION
`
`[75]
`
`inventors: Jiirgen Spona, Vienna, Austria; Ber nd
`Diister bcrg, Berlin, Germany
`
`[73] Assignee: Schering AG, Berlin, Germany
`
`[ * ] Notice:
`
`This patent is subject to a term inal dis(cid:173)
`claimer.
`
`[21] Appl. No.:
`
`08/930,630
`
`[22] PCf Filed:
`
`Apr. 4, 1996
`
`[86] PCf No.:
`
`PCT/EP96/01529
`
`§ 371 Date:
`
`J an. 27, 1998
`
`§ 102(e) Date: J a n. 27, 1998
`
`[87] PCf Pub. No.: W096/32114
`Pe r Pub. Date: Oct. 17, 1996
`Foreign Application Priority Data
`
`[30]
`
`[DE] Germany ........................... 195 13 662
`
`1\pr. 8, 1995
`rnt. C l.6
`...•...•..•••.•. ..•...... .. A61K 31/57; A61K 31/56
`[51]
`[52] U.S. Cl . .......................... 424/464; 514/177; 514/178;
`514/170; 514/182; 514/843; 514/173
`[58] Field of Search ..................................... 424/465, 464;
`514/177, 178, 170, 182, 843, 173
`
`[56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,502,772
`4,921,843
`5,280,023
`
`3/ 1970 ljzerman .
`5/1990 Pasquale .
`1/1994 E.lulicb ct al. .
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005980940A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,980,940
`*Nov. 9, 1999
`
`5,583,129 12/1996 Spona .
`5/1997 Oeuel et at. .
`5,633,242
`5,756,490 5/ 1998 Laclmit et at. .
`Primary Examiner-Thurman K. Page
`Assistanl Examiner----Brian K. Seidlecb
`Auorne)r, Agen1, or Finn-Millen, White, Zelano &
`Branigan
`
`[57]
`
`ABSTRACT
`
`The invention provides a pharmaceutical combination
`preparation witb 1\vo hormone components in a packaging
`unit and intended for time-sequential oral administration,
`comprising a number of daily dosage units physically sepa(cid:173)
`rate and individually removable in tbe packaging unit,
`whereby as a hormonal active ingredient a first hormone
`component contains in combination an estrogen preparation
`aod in at least a dosage thai is sufficieo.t to iobibil ovulatioo
`a gestagen preparation, and as a hormonal active ingredieot
`tbe secood hormooe compooeot coota.ios only ao estrogen
`preparation, whereby tbe first hormone component com(cid:173)
`prises 23 or 24 daily uniL'> and the second hormone 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 da.ys are indicated, and
`the total number of hormone daily units and the active
`iogredient-free daily units or the blank pill days is equal to
`the iotal number of days of the desired cycle, but at least 28
`days in length. Tbis combination preparation is useful for
`fema le birth cootrol, and allows for an estrogen cootent tbat
`is as low as possible in each individual dosage unit aod also
`bas a low total hormone content per administration cycle,
`witb high contraceptive reliability, low incideoce of follicu(cid:173)
`lar development, and satisfactory cycle control, with reliable
`avoidance of intracyclic menstrual bleeding as well as of
`undesirable side-effects.
`
`10 Claims, No Drawings
`
`Petitioner Exhibit 1009
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`5,980,940
`
`1
`PHARMACEUTICAL COMBINATION
`PREPARATION FOR HORMONAL
`CONTRACEPTION
`
`This application is a 371 of PCT/ EP96/01529, filed on 5
`Apr. 4, 1996.
`
`DESCRIPT ION
`lois invention relates to a pharmaceutical combination
`preparation with two hormone components which are manu(cid:173)
`factured physicaUy separately in a packaging unit and arc
`intended for oral administration that is sequential in time and
`which consist in each case of a number of pbysicaUy
`separate and individually removable da ily dosage units
`placed in the packaging un it, w he reby as a hormonal active
`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 or multi-stage structuring and as a hormonal
`active ing:redient the second hormone component contains
`only an estrogen preparation, w hereby the first hormone
`component comprises 23 or 24 daily units and the second
`hormone component comprises 4, 3 or 2 daily units; and
`between these two ho rmone components, 2 or 1 active
`ingredient-free da ily units (placebos) arc present or 2 or 1
`blank pill days are indicated, and the to tal number of
`hormone daily uni ts 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 pacJ..:ing that contains this combination
`preparatio11.
`Oral contraceptives in the form of combination prepara(cid:173)
`tions have been known as so-called onc-pbasc preparations
`since 1960. These preparations consist of 21 active
`ingredient-containing dosage units and 7 active ingredient(cid:173)
`free tablets o r coated tablets. The da ily dosage u nit consists
`of an estrogen and a gestagen. lo one-phase preparations, the
`dose of the active substance that is to be admi niste red daily
`is equally high in each dosage unit. 1( the dose of the active
`components that is to be administered daily is differen t in the
`individual dosage units in individual sections over the
`administration cycle, these arc so-caUed multi-phase prepa(cid:173)
`rations. Triquilar® can be cited as an especially well-known
`representa tive (DE-A 23 65 103).
`lt was possible to reduce the daily gestagen dosage
`continuously through the development of new, more effec(cid:173)
`tive gestagcns than those contained in the first o ral contra(cid:173)
`ceptives. It was also possible to lower the daily estrogen
`dosage, although in most cases ethinylestradiol is still con(cid:173)
`tained as an estrogen in hormonal contraceptives.
`Because of the development of new, improved oral
`contraceptives, the following three points were (and a re)
`emphasized:
`(1) Contraceptive re liabili ty,
`(2) good cycle control, i.e., low incidence of intracyclic
`menstrual bleeding a nd
`(3) a minimum of undesirable side-effects are to be
`ensured.
`Contraceptive reliability is mainly provided by the
`gestagen component. The amount of its da ily dosage corre(cid:173)
`sponds in each case to at least the maximum dose that is
`considered necessary for the gestagen in question to inhibit
`ovulation. The ethinylestradiol that is used in most cases as
`an estrogen in combination preparations is supposed to
`increase tbe ovulation-inhibiting eliect of the gestagen and
`mainly to ensure cycle stabili ty. The daily dose in the case
`
`2
`of eth inylestrad iol administered alone, which must be used
`to inhibit ovulation, is 100 Jtg.
`Combination preparations with the most recent generation
`of gestagens a re, e.g., the one-phase preparation Femovan
`(DE-PS 2546062) o r Marvelon (DE-OS 2361120). Mi lv(cid:173)
`ane® can be men tioned (EP-0 148 724) as an example of a
`multi-phase preparation whose dosage un its contain a
`gestagen of the most recent generation, namely gcstodene.
`In the case of these three-phase preparations, in most cases
`10 4-6 coated tablets are administered in the first phase, in
`which each coated tablet contains an amoun t of estrogen in
`a low dose and a gestagen in a low dose. ln the second phase
`of 4-6 coated tablets, each dosage unit contains a n estrogen
`at a dose that is equal or slightly raised, increased to a
`J5 maximum up to 2-fold, and a gestagen at a dose tha t is equal
`or sligblly raised, increased to a maximum up to 1.5-fold. In
`a third phase of 9-11 units, each coated table t 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
`20 that is further raised, increased to a maximum of 3 times the
`initial value. T he n come 7 pill-free days.
`Recently, multi-phase combination preparations we re also
`proposed which can provide a n extended, i.e., up to 24-day,
`intake of active ingredient-containing dosage uni ts in a
`25 28-day cycle. ln this case, the daily gestageo-dosage amount
`either increases from the first through the second to tbe third
`phase (EP-A 0 491 415), or it decreases (EP-A 0 491 438).
`To complete the 28-day cycle, in the first case 4 blank pill
`days, 4 placebos, or else 4 exclusively gestagen-containing
`30 dosage units follow, or in the second case 4 to 7 blank pill
`days o r 4 to 7 placebos follow.
`The purpose of the development of new oral contracep(cid:173)
`tives with a reduced daily hom10ne dose was to minim ize the
`side-effects that are described in epidemiological studies.
`35 Recent epidemiological da ta point to such a trend toward
`bette r compatibility of low-closed preparations with respect
`to cardiovascular side-effects. [Thorogoocl M ., Oral Contra(cid:173)
`ceptives a nd Cardiovascular Disease: An Epidemiologic
`Overview; Pbarmacoepidemiology and Drug Safety, Vol. 2:
`40 3- 16 (1993); Gerstman, 13. 13.; Piper, J. M .; Tomita, D. K.;
`Ferguson, W. J .; Stadel, B. V.; Lundin, F. E.; Oral Contra(cid:173)
`ceptive Estrogen Dose a nd the Risk of Deep Venous T hrom(cid:173)
`boembolic Disease, Am J E, Vol. L33, No. 1, 32- 36 (1991);
`Liclegaard 0, Oral Contracep tion and Risk of a Cerebral
`45 Thromboembolic Attack: Results 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 S tudy; BMJ,
`Vol. 292, (1986); Mishell, D. R., Oral Contraception: Past,
`50 Prescot and Future Perspectives; lnt J Fertile, 36 S uppl.,
`7-18 (1991)].
`A correlation between the amount of the daily estrogen
`dose a nd the frequency of cardiovascul ar complications is
`assumed.
`The preparation wit h the lowest-dosed amoun t of estrogen
`at this time is marketed as Mercilon® and contains 20 pg of
`ethinylestradiol in combination wi th 150 pg of desogestrel in
`each daily dosage unit over 21 days, followed by a 7-day
`pill-free interval. The cycle control of this preparation is
`60 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
`tha t contai ns 20 pg of etbinylestradiol represents another
`clinically important problem. Obviously, for many women
`65 this very low estrogen dose can result io the maturation of
`follicles, as has been detected in ultrasound studies or
`hormone studies [Lunell, N. 0.; Carlstrom, K.; Zador, G .,
`
`55
`
`Petitioner Exhibit 1009
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`5,980,940
`
`10
`
`30
`
`3
`Ovulation Inhibition with a Combined Oral Contraceptive
`Containing 20 ftg of Ethinylestradiol and 250 pg of
`Levonorgestrcl; Acta Obstet Gynecol Scand Suppl. 88:
`17- 21 (1979); Malt-1-laefeli, M.; Weroer-Zodrow, 1.; Huber,
`P. R., Klinische Erfabrungen mit Mercilon und Marvelon
`unter besondcrcr Berucksichtigung der Ovar-Funktion
`[Clinical Experiments with Mercilon and Marvelon with
`Special Consideration of Ovarian Function); Geburtsh. und
`Frauenheilk. [Childbirth and Gynecology], 51, 35-38,
`Georg Thieme Verlag, Stuttgart-New York (1991); Strobel,
`E., Behandlung mit oralen Kontrazeptiva [Treatment with
`Oral Contraceptives]; Fortscbr. Med. 110 .Jg. No. 20 (1992);
`Letter to Editor, Contraception 45: 519- 521 (1992);
`Teichmann, A T.; Brill, K., Can Dose Reduction of Ethi(cid:173)
`nylestradiol in OCs Jeopardize Ovarian Suppression and
`Cycle Control? Abstract Book, Vlllth World Congress on
`Human Reproduction, Bali, Indonesia (1993)).
`Other preparations have been 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 unit that contains an estrogenic and gestagenic active
`ingredient precedes the intake of exclusively estrogen(cid:173)
`containing dosage units (ljzerman, U.S. Pat. No. 3,502,772:
`Pasquale, U.S. Pat. No. 4,921,843; Kuhl et al., EP-A 0 499
`348). In the case of these preparations, the patient begins
`taking dosage units that contain only one estrogenic active
`ingredient, specifically at a dosage that lies below the
`ovulation-inhibiting dose of the estrogenic component,
`which can lead to folticular development, either as early as
`on the first cycle day (Kuhl) or at the earliest on the second
`cycle day (Pasquale). Follicular development is thought to
`be responsible for breakthrough ovulations (Chowdhury et
`al., '·Escape" Ovulation in Women Due to the Mis.~ing of
`Low-Dose Combination Oral Contraceptive Pills,
`Contraception, 22: 241-247, 1980; Molloy, B. G. et al.,
`"Mis.~d Pill" Conception: Fact or Fiction? Brit. Meet. J. 290,
`1474-1475, 1985). Comraceptive protection is thus jeopar(cid:173)
`dized. The risk of pregnancy is therefore high, especially in
`the case of intake errors below the 20 pg ethinylestradiol
`preparations.
`The object of this invention is to make available a 40
`combination preparation with an estrogen cooteni that is as
`low as pos.sible in each individual dosage unit but also with
`a low total hormone content per administration cycle,
`whereby with high contraceptive reliability, an incidence of
`follicu lar development that is as low as possible and satis- 45
`factory cycle control with reliable avoidance of intracyclic
`menstrual bleeding such as breakthrough bleeding and
`''spottings" as well as as tiute amenorrhea as possible are to
`be achieved and undesirable side-efJects are to be avoided.
`This object is achieved by the provision of the above- so
`indicated two-phase combination preparation, in which
`between the first and the second hormone component, 2 or
`1 active ingredient-free daily units (placebos) are present or
`2 or 1 blank pill days are indicated.
`ln the first phase, beginning with the first day of the cycle, 55
`a dosage unit that contains an estrogen in combination with
`a gestagenic component is administered daily over 23 or 24
`days. Subsequent 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 which an estrogen is administered over 4, 3 or 2 days over 60
`the remaining period in the cycle, which preferably com(cid:173)
`prises 28 days.
`ln this case, the first phase which contains both estrogen
`and gestageo can also be structured io multiple stages in a
`way that is familiar to one skilled in the art.
`When the combination preparation according to the
`invention is taken, the recruitment of the dominant follicle,
`
`4
`wh ich in the spontaneous cycle occurs during the first 6 days
`of the menstrual cycle, is already efficiently suppressed in
`the first administration cycle. Thus, with the combination
`preparation of this invention, fo llicular development can be
`5 suppres.~ed as early as in the first intake cycle, aod thus
`breakthrough ovulations can be avoided, thereby increasing
`contraceptive reliability.
`This is of eminent importance mainly in the case of intake
`errors, namely especially with hormonal contraceptives with
`low daily ethinylestradiol dose amou.nts. Since, in the case
`of 25% of women who take the pill, intake errors (skipping
`dosage units or extending the interval between the daily
`intake of two dosage units to more than 24 hours) are known
`(Finlay, I. G.; Scott, M. B. G.: Pattems of Contraceptive
`Pill-taking in an Inner City Practice. Br. Meet. J. 1986, 293:
`15 601-602), the combination preparation according to the
`invention, if it is used as an ovulation-inhibiting agent,
`increases contraceptive reliability. This is true especially in
`the case of lowest-dosed preparations.
`The increase in the number of dosage units that contain
`20 both estrogen and gestagen above the usual number of 21
`days to 23 or 24 days produces an effective shortening oft he
`pill-free interval, in which the selection of follicles occurs
`with conventional combination preparations as in a normal
`menstrual cycle, and thus follicular development results and
`25 increased endogenic estrogen is formed. These follicles lead
`to breakthrough ovulations, as already stated above. These
`breakthrough ovulations occur to an increased exteot espe(cid:173)
`cially in the case of intake errors.
`The subsequent administration of 2 or 1 hormone-free
`daily uni ts or inclusion of 2 or 1 blank pill days as well as
`the subsequent phase, in which dosage units that contain
`only one estrogenic component as a hormonal active ingre(cid:173)
`dient are administered daily over 4, 3 or 2 days, ensures
`withdrawal bleeding and produces in the subsequent admin(cid:173)
`istration cycle a reduced rate ofintracyclic menstrual bleed-
`35 ing compared with conventional, low-dosed preparations.
`According to a preferred embodiment of the invention,
`tbe estrogen of the first ho rmone component is selected from
`the group of compounds
`J 7~-estradio l ,
`ethinylestradiol and
`17~-estradiol valerate
`and the gestagen is selected (rom the group of compounds
`gestodene,
`levonorgeslrel,
`desogestrel,
`3-ketodesogestrel,
`drosp ironeno ne,
`cyproterone acetate,
`norgestimate and
`oorethisterone and
`the estrogen of the second hormone component is selected
`from the group of compounds
`17~-estradiol,
`etbinylestradiol and
`17~-estradio l valerate.
`According to another preferred variant of this invention,
`tbe estrogeo of tbe first bormooe compooent in each daily
`dosage unit is cootained in a dose of
`1.0 to 6.0 rug of 17~ -estradiol,
`0.015 to 0.025 rug of ethinylestradiol,
`l.O 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,
`
`Petitioner Exhibit 1009
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`5,980,940
`
`5
`0.05 to 0.125 mg of Jevonorgestrel,
`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 norgcstimate,
`0.35 to 0.75 mg of norethisterone.
`The second hormone compouent contains the estrogen in
`each dail y dosage unit preferably in an amount of
`1.0 to 6.0 mg of 17~-estradiol,
`0.002 to 0.04 mg of cthinylcstradiol,
`1.0 to 4.0 mg of 17~ -estradiol valerate.
`According to an espcciaUy preferred embodiment, the
`second hormone component in each daily dosage unit
`contains, as estrogen, ethinylestradiol in an amount of 0.01
`to 0.015 mg.
`A preparation according to this inventioo cootains a total
`of preferably 28 hormone daily units.
`As an esLiogen for both the first and the second hom1one
`component, primarily ethloylestradiol is considered.
`Of the above-mentioned gestagens for the second hor(cid:173)
`mone component, gestodene is to be emphasized; also
`Jevonorgestrel is preferred.
`17~-estradiol valerate, which can be contained as estro- 25
`geo both in the first aod in tbe secood hormone compooent,
`is mentioned only as a possible representative of this 17~­
`estradiol ester; other such homologous esters can also be
`used as estrogenic components w ithin tbe scope of this
`invention.
`The following examples are used to explain this invention
`in more detail:
`
`20
`
`30
`
`6
`mone pause, followed by 4, 3 or 2 daiJy dosage units that
`cootaio exclusively an estrogen (E), during a total of at least
`28 days in the administration cycle. With this combination
`preparation, pronounced ovarian suppression without fre-
`5 quent follicle stimulation, as well as excellent cycle control
`in the case of low daily estrogen dosage, low total amounts
`of estrogen, and low to tal amounts of hormone per admin(cid:173)
`istration cycle can be achieved.
`T he advantages of this combioatioo preparation
`10 (ovu lation-inhibiting agent) according to the invention that
`is administered over generally 28 days compared to the
`previously described preparations, especially those with a
`daily cthinylestradiol dose of less than 30 pg and those with
`a prolonged pill-free interval, can be characterized as fol(cid:173)
`lows:
`15 1. A significantly lower frequency of follicular development
`in the user. 'Ibis 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 of the dominant follicle is suppressed as
`early as in the fi rst cycle by extend:ing the intake of the
`combination 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
`combinatioo dosage aod the two- or o ne-clay pause results
`in considerably improved cycle c<lntrol and a lower
`incidence of side-e[ects, such as headaches, within the
`framework of the premenstrual syodrome.
`4. Other clinical symptoms that arc attributable to greatly
`fluctuating endogenic estrogen levels, such as, for
`example, breast tcnscncs.s, are reduced also clearly owing
`to the considerably greater ovarian suppression.
`5. Better cycle control, specificaUy from the first intake
`cycle, results. Reliable breakthrougb bleeding is ensured
`by the 1- or 2-day intake pause in connection with 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 formu lation of an estrogen and a gcstagen for the
`production of a combination preparation according to the
`invention is carried out completely analogously to tbe way
`already known for conventional oral contraceptives with a
`21-day intake period of the active ingredients, such as, for
`45 example, Femovan® (ethinylestradioVgestodene) or Micr(cid:173)
`ogynoo® ( ethinylestradiol/levonorgestrel). 'lbe formu Jatioo
`of the dosage units that contain only estrogen can also be
`carried out quite analogously to the way !mown for already
`obtained estrogen-containing agents that are intended (or
`so oral use, for example, Progynon C®.
`A packing that contains a combination preparation
`according to tbe invention is also built up analogously to
`packings for already known oral contraceptives that arc on
`the market, with the difference that, instead of the usual 21
`55 dosage units that contain active components, now 23 or 24
`such dosage units, whicb are indicated by 2 or l active
`ingredient-free daily units or 2 or 1 blank pill clays, aod
`another 4, 3 or 2 dosage units that contain only estrogen arc
`present. As a packaging form for the combination prepara(cid:173)
`tion according to the invent'ion, gcncraUy a conventional
`60 blister pack is used, but other packaging forms that are
`known for this purpose are also conceivable.
`To determine equivalent-action amounts of ethinylestra(cid:173)
`diol and 17~-estradiol, on Lhe one hand, and various
`gestagens such as gestodene, levonorgestrel, desogestrel and
`65 3-ketodesogestrel, on the other hand, reference is made to
`the indications given in EP-A-0 253 607. Other details (or
`determining dose equivalents of various gestagcoic active
`
`35
`
`40
`
`EXAMPLES
`
`Day
`Composition
`Day
`Composition
`Day
`Composition
`Day
`Composition
`
`2
`l
`c c
`8
`9
`c c
`15 16
`c c
`22 23
`c c
`c c
`c c
`c c
`
`4
`3
`c c
`10 Jl
`c c
`]7 18
`c c
`24 25
`c
`p
`p
`I'
`c
`I'
`p E
`
`6
`5
`c c
`12
`l3
`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 1
`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 ( • first hormone component)
`E • estrogen (• second hormone component)
`P • placebo or indications of a blank pill day.
`
`The dosage units arc formulatc.d conventiona lly using
`cstrogen-/gestagen- and exclusively estrogen-containing
`tablets, pills, coated tablets, etc. of known adjuvants for
`production.
`Tbe active ingredient-free daily units are formulated
`exclusively from these adjuvants. Instead of 2 or l 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 unit before proceeding
`with the second hormone component with the four-, three- or
`two-day intake.
`1be 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 tbe menstrual cycle (first day
`of menstrual bleeding), a subsequent two- or one-day hor-
`
`Petitioner Exhibit 1009
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`

`5,980,940
`
`7
`ingredients are found in, fo r example, ''Probleme der Dos(cid:173)
`isfindung: Sexua lhormone [Problems of Dose Finding: Sex
`HormonesT'; F. Neumann et a!., in "Arzneimitteltorschung
`[Pharmaceutical Agent Research)" (Drug Research) 27, 2a,
`296-318 (1977) as well as in ·'AkrueUe Eotwicklungen in 5
`der hormonalen Kontrazeption [Current Developments in
`Hormonal Contraception)": H. Kubl
`in "Gynakologe
`[Gynecologist]" 25: 231-240 (1992).
`We claim:
`1. A pharmaceutical combination preparation with two 10
`hormone components that are manufactured physically
`separately in a packaging unit and that are intended for
`time-sequential 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 ovulation of a gestagen 20
`preparation, in either a one-stage or multi-stage
`structure; and
`said second hormone component consisting essentiaiJy
`of ao estrogen preparation, whereby
`the first hormone component comprises 23 or 24 daily 25
`units and
`the second hormone component comprises 4, 3 or 2 daily
`units, and
`between these two hormone components, 2 or 1 active
`ingredient-rree daily unitS are present or 2 or 1 blank
`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
`days in length, and
`whereby the low effective 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
`17B-estradiol,
`ethinylestradiol and
`17~-estradiol valerate
`and tbe gestagen is selected from the group consisting of
`gestodene,
`levonorgestrel,
`desogestrel,
`3-ketodesogestrel,
`drospironenone,
`cyproterone acetate,
`norgestimate and
`noretbisterone and
`the estrogen of the second hormone component is selected
`(rom the group consisting of
`17~-estradio l,
`ethinylestradiol and
`17B-estradiol valerate.
`3. A combinatioo preparation of claim 2 , wherein the
`estrogen of the first hormone component in each daily
`dosage unit is present in a dose of
`1.0 to 6.0 mg of 17~-estradiol ,
`
`35
`
`50
`
`8
`0.015 to 0.025 mg of ethinylestradio l or
`1.0 to 4.0 mg of 17B-estradiol valerate;
`and the gestagen in each daily dosage unit is present in a
`dose of
`0.05 to 0.075 mg of gestoclene,
`0.05 to 0.125 cog of 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 rng of norgestimate or
`0.35 to 0.75 mg of oorethisterone.
`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 ethinylestradiol or
`1.0 to 4.0 mg of 17~-estradio l valerate.
`5. A combination preparation of claim 4, wherein tbe
`second hormone component in each daily dosage unit con(cid:173)
`tains ethinylestradiol in an amount of ().01 to 0.015 mg.
`6. A combination preparation of claim 1, wherein the total
`number of hormone daily units and the active ingredient-free
`daily units or blank pill days is 28.
`7. A method of inducing a contraceplive effect for female
`birth control, comprising administering a sequential daily
`dosage unit of a pharmaceutical combination preparation of
`30 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 high contraceptive reliability, low
`incidence of follicular development, aod satisfactory cycle
`control, with reliable avoidance of intracyclic menstrual
`bleeding and undesirable side-effects.
`9. A method of claim 8, wherein the low e(Iective estrogen
`content of the first hormone component in each daily dosage
`40 unit comprises
`1.0 to 6.0 mg of 1713-estradiol,
`0.015 to 0.025 mg of ethinylestradio l or
`1.0 to 4.0 mg of 17~ -estradiol valerate;
`45 and the low effective gestagen content comprises
`0.05 to 0.075 mg of gestodene,
`0.05 to 0.125 mg of levonorgestrel,
`0.06 to 0.15 mg of desogestrel,
`0.06 to 0.15 mg of 3-ketoclesogestrel,
`1.0 to 3.0 mg of drospirooenone,
`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 noretbisterone; and
`ss the low effective estrogen content of the second hormone
`component comprises
`1.0 to 6.0 mg of 17~-estradiol,
`0.002 to 0.04 mg of ethinylestradiol or
`1.0 to 4.0 mg of 1713-estradiol valerate.
`10. A pharmaceutical combination preparation of claim 1,
`whereby high contraceptive reliability, low incidence of
`follicular development, and satisfactory cycle control, with
`reliable avoidance of intracyclic menstrual bleeding and
`undesirable side-effects are provided.
`
`60
`
`65
`
`* * *
`
`*
`
`Petitioner Exhibit 1009
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`JNVENTOR(S)
`
`: 5.980,940
`:November 9, 1999
`: Jurgen Spona: Bernd Dusterberg
`
`Page I of 1
`
`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 J,
`Line 32, inserr the term "active ingredient-free daily units. and/or blank pill days" after
`" the total number of hormone daily units,".
`
`Signed and Sealed this
`
`Ninth Day of October, 2001
`
`AtTest:
`
`Arre.vting OffiC'er
`
`NICHOLAS P. GODICI
`AC'ting Diraror of thl.' United Stati.'S Patl.'lll and Trademark Offici!
`
`Petitioner Exhibit 1009
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`