EXHIBIT 1008
`
`EXHIBIT 1008
`
`

`

`II 1111111111111
`
`US005756490A
`[111 Patent Number:
`[451 Date of Patent:
`
`5,756,490
`May 26, 1998
`
`United States Patent [191
`Lacbnit et al.
`
`[54) PHARMACEUTICAL COMBINATION
`PREPARATION FOR HORMONAL
`CONTRACEPI'ION
`
`[75]
`
`Inventors: Ursula Lachnit; Bernd Diisterberg.
`both of Berlin. Germany; Jiirgen
`Spooa. Wein. Australia
`
`[73] Assignee: Schering Aktiengesellsdtaft. Berlin.
`Germany
`
`[21] Appl. No.:
`
`718,401
`
`[22] PCr Filed:
`
`Mar. 30, 1995
`
`[86) PerNo.:
`
`PCTJEP95/01190
`
`Dec. 16, 19%
`§ 371 Date:
`§ 102(e) Date: Dec. 16, 19%
`[87] PCr Pub. No.: W095/2673()
`
`PCr Pub. Date: Oct. 12, 1995
`
`[30]
`
`Foreign Application Priority Data
`
`[DE] Germany .......................... 44 11 585.7
`
`Mar. 30, 1994
`Int. CL 6
`[51]
`..................................................... A61K 31/56
`[52] U.S. Cl .............................................. 517117t; 514/843
`[58] Field of Search ...................................... 514/170. 843
`
`[56]
`
`References Cited
`U.S. PATENf DOCUMENTS
`
`5/1990 Pasquale ................................. 5141170
`4,921,843
`5,262,408 11/1993 Bergink. ................................... 514/182
`5,280,023
`1/1994 Ehrlich eta! ........................... 5141177
`
`Primary Examiner-Kimberly Jordan
`Attorney. Agent, or Firm-Millen. White. Zelano &
`Branigan. P.C.
`
`[57]
`
`ABSTRACT
`
`A pharmaceutical combination preparation with two hor(cid:173)
`mone components that are manufactured physically sepa(cid:173)
`rately in a packaging unit and that are intended for time(cid:173)
`sequential oral administration. which in each case consist of
`a number of dally dosage units that are placed physically
`separately and are individually removable in the packaging
`unit. As a hormonal active ingredient. a first hormone
`component contains in combination an estrogen preparation
`and. in at least a dosage that is sufficient to inhibit ovulation.
`a gestagen preparation. and as a hormonal active ingredient
`the second hormone component contains only an estrogen
`preparation. The first hormone component comprises 23 or
`24 daily units and the second hormone component com(cid:173)
`prises 4 to 10 daily units. 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. This combination preparation
`is used for female birth control. and allows for an estrogen
`content that is as low as possible in each individual dosage
`unit and also has a low total hormone content per adminis(cid:173)
`tration cycle. with high contraceptive reliability. low inci(cid:173)
`dence of follicular development. and satisfactory cycle
`control. with reliable avoidance of intracyclic menstrual
`bleeding as well as of undesirable side-effects.
`
`3.5f1}..772 3/1970 Ijz.erman ................................. 4241239
`3,639,600 2/1972 Hendrix .................................. 4241242
`
`13 Claims, No Drawings
`
`Petitioner Exhibit 1008
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`5,756,490
`
`1
`PHARMACEUTICAL COMBINATION
`PREPARATION FOR HORMONAL
`CONTRACEPTION
`
`DESCRIPTION
`This invention relates to a phannaceutical combination
`preparation with two hormone components which are manu(cid:173)
`factured physically separately in a packaging unit and are
`intended foe oral 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
`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 either
`one-phase or multiple-phase structuring and as a hormonal
`active ingredient the second hormone component contains
`only an estrogen preparation. whereby the first hormone
`component comprises 23 or 24 daily units and the second
`hormone component comprises 4 to 8 daily units; the daily
`units of the first hormone component do not contain the
`combination of a biogenic estrogen and a synthetic estrogen.
`and the total nwnber of hormone daily units 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 preparation.
`Oral contra.ceptives in the form of combination prepara(cid:173)
`tions have been known as so-called one-phase preparations
`since 1960.
`These preparations consist of 21 active ingredient(cid:173)
`containing dosage units and 7 active ingredient-free tablets
`or coated tablets. The daily dosage unit consists of an
`estrogen and a gestagen. In one-phase preparations. 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 di1ferent in the
`individual dosage units in individual sections ovec the
`administration cycle. these are so-called multiple-phase
`preparations. Triquilar® can be cited as an especially well(cid:173)
`known representative (DE-A 23 65 103).
`The daily gestagen dosage has been continuously reduced
`through the development of new, more effective gestagens
`than those contained in the first oral contraceptives. It was
`also possible to lowec. the daily estrogen dosage, although in
`most cases ethinylestradiol is still contained as an estrogen
`in hormonal contraceptives.
`Because of the development of new. improved oral
`contraceptives. the following 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 undesirable side-effects are to be
`ensured.
`Contraceptive reliability is mainly provided by the
`gestagen 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 gestagen in question to inhibit
`ovulation. The ethinylestradiol that i s used in most cases as
`an estrogem in combination preparations is supposed to.
`increase the ovulation-inhibiting effect of the gestagen and
`mainly to ensure cycle stability. The daily dose in the case
`of ethinylestradiol administered alone. which must be used
`to inhibit ovulation. is 100 Jig.
`Combination preparations with the most recent generation
`of gestagens are. e.g .. the one-phase preparation Femovan
`
`2
`(DE-PS 2546062) or Marvelon (DE-OS 2361120). Milv(cid:173)
`ane® can be mentioned (EP-0 148 724) as an example of a
`multiple-phase preparation whose dosage units contain a
`gestagen of the most recent genecation. namely gestodene.
`s 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 gestagen in a low dose. In the second phase
`of 4-.(5 coated tablets. each dosage unit contains an estrogen
`10 at a dose that is equal or slightly raised. increased to a
`maximum up to 2-fold. and a gestagen at a dose that is equal
`or slightly raised. increased to a rnaJtimum up to 1.5-fold. In
`a third phase of 9-11 units. each coated tablet contains an
`estrogen at a dose that is equal or is further raised. increased
`15 to a maximum of 3 times the initial value. Then come 7
`pill-free days.
`Recently. multiple-phase combination preparations were
`also proposed which can provide an extended. i.e .. up to
`24-day. intake of active ingredient-containing dosage units
`20 in a 28-day cycle. In this case. the daily gestagen-dosage
`amount either increases from the first through the second to
`the third phase (EP-A 0 491 415). or it decreases (EP-A 0
`491 438). To complete the 28-day cycle. 4 blank pill days.
`4 placebos. or else 4 exclusively gestagen-containing dosage
`2S units follow. or in the second case 4 to 7 blank pill days oc
`4 to 7 placebos follow.
`The purpose of the development of new oral contracep(cid:173)
`tives with a reduced daily hormone dose was to minimize the
`side- effects that are described in epidemiological studies.
`30 Recent epidemiological data point to such a trend toward
`better compatibility of low-dosed preparations with respect
`to cardiovascular side-effects. [Tborogood M .. Oral Contra(cid:173)
`ceptives and Cardiovascular Disease: An Epidemiologic
`Overview; Phannacoepidemiology and Drug Safety. Vol. 2:
`35 3-16 (1993); Gerstman B. B .. Piper J. M .. Tomita D. K..
`Ferguson W. J .• Stadel B. V .. Lundin F. E.; Oral Contracep(cid:173)
`tive Estrogen Dose and the Risk of Deep Venous 'Throm(cid:173)
`boembolic Disease. AmJ E Vol. 133. No. 1. 32-36 (1991);
`Lidegaard 0 .. Oral Contraception and Risk of a Cerebral
`40 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(cid:173)
`'Thromboembolism: F'rndings in a Large Prospective Study;
`BMJ. Vol. 292. (1986); Mishell D. R .. Oral Contraception:
`45 Past. Present and Future Perspectives; lot J Fertile. 36
`Suppl.. 7-18 (1991)].
`A correlation between the amount of the daily estrogen
`dose and the frequency of cardiovascular complications is
`assumed.
`The preparation with the lowest-dosed amount of estrogen
`at this time is marketed as Mercilon® and contains 20 J.l& of
`ethinylestradiol in combination with 150 j.lg of desogestrel in
`each daily dosage unit over 2 1 days. followed by a 7-day
`pill-free interval. The cycle control of this preparation is
`55 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 IJ& of ethinylestradiol represents another
`clinically important problem. Obviously. for many women
`60 this very low estroge.n dose can result in the maturation of
`follicles. as has been detected in ultrasound studies or
`hormone studies JLunell N. 0 .. Carlstrom K.. Zador G ..
`Ovulation Inhibition with a Combined Oral Contraceptive
`Containing 20 J.lg of Ethinylestradiol and 250 J.lg of
`65 Levonorgestrel; Acta Obstet Gynecol Scand Suppl. 88:
`17-21 (1979); Mall-Haefeli M .. Werner-Zodrow 1 Huber P.
`R .. Klinische Ecfahrungen mit Mercilon und Marvelon untec
`
`so
`
`Petitioner Exhibit 1008
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`5.756,490
`
`3
`besonderer BerUcksichtigung der Ovar-Funktion [Clioical
`Experiments with Mercilon and Marvelon with Special
`Consideration of Ovarian Function]; Geburtsh. und Frauen(cid:173)
`heilk. [Childbirth and Gynecology]. 51. 35-38. Georg Thi(cid:173)
`eme Verlag. Stuttgart-New York (1991); Strobel E .. Behan(cid:173)
`dlung mit oralen Kontrazeptiva [Treatment with Oral
`Contraceptives] ; Fortschr. Med. 110 Jg. No. 20 (1992);
`Letter to Editor. Contraception 45: 519-521 (1992);
`Teiclunann 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)].
`Until recently. a multiple-day break in the intake of coated
`tablets that cont.ain active ingredients was deemed necessary
`to trigger withdrawal bleeding and to ensure adequate cycle
`control.
`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. US-A 3.502,772:
`Pasquale. US-A 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 follicular 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 Missing of
`Low- Dose Combination Oral Contraceptive Pills.
`Contraception. 22: 241-247. 1980; Molloy B. G. et al ..
`"Missed Pill" Conception: Fact or Fiction? Brit Med. J. 290.
`1474-1475. 1985). Contraceptive protection is thus jeopar(cid:173)
`dized. The risk of pregnancy is therefore high. especially in
`the case of intake errors below the 20 IJg ethinylestradiol
`preparations.
`From DE-PS 43 08 406 (not prepublished). an ovulation(cid:173)
`inhibiting agent in the fonn of a combination preparation for
`oontraception is already kDown. in which at least one
`hormone component that contains both estrogen and
`gestagen is provided. in which the daily units contain both
`a biogenic estrogen and a synthetic estrogen. This invention
`does not relate to such preparations.
`The object of this invention is to make available a
`combination preparation with an estrogen content that is as
`low as possible in each individual dosage unit but also with
`a low total hormone content per administration cycle.
`whereby with high contraceptive reliability. an incidence of
`follicular development that is as low as possible and satis(cid:173)
`factory cycle control with reliable avoidance of intracyclic
`menstrual bleeding such as breakthrough bleeding and
`"spottings" are to be achieved and undesirable side-effects
`are to be avoided.
`This object is achieved by the provision of the above(cid:173)
`indicated two-phase combination preparation.
`According to this invention. preferred are oombination ss
`preparations whose first hormone oomponent oornprises 24
`daily units and whose second hormone component oom(cid:173)
`prises 4 to 8 daily units.
`In the first phase. beginning with the first day of the cycle.
`a dosage unit that contains an estrogen in combination with
`a gestagenic oomponent is administered daily over 23 or 24 60
`days. After that is the second phase. in which an estrogen is
`administered over S days or 4 days over the remaining
`period in the cycle. which also oomprises 28 days.
`In the preferred case. 24 daily dosage units that contain an
`estrogen and a gestagen preparation. as well as 4 daily 65
`dosage units that contain only an estrogen preparation. are
`administered.
`
`4
`In thi.s case. the first phase which contains both estrogen
`and gestagen can also be structured in multiple phases. for
`example, in three phases. in a way that is familiar to one
`skilled in the art (in this connection. see. for example. EP-A
`5 0 148 724). Such a preparation is then referred to as a
`four-phase preparation.
`The one-phase structure of the first hormon.e component
`is preferred. however.
`When the combination preparation acoording to the
`invention is taken. the recruitment of the dominant follicle.
`which 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. follicular development can be
`suppressed as early as in the first intake cycle. and thus
`15 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 amounts. Since. in the case
`20 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.: Patterns of Contraceptive
`Pill-taking in an Inner City Practice. Br. Med. J. 1986. 293:
`25 601-602), the oombination 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 above the
`usual number of 21 days to 23 or 24 days produces an
`30 effective shortening of the pill-free interval. in which the
`selection of follicles occurs with oonventional combination
`preparations as in a normal menstrual cycle. and thus
`follicular development results and increased endogenic
`estrogen is formed. These follicles lead to breakthrough
`35 ovulations. as already stat.ed above. These breakthrough
`ovulations occur to an increased extent especially in the case
`of intake errors.
`The subsequent phase. in which dosage units that contain
`only one estrogenic component as a hormonal active ingre-
`40 dient are administered daily over 4 to 8 days. ensures
`withdrawal bleeding and produces stimulation of progester(cid:173)
`one receptors in the endometrium. thus ensuring in the
`subsequent administration cycle a reduced rate of intracyclic
`menstrual bleeding compared with conventional. low-dosed
`45 preparations.
`According to a preferred embodiment of the invention.
`the estrogen of the first honnone component is selected from
`the group of compounds
`17ji-estradioL
`ethinylestradiol and
`17(i-estradiol valerate
`and the gestagen i s selected from the group of compounds
`gestodene.
`levonorgestreL
`desogestrel.
`3-ketodesogestrel,
`drospironenone.
`cyproterone acetate.
`norgestimate and
`nOI'ethisterone and
`the estrogen of the second hormone oomponent is selected
`from the group of compounds
`17(i-estradiol
`ethlnylestradiol and
`17 ~-estradiol valerate.
`
`10
`
`so
`
`Petitioner Exhibit 1008
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`5,756,490
`
`s
`
`10
`
`15
`
`6
`The dosage units are formulated conventionally using
`estrogen-/gestagen- and exclusively estrogen-containing
`tablets. pills. coated tablets. etc. of known adjuvants for
`production.
`The number of daily units in the individual phases within
`the first hormone component in the case of the structure of
`the combination preparation accocding to the invention as a
`four-phase preparation is indicated below:
`
`1st Phase
`
`2nd Phase
`
`3rd Phase
`
`4th Phase
`
`4 to9 Cl
`
`4 to9 C2
`
`9 to 13 C3
`
`E =
`28 - (CI + C2 + C3)
`
`Number
`of daily
`units
`
`Cl. C2. C3=combination gestagen and estrogen within
`the first hormone component
`According to the invention . the estrogeolgestagen dosage
`ratios in the daily dosage units of the individual phases
`should lie within the ranges indicated below. In this case. the
`dosage in the first phase is set as 1. and the dose ranges in
`the following phases are indicated as multiples of the dosage
`in the first phase:
`
`2S -------------------------------------
`2nd Phase
`4th Phase
`3rd Phase
`1st Phase
`
`estrogen
`gestagen
`
`1-2
`1-l.S
`
`0.$- 1.5
`1.$- 3
`
`O.S--1
`
`The composition of a combination preparation according
`to the invention in four-phase structure can be seen in the
`example below:
`
`5
`According to another preferred variant of this invention.
`the estrogen of the first hormone component in each daily
`dosage unit is contained in a dose of
`1.0 to 6.0 mg of 17~-estrad.iol.
`0.01 to 0.04 mg of ethinylestradiol.
`1.0 to 6.0 mg of 17~-estradiol valerate
`and the gestagen in each daily dosage unit is contained in a
`dose of
`0.04 to 0.075 mg of gestodene.
`0.05 to 0.125 rng 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 rng of cyproterone acetate.
`0.2 mg to 0.3 mg of norgestirnate.
`0.35 to 0.75 mg of norethisterone.
`As the daily amounts in the daily units of the first
`hormone component. 0.015 to 0.025 mg is especially pre- 20
`ferred for ethinylestradiol. 1.0 to 4.0 mg is especially
`preferred for 17~estradiol valerate. and 0.05 to 0.075 mg is
`especially preferred for gestodene.
`The second hormone component contains the estrogen in
`each daily dosage unit preferably in an amount of
`1.0 to 6.0 mg of 17~stradiol.
`0.002 to 0.04 rng of ethinylestradiol.
`1.0 to 6.0 mg of 17~estradiol valerate.
`According to an especially preferred embodiment. the
`second hormone component in each daily dosage unit 30
`contains. as estrogen. ethinylestradiol in an amount of 0.01
`to 0.025 mg. 17~estradiol in an amount of 1.0 to 3.0 mg. or
`17~estradiol valerate in an amount of 1.0 to 4.0 mg.
`A preparation accocding to this invention contains a total
`of preferably 28 hormone daily units.
`As an estrogen for both the first and the second hormone
`component. primarily ethinylestradiol or 17~-estradiol is
`considered.
`Of the above-mentioned gestagens for the first hormone
`component. gestodene is to be emphasized; also levonorg(cid:173)
`estrel is preferred.
`l7~stradiol. which can be contained as estrogen both in
`the first and in the second hormone component. is mentioned
`only as a possible representative of this 17~stradiol ester;
`other such homologous esters can also be used as estrogenic
`components within the scope of this invention.
`The following example is used to explain this invention in
`moce detail:
`
`3S
`
`Number of
`daily units
`ethinyl-
`estr.odio1
`40 (~g) or
`17Jkstra-
`diol [mgj
`aod
`ges!Odene
`(mgl or
`levooor-
`gcstrcl (mg]
`
`4S
`
`1st Phase
`
`2ocl Phase
`
`3rd Phase
`
`4th Phase
`
`SCI
`
`0.020
`
`7 C2
`
`0.025
`
`12C3
`
`0.020
`
`4E
`
`0.010
`
`2.000
`
`3:.000
`
`2.000
`
`1.000
`
`o.oso
`o.oso
`
`0 .(){()
`
`O.O?S
`
`0.070
`
`0.100
`
`The combination preparation according to the invention is
`used in female contraception by administering the daily
`so dosage units of the first horm<lne component over 23 or 24
`days. beginning on day one of the menstrual cycle (first day
`of menstrual bleeding). followed by 4 to 8 daily dosage units
`that contain exclusively one estrogen (E). during a total of
`at least 28 days in the administration cycle. With this
`55 combination preparation. pronounced ovarian suppression
`without frequent follicle stimulation can be achieved. as
`well as excellent cycle control in the case of low daily
`estrogen dosage. low total amounts of estrogen. and low
`total amounts of hormone per administration cycle.
`T he adva ntages of this combination preparation
`(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 J.lg and those with
`65 a pill-free interval. can be characterized as follows:
`1. A significantly lower frequency of follicular development
`in the user. This means 'a lower risk of breakthrough
`
`60
`
`Petitioner Exhibit 1008
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`EXAMPLE 1:
`
`Day
`Composition
`
`Day
`Composition
`
`Day
`Composition
`
`Day
`Composition
`
`1
`c
`
`8
`c
`
`IS
`c
`
`22
`c
`
`2
`c
`
`9
`c
`
`16
`c
`
`23
`c
`
`3
`c
`
`10
`c
`
`17
`c
`
`24
`CorE
`
`4
`c
`
`11
`c
`
`18
`c
`
`2S
`E
`
`s
`c
`
`12
`c
`
`19
`c
`
`26
`E
`
`6
`c
`
`13
`c
`
`20
`c
`
`21
`E
`
`7
`c
`
`14
`c
`
`21
`c
`
`28
`E
`
`Day=Day of the menstrual cycle. day 1 is the first day of
`bleeding
`C=combination of estrogen and gestagen (:first hormone
`component)
`E:=estrogen (=second hormone component).
`
`

`

`7
`ovulation and thus greater contraceptive reliability. espe(cid:173)
`cially in the case of intake errors.
`2. The recruionent of the dominant follicle is suppressed as
`early as in the first cycle by extending the intake of the
`combination to 23 or 24 days.
`3. The intake of 4 to 8 daily estrogen dosage units each in
`connection with the administration of the 23- or 24-day
`combination dosage results in considerably improved
`cycle control and a lower incidence of side-effects. such
`as headaches. within the framework of the premenstrual
`syndrome.
`4. Other clinical symptoms that are attributable to greatly
`fluctuating endogenic estrogen levels. such as. for
`example. breast tenseness. are reduced also clearly 0.015
`to 0.025 mg owing to the considerably greater ovarian
`suppression.
`The above-mentioned advantages. especially the suppres(cid:173)
`sion of follicular development and the accompanying inhi(cid:173)
`bition of endogenic estrogen production. are more pr<r
`nounced in the case of the combination preparations
`according to the invention. which comprise 24 daily units of
`the first hormone component and thus. as mentioned above.
`the latter are preferred.
`The formulation of an estrogen and a gestagen for the
`production of a combination preparation according to the 25
`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® (etbinylestradioVgestodene) or Micr(cid:173)
`ogynon® (etbinylestradioVlevonorogestrel). The formula- 30
`tion of the dosage un.its that contain only estrogen can also
`be carried out quite analogously to the way known for
`already obtained estrogen-containing agents that are
`intended for oral use. for example. Progynon C®.
`A packing that contains a combination preparation 35
`according to the invention is also built up analogously to
`pack:ings for already known oral contraceptives that are on
`the market. with the difference that. instead of the usual 21
`dosage units that contain active components. now 23 or 24
`such dosage units and another 4 to 8 dosage units that
`contain only estrogen are present. As a packaging form for
`the combination preparation according to the invention.
`generally a conventional blister pack is used. but other
`packaging forms that are known for this purpose are also
`conceivable.
`In addition. the invention relates to a process for female
`contraception in which the above-described combination
`preparation is administered in the indicated way.
`To determine equivalent-action amounts of ethinylestra(cid:173)
`diol and !?~estradiol. on the one band. and various
`gestagens such as gestodene. levonorgestrel. desogestrel and
`3-ketodesogestrel. on the other hand. reference is made to
`the indications given in EP-A-0 253 6fJ7. Other details for
`determining dose equivalents of various gestagenic active
`ingredients are found in. for example. "Probleme der Dos(cid:173)
`isfindung: Sexualborroone [Problems of Dose Fmding: Sex
`Hormones]"; F. Neumann et al .. in "Arzneimittelforschung
`LPharmaceutical Agent Research]" (Drug Research) 27. 2o,
`2%-318 (1977) as well as in "Aktuelle Entwicklungen in
`der hormonalen Kontrazeption [Current Developments in
`Hormonal Contraception)": H. Kuhl in "Gyniikologe
`[Gynecologist]" 25: 231-240 (1992).
`We claim:
`1. Pharmaceutical combination preparation with two hor(cid:173)
`mone components that are manufacrured physically sepa(cid:173)
`rately in a packaging unit and that are intended for time(cid:173)
`sequential oral administration. which in each case consist of
`
`8
`a number of daily dosage units that are placed physically
`separately and individually removable in the packaging unit.
`whereby as a hormonal active ingredient a first hormone
`component contains in combination an estrogen preparation
`s and in at least a dosage that is sufficient to inhibit ovulation
`a gestagen preparation in either a one-phase or multiple(cid:173)
`phase structure and as a hormonal active ingredient the
`second hormone component contains only an estrogen
`preparation. whereby the first hormone component com-
`10 prises 23 or 24 daily units and the second hormone com(cid:173)
`ponent comprises 4 to 10 daily units. the daily un.its of the
`first hormone component do not contain the combination of
`a biogenic estrogen and a synthetic estrogen. and the total
`number of hormone daily un.its is equal to the total number
`IS of days of the desired cycle. but at least 28 days in length.
`2. Combination preparation according to claim 1. wherein
`the estrogen of the first hormone component is selected from
`the group of compounds
`17~stradiol
`ethinylestradiol a.nd
`17~stradiol valerate and the gestagen is selected from
`the group of compounds
`gestodene.
`levonorgestrel.
`desogestrel.
`3-ketodesogestreJ.
`drospironenone.
`cyproterone acetate.
`norgestimate and
`norethisterone and
`the estrogen of the second hormone component is selected
`from the group of compounds
`17~stradiol.
`etbinylestradiol and
`!?~estradiol val.erate.
`3. Combination preparation according to claim 2. wherein
`40 the estrogen of the first hormone component in each daily
`dosage un.it is contained in a dose of
`1.0 to 6.0 mg of 17~-estradiol.
`0.015 to 0.025 mg of ethinylestradioL and
`1.0 to 4.0 mg of 17~stradiol valerate
`45 and the gestagen in each daily dosage unit is contained in a
`dose of
`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-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 norgestiroate and
`035 to 0.75 mg of norethisterone.
`4. The combination preparation of claim 3. wherein the
`second hormone component contains. in each daily dosage
`unit. an amount of:
`l.O to 6.0 mg of !?~estradiol.
`0.002 to 0.04 mg of ethinylestradiol. and
`1.0 to 4.0 mg of l7~estradiol valerate.
`5. Combination preparation according to claim 2. wherein
`the second hormone component contains. in each daily
`65 dosage un.iL an amount of
`1.0 to 6.0 mg of 17~stradiol
`0.002 to 0.04 mg of ethinylestradiol. and
`
`20
`
`50
`
`55
`
`60
`
`Petitioner Exhibit 1008
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`5.756.490
`
`9
`1.0 to 4.0 mg of 1713-estradiol valerate.
`6. Combination preparation according to claim 5. wherein
`the second hormone component in each daily dosage unit
`contains ethinylestradiol in an amount of 0.01 to 0.025 mg.
`7. The combination preparation of claim 2. wherein the
`second hormone component contains. in each daily dosage
`unit. an amount of:
`1.0 to 3.0 mg of 171)-estradiol.
`0.01 to 0.025 mg of ethinylestradiol. and
`1.0 to 4.0 mg of 171)-estradiol valerate.
`8. Combination preparation according to claim 1. wherein
`the total number of hormone daily units is 28.
`9. The combination preparation according to claim 1.
`wherein the first hormone component has 24 daily units and
`the second hormone component has 4-8 daily units.
`
`10
`10. The combination preparation according to claim l.
`wherein the first hormone component has 24 daily units and
`the second hormone component has 4 daily units.
`11. The combination preparation of claim 1. wherein the
`5 estrogen in both the first and second hormone components is
`selected from ethinylestradiol or 17~estradiol.
`12. The combination preparation of claim 1. wherein the
`gestagen in the first hormone component is selected from
`gestodene or levonorgestel.
`13. The combination preparation of claim 1. wherein the
`first hormone component has three phases of daily units
`wherein the estrogen and/or the gestagen amounts differ
`between phases.
`
`10
`
`* * * * *
`
`Petitioner Exhibit 1008
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`