EXHIBIT 1005
`
`EXHIBIT 1005
`
`

`

`United States Patent
`Hodgen
`
`[19]
`
`11111111111111111 1111111111111111111111111 1111111111 1111111111111111111 1111
`US005552394A
`[1 1] Patent Number:
`(45] Date of Patent:
`
`5,552,394
`Sep.3, 1996
`
`[54] LOW DOSE ORAL CONTRACEPTIVES
`WITH LESS BREAKTHROUGH BLEEDING
`Al'ill SUSTAINED EFFICACY
`
`[75]
`
`Inventor: Gary D. Hodgen, Norfolk, Va.
`
`[73] Assignee: The Medical College of Hampton
`Roads, Norfolk, Va.
`
`[21) Appl. No.: 279,300
`
`[22) Filed:
`
`Jul. 22, 1994
`
`Int. CL." ..................................................... A61K 31/56
`[51]
`[52] U.S. Cl . .......................... 514/178; 514/170; 514/182;
`514/843
`[58] Field of Search ..................................... 5141170, 178,
`5141182, 843
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,932,635
`5,010,070
`5,098,714
`5,262,408
`
`1/1976 Segre ...................................... 4241239
`4/J991 Boissonneault ......................... 514/171
`311992 Wright .................................... 424/473
`llll993 Bcrgink ................................... 514/182
`
`FOREIGN PATENT DOCUMENTS
`
`253607
`
`lll988 European Pal. Off ..
`
`OTHER PUBLICATIONS
`
`CA 76:30782, Craft et al., 1971.
`Martindale, The Extra Pharmacopoeia, Edited by James E. F.
`Reynolds, pp. 2003-2004, Thirtieth Edition. (1993).
`AHFS Drug Information 33, p. 2348. (1993).
`Drug Information for the Health Care Professional, vol. I ,
`USP DI 1993, 13th Edition, Chapter 50.
`
`Primary Examiner- Kimberly Jordan
`Attorney, Agent, or Fimz- Ostrolenk, Faber, Gerb & Soffen,
`LLP
`
`[57)
`
`ABSTRACT
`
`A method of female contraception which is characterized by
`a reduced incidence of breakthrough bleeiling after the first
`cycle involves monophasicly administering a combination
`of estrogen and progestin for 23- 25 consecutive days of a 28
`day cycle in which the daily amounts of estrogen and
`progestin are equivalent to about 5-35 meg of ethinyl
`estradiol and about 0.025 to 10 mg of norethindrone acetate,
`respectively and in which the weight ratio of estrogen to
`progestin is at least 1 :45 calculated as ethinyl estradiol to
`norethindrone acetate.
`
`12 Claims, 2 Drawing Sheets
`
`Petitioner Exhibit 1005
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`Petitioner Exhibit 1005
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`Petitioner Exhibit 1005
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`5,552,394
`
`1
`LOW DOSE ORAL CONTRACEPTIVES
`WITH LESS BREAKTHROUGH BLEEDING
`AND SUSTAINED EFFICACY
`
`BACKGROUND OF THE INVENTION
`
`The ovarian/menstrual cycle is a complex event charac(cid:173)
`terized by an estrogen rich follicular phase and, after ovu(cid:173)
`lation, a progesterone rich luteal phase. Each has a duration
`of approximately 14 days resulting in an intermenstrual
`interval of about 28 days. The endometrial tissue responds to
`the changes in hormonal milieu.
`The onset of menstruation is the beginning of a new
`menstrual cycle and is counted as day 1. During a span of 15
`about 5 to 7 days, the superficial layers of the endometrium,
`which grew and developed during the antecedent ovarian/
`menstrual cycle, are sloughed because demise of the corpus
`luteum in the non-fertile menstrual cycle is associated with
`a Joss of progesterone secretion. Ovarian follicular matura- 20
`tion occurs progressively resulting in a rise in the circulating
`levels of estrogen, which in turn leads to new endometrial
`proliferation_
`The dominant ovarian follicle undergoes ovulation at
`mid-cycle, generally between menstrual cycle days 12 to 16 25
`and is converted from a predominantly estrogen source to a
`predominantly progesterone source (the corpus luteum). The
`increasing level of progesterone in the blood converts the
`proliferative endometrium to a secretory phase in which the
`tissue proliferation bas promptly abated, leading to the 30
`formation of endometrial glands or organs. When the ovu(cid:173)
`lated oocyte is viably fertilized and continues its progressive
`embryonic cleavage, the secretory endometrium and the
`conceptus can interact to bring about implantation (nida(cid:173)
`tion), beginning about 6 to 8 days after fertilization.
`If an ongoing pregnancy is to be established via implan(cid:173)
`tation, the embryo wiJI attach and burrow into the secretory
`endometrium and begin to produce human chorionic gona(cid:173)
`dotropin (HCG). The HCG in tum stimulates extended
`corpus Iuteum function, i.e. the progesterone production 40
`remains elevated, and menses does not occur in the fertile
`menstrual cycle. Pregnancy is then established.
`In the non-fertile menstrual cycle, the waning level of
`progesterone in the blood causes the endometrial tissue to be 45
`sloughed. This starts a subsequent menstrual cycle.
`Because endometrial proliferation serves to prepare the
`uterus for an impending pregnancy, manipulation of hor(cid:173)
`mones and of the uterine environment can provide contra(cid:173)
`ception. For example, estrogens are known to decrease 50
`follicle stimulating hormone secretion by feedback inhibi(cid:173)
`tion. Under certain circumstances, estrogens can also inhibit
`luteinizing hormone secretion, once again by negative feed(cid:173)
`back. Under normal circumstances, the spike of circulating
`estrogen found just prior to ovulation induces the surge of 55
`gonadotropic hormones that occurs just prior to and result(cid:173)
`ing in ovulation. High doses of estrogen immediately post(cid:173)
`coitally also can prevent conception probably due to inter(cid:173)
`ference with implantation.
`Progestins can also provide contraception. Endogenous 60
`progesterone after estrogen is responsible for the progesta(cid:173)
`tional changes of the endometrium and the cyclic changes of
`cells and tissue in the cervix and the vagina. Administration
`of progestin makes the cervical mucus thick, tenacious and
`cellular whlch is believed to impede spermatozoal transport. 65
`Administration of progestin also inhibits luteinizing hor(cid:173)
`mone secretion and blocks ovulation in humans.
`
`2
`The most prevalent form of oral contraception is a pill that
`combines both an estrogen and a progestin, a so-called
`combined oral contraceptive preparation.
`Alternatively, there are contraceptive preparations that
`5 comprise progestin only. However, the progestin-only
`preparations have a more varied spectrum of side effects
`than do the combined preparations, especially more break(cid:173)
`through bleeding. As a result, the combined preparations are
`the preferred oral contraceptives in use today (Sheth et al.,
`10 Contraception 25:243, 1982).
`Whereas the conventional 21 day pill packs with a 7 day
`"pill free" or placebo interval worked well when oral con(cid:173)
`traceptives were of higher dosage, as the doses have come
`down, for both the estrogen and progestin components,
`bleeding problems have increased in frequency, especially in
`the early months of oral contraceptive usc, but even persis-
`tently so in some patients.
`Since the advent of combined estrogen-progestin medi(cid:173)
`cations as oral contraceptives, there bas been a steady
`downward adjustment of the daily estrogen dosage. Con(cid:173)
`currently, where exposure to the progestin component has
`also been lowered, reduced androgenicity has remained an
`ongoing priority. Together these adaptions in formulation
`have been presented in a variety of regimens, both monopha(cid:173)
`sic and multiphasic. Each have their own advantages and
`disadvantages. All-in-all, today' s oral contraceptives are
`much safer with regard to the incidence and severity of
`estrogen-linked clotting disorders as well as the suggested
`cumulative impact of more "lipid friendly" progestins that
`maintain the potentially advantageous high density lipopro(cid:173)
`tein cholesterol levels in Circulation.
`U.S. Pat. No. 4,390,531 teaches a triphasic regimen in
`which each phase uses about 20-40 meg ethinyl estradiol,
`phases 1 and 3 use 0.3-0.8 norethindrone and phase 2
`35 doubles the amount of the norethindrone. These three phases
`consume 21 days of a 28 day cycle. European published
`application 0 226 279 states that this regimen is associated
`with a hlgh incidence of breakthrough bleeding and substi-
`tutes a three phase oral contraceptive regimen using a
`relatively low amount of ethinyl estradiol (10-50 1-1g) and a
`relatively high amount of norethindrone acetate (0.5- 1.5
`mg) in each phase provided that the amount of estrogen in
`any two phases is never the same. A "rest" phase of about 7
`days is used in this regimen.
`U.S. Pat. No. 5,098,714 teaches an osmotic, oral dosage
`form. One "pill" is administered per day but the adminis(cid:173)
`tration is, in effect, polyphasic. The dosage form is con(cid:173)
`structed such that it provides an initial pulse delivery of
`estrogen and progestin followed by prolonged delivery of
`estrogen.
`European published patent application 0 253 607
`describes a monophasic contraceptive preparation contain(cid:173)
`ing units having 0.008-0.03 mg of ethinyl estradiol and
`0.025-0.1 mg of desogestrel (or equivalent) and a regimen
`where the preparation is administered over a 23- 25 day
`period, preferably 24 days, followed by a 2-5 day pill-free
`period. The object of this regimen is to provide hormonal
`replacement therapy and contraceptive protection for the
`pre-menopausal woman in need thereof by supplying a low
`dose of an estrogen combined with a "very low dose of a
`progestogen."
`In 1989, the accumulating data from the evolution of oral
`contraceptive pill formulations containing only 20-35 J.lg of
`estrogen per day spurred the Food and Drug Administra(cid:173)
`tion's Fertility and Maternal Health Drugs Advisory Com-
`mittee to recommend indication of low dose oral contracep-
`
`Petitioner Exhibit 1005
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`

`5,552,394
`
`3
`lives for healthy, non-smoking women even during the
`perimenopausal years, such as, for instance, ages 35-50. In
`Japan, oral contraceptives are being evaluated for safety and
`efficacy, as well as social acceptability, for the first time.
`In establishing a estrogen-progestin regimen for oral
`contraceptives, two principal issues must be confronted.
`First, efficacy must be maintained and second, there must be
`avoidance of further erosion in the control of endometrial
`bleeding. In general, even the lowest dose oral contraceptive
`products commercially available have demonstrated efficacy
`but the overall instances of bleeding control problems has
`increased as the doses were reduced, as manifest both in
`breakthrough bleeding (untimely flow or spotting) or with(cid:173)
`drawal amenorrhea during the "pill free" week (expected
`menses).
`lt is the object of the present invention to provide a new
`estrogen-progestin combination and regimen for oral con(cid:173)
`traceptive usc which maintains the efficacy and provides
`enhanced control of endometrial bleeding. This and other
`objects of the invention will become apparent to those
`skilled in the art from the following detailed description.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 illustrates the circulating levels of LH, FSH,
`estradiol and progesterone among five primates receiving
`the traditional regimen of 21 treatment days, plus 7 "pill
`free" days.
`FIG. 2 illustrates the circulating levels of LH, FSH,
`estradiol and progesterone among five primates receiving
`the regimen of 24 treatment days, plus 3 "pill free" days.
`
`SUMMARY OF THE INVENTION
`
`25
`
`This invention relates to a method of female contraception
`which is characterized by a reduced incidence of break(cid:173)
`through bleeding. More particularly, it relates to a method of
`female contraception which involves monophasicly admin(cid:173)
`istering a combination of estrogen and progestin for 23--25
`consecutive days of a 28 day cycle in which the daily
`amounts of the estrogen and progesterone are equivalent to
`about 1-35 meg of ethinyl estradiol and about 0.025- 10 mg
`of norethindrone acetate, respectively, and in which the
`weight ratio of estrogen to progestin is at least 1:45 calcu(cid:173)
`lated as cthinyl estradiol to norethindrone acetate. Surpris- 45
`ingly, there is a reduced incidence of breakthrough bleeding
`after the first cycle. This reduced incidence is not manifest
`during the first cycle.
`
`4
`Other estrogens vary in potency from ethinyl estradiol.
`For example, 30 meg of cthinyl estradiol is roughly equiva(cid:173)
`lent to 60 meg of mestranol or 2,000 mg of 17 ~-estradiol.
`Likewise, other progestins vary in potency from norethin-
`5 drone acetate. Thus, 3.5 mg of norethindrone acetate is
`roughly equivalent to 1 mg of levonorgestrel or desogestrcl
`and 3-ketodesogestrel and about 0.7 mg of gastodene. The
`values given above are for the ethinyl estradiol and the
`norethindrone and if a different estrogen or progestin is
`10 employed, an adjustment in the amount based on the relative
`potency should be made. The correlations in potency
`between the various estrogens and progestins are known.
`Other useable estrogens include the esters of estradiol and
`ethinyl estradiol such as the acetate, valerate or benzoate,
`15 and conjugated equine estrogens. The estrogen is adminis(cid:173)
`tered in the conventional manner by any route where it is
`active, for instance orally or transdermaJiy. Most estrogens
`are orally active and that route of administration is therefore
`preferred. Accordingly, admirtistration forms can be tablets,
`20 dragees, capsules or pills which contain the estrogen (and
`preferably the progestin) and a suitable pharmaceutically
`acceptable carrier.
`Pharmaceutical formulations containing the progestin and
`a suitable carrier can be solid dosage forms which includes
`tablets, capsules, cachets, pellets, pills, powders or granules;
`topical dosage forms which includes solutions, powders,
`fluid emulsions, fluid suspensions, semi-solids, ointments,
`pastes, creams, gels or jellies and foams; and parenteral
`dosage forms which includes solutions, suspensions, emul-
`30 sions or dry powder comprising an effective amount of
`progestin as taught in this invention. It is known in the art
`that the active ingredient, the progestin, can be contained in
`such formulations in addition to pharmaceutically accept(cid:173)
`able diluents, fillers, disintegrants, binders, lubricants, sur-
`35 factants, hydrophobic vehicles, water soluble vehicles,
`emulsifiers, buffers, humectants, moisturi.zcrs, solubilizers,
`preservatives and the like. The means and methods for
`administration are known in the an and an artisan can refer
`to various pharmacologic references for guidance. For
`40 example, " Modem Pharmaceutics", Banker & Rhodes, Mar(cid:173)
`cel Dekker, Inc. 1979; "Goodman & Gilman's The Pharma(cid:173)
`ceutical Basis of Therapeutics", 6th Edition, MacMillan
`Publishing Co., New York 1980 can be consulted.
`The pharmaceutical formulations may be provided in kit
`form containing at least about 23, and preferably 28 tablets,
`intended for ingestion on successive days of the menstrual
`cycle. Preferably administration is daily for 24 days using
`tablets contain the both the estrogen and the progestin and
`then for 4 d!iYS with placebo.
`In order to further illustrate the present invention, specific
`examples are set forth below. It will be appreciated, how(cid:173)
`ever, that these examples arc illustrative only and are not
`intended to limit the scope of the invention. They also
`55 demonstrate the outstanding results achieved when the estro(cid:173)
`gen dose is very low, the estrogenlprogentin ratio is at least
`1:45 and the treatment is monphasic for 23 to 25 days.
`
`DESCRIPTION OF INVENTION
`
`50
`
`In accordance with the present invention, a women in
`need of contraception is administered a combined dosage
`form of estrogen and progestin monophasicly for 23 to 25
`consecutive days of a 28 day cycle, preferably 24 days of the
`cycle, in which the daily amounts of estrogen and progestin
`are equivalent to about 5-35 meg of ethinyl estradiol and
`about 0.025 to 10 mg of norethindrone acetate, respectively,
`and in which the weight ratio of estrogen to progesterone is
`at least I :45 calculated as ethinyl estradiol to norethindrone 60
`acetate.
`The preferred estrogen and progestins are ethinyl estradiol
`and norethindrone acetate although other estrogens and
`progestins can be employed. The weight ratio of these two
`active ingredients is at least 1:45 and preferably at least 1:50. 65
`The preferable amount of the norethindrone acetate is about
`0.5-1.5 mg.
`
`EXAMPLE 1
`
`A study was carried out at the Eastern Virginia Medical
`School which maintains a fully accredited animal research
`facility which complies through its animal care and use
`committee with the review standards set forth in the
`National Instirute of Health's "Guide for Care and Use of
`Laboratory Animals", the Public Health Services' "Prin(cid:173)
`ciples for the Care and Use of Laboratory Animals", and the
`
`Petitioner Exhibit 1005
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`5,552,394
`
`10
`
`15
`
`5
`United States Department of Agriculture's Implementation
`Regulations of the 1985 Amendments for the Animal Wel(cid:173)
`fare Act.
`Ten adult female cynomolgus monkeys (macaca fasicu(cid:173)
`Iaris) having regular presumably ovulatory menstrual cycles 5
`(28.9±3.1 days for the month prior to study entry) were
`selected. Their duration of spontaneous menses was 3.4±1.4
`days. Mean body weight of the monkeys was 4.9±1.1 kg
`(X±SEM). They were housed individually in a controlled
`environment (12 hours of light and 23° C.). Their diet was
`a commercial primate food (Purina, St. Louis, Mo.) with
`water ad libitum.
`The monkeys were divided at random into two groups
`(N=5 each). The studies began with spontaneous menstrua(cid:173)
`tion in a pretreatment control cycle. At the onset of the next
`spontaneous menses, alternatively, they were assigned to
`receive on cycle day one an ultra low dose oral contraceptive
`for either 21 consecutive days, followed by 7 non-treatment
`days or 24 consecutive days, followed by a 4 non-treatment 20
`days. These regimens were continued through three treat(cid:173)
`ment cycles. The study concluded with each group of
`primates being followed during a post-treatment spontane(cid:173)
`ous ovarian menstrual cycle.
`Femoral blood was collected daily and the serum frozen 25
`for subsequent RIA of estradiol, progesterone, FSH and LH
`in the pretreatment and post-treatment cycles and every 3rd
`day during all three treatment cycles, except daily through
`the "pill free" interval. Bleeding profiles were kept by daily
`vaginal swabs, indicating spontaneous menstruation, with- 30
`drawal bleeding, breakthrough bleeding, or withdrawal
`amenorrhea. Breakthrough bleeding was defined as detect(cid:173)
`able blood in the vagina outside of the first 8 days after the
`last dose of oral contraceptive or the onset of spontaneous
`menses in non-treatment cycles.
`Since the objective was to test an ultra low dose oral
`contraceptive, the medication used was adjusted to fit the
`smaller (than human) body weight of these laboratory pri(cid:173)
`mates. The dose of ethinyl estradiol was 1.2 flg/day, while
`the dose of norethindrone acetate was 0.06 mg/day. This 40
`"in-house" reformulation was achieved by grinding to pow(cid:173)
`der a commercially available monophasic pill (Loestrin
`l/20, Parke Davis, Morris Plains, N.J. ), which originally
`contained 1 mg of norethindrone acetate and 20 flg of ethinyl
`estradiol per tablet, contained in a conventional 21 day pack 45
`along with 7 iron-containing placebos.
`In terms of comparison to human dose equivalents, the
`daily dose received by the monkeys (with a monkey's body
`weight about 5 kg and a woman's at 50 kg) was about 12 f.l&
`of ethinyl estradiol and 0.6 mg of norethindrone acetate.
`Thus, this ultra low dose oral contraceptive formulation
`presented a 40% reduction in daily estrogen-progestin expo(cid:173)
`sure as compared to one of the lowest estrogen dose com(cid:173)
`bination oral contraceptives commercially available today in
`America or Europe. Taking into account that when a 24 day
`ultra low dose regimen was used, versus the traditional 21 + 7
`day protocol, that there would be 3 more treatment days each
`cycle and 39 more doses on an annualized basis, still the
`exposure to medication was reduced by more than 30%
`yearly.
`Differences between group results calculated as the means
`and standard errors, were compared using the F statistic,
`testing a P<0.05 level of significance.
`Table I below summarizes the intermenstrual intervals for
`both groups, including the spontaneous cycles (pretreatment
`and post treatment) and the three treatment cycles.
`
`6
`
`TABLE I
`
`Comparntive Data Using Ultra Low Dose OC Regimens
`lntcnnenstrual Intervals (:X ± SEM)
`
`Spontaneous
`Cycles•
`
`Treat·
`
`mente
`
`Days
`1-21
`Days
`1-24
`
`Pre-
`treat-
`
`Posureat-
`
`Treatment C~cles•
`
`ment
`
`men I
`
`29.3 ±
`2.4
`28.6±
`2.5
`
`30.1 ±
`3.0
`29.1 ±
`2.9
`
`2
`
`3
`
`24.4 ± 2.o•
`
`27:6 ± 2.5
`
`28.1 ± 3.3
`
`26.0 ±3.1
`
`27.8 ± 2.1
`
`27.2 ± 2.2
`
`Petitioner Exhibit 1005
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`"Menses length was 4.2 ± 0.8 days in spontaneous cycles
`•Menses length was 2.8 ± 0.5 days in treatment cycles; p < 0.05, significantly
`less than a
`~ = 6 monkeys in all groups, except that one monkey was removed from the
`study early in the treatment cycle 3 due to an infection
`dlntermenstrual interval significantly Jess than treatment cycles 2 and 3 (p <
`0.05)
`Except for the initial treatment cycle which was only
`24.4±1.2 days in association with withdrawal of the oral
`contraceptive after 21 treatment days, all groups had mean
`intermenstrual intervals of about 26 to 30 days.
`Regarding non-menstrual and non-withdrawal bleeding,
`untimely breakthrough bleeding occurred on 37, 27 and 27
`days, respectively, for the five monkeys on the 21 day
`regimen versus 36, 18 and 11 times for females on the 24 day
`therapy, cycles one through three. During spontaneous
`cycles in the pre- or post -treatment intervals, breakthrough
`bleeding was observed on only 16 occasions overall (4
`cycles) for both groups. Statistical analysis revealed that
`untimely bleeding was significantly higher in both treatment
`35 groups than in spontaneous cycles (p<O.OS). More impor(cid:173)
`tantly, monkeys receiving their ultra low dose oral contra(cid:173)
`ceptive regimen for 24 days manifest significantly less (p
`<0.05) breakthrough bleeding in their second and third
`treatment cycle than females in the 21 day protocol. This
`trend was not IN evidence in the first treatment cycle
`(p>O.OS).
`Note that withdrawal amenorrhea occurred in two mon(cid:173)
`keys, one in each treatment group, both at the end of the
`second treatment cycle.
`In Table I, among the footnotes (a and b) notice that the
`duration of menses was significantly Jess (p<0.05) after
`administration of both treatments versus spontaneous
`menses. Treatment groups did not differ in this regard.
`FIG. 1 illustrates the circulating levels of LH, FSH,
`estradiol and progesterone among the five primates receiv(cid:173)
`ing the traditional regimen of 21 treatment days, plus 7 "pill
`free" days. In contrasting these hormonal patterns to those in
`FIG. 2, wherein monkeys were on an extended 24+4 day
`treatment protocol, three differences in serum hormonal
`level are apparent. Despite some instances of substantial
`individualism of response, the mean values illustrated (±one
`SEM) reveal significantly greater elevations of estradiol,
`FSH and LH whenever 7 day "pill free" intervals occurred.
`Notice that the circulating levels of estradiol in particular
`were highest on the 5th, 6th and 7th "pill free" days. Indeed,
`peak serum estradiol averaged 52±14 pglml versus 31±9
`pglml for the 21 versus 24 day treatment groups, respec(cid:173)
`tively (p<0.05), across all treatment cycles.
`Even so, that both regimens were apparently efficacious in
`65 blocking ovulation is indicated by the rapid truncation of
`these transient "pill free" associated elevations of serum
`pituitary gonadotropins and estradiol as soon as the medi-
`
`50
`
`55
`
`60
`
`

`

`5,552,394
`
`8
`
`7
`cation was resumed. Also, serum progesterone remained
`near the baseline throughout the treatment cycles for all
`monkeys.
`Pre- and post-treatment cycles were essentially indistin(cid:173)
`guishable, irrespective of treatment assignments.
`The data presented indicate that in this primate model
`ultra low doses of norethindrone acetate in combination with
`cthinyl estradiol-
`that is, 40% less daily (on a body weight
`basis) than is commercially available now-reliably pre(cid:173)
`vented ovulation. Even using the extended 24 day treatment 10
`regimen, total annual exposure to the medication would
`decline by more than 30% compared to existing formula(cid:173)
`tions now in clinical use.
`
`EXAMPLES 2-5
`
`The example 1 procedure is repeated using the following
`combinations of estrogen and progestin:
`
`Example
`
`Estrogen
`
`Progestin
`
`2
`
`3
`
`4
`
`5
`
`mestranol
`
`17-beta·
`estradiol
`ethinyl
`estradiol
`mestranol
`
`lcvo·
`norgcstrel
`3·kC!O·
`desogcstrcl
`dcsogcstrel
`
`gastodonc
`
`Treatment
`Days
`
`24
`
`25
`
`23
`
`24
`
`20
`
`What is claimed is:
`1. A method of female contraception which is character(cid:173)
`ized by a reduced incidence of breakthrough bleeding after
`the first cycle which comprises monophasicly administering
`5 a combination of estrogen and progestin for 23- 25 consecu(cid:173)
`tive days of a 28 day cycle in which the daily amounts of
`estrogen and progestin are equivalent to aboutl-35 meg of
`ethinyl estradiol and about 0.025 to 10 mg of norethindrone
`acetate, respectively, and in which the weight ratio of
`estrogen to progestin is at least I :45 calculated as ethinyl
`estradiol to norethindrone acetate.
`2. The method of claim 1 in which the daily amount of
`progestin is equivalent to 0.5-0.75 mg of norethindrone
`15 acetate.
`3. The method of claim 2 in which the weight ratio is at
`least 1:50.
`4. The method of claim 3 in which the combination is
`administered for 24 days of the 28 day cycle.
`5. The method of claim 4 in which the estrogen is etbinyl
`estradiol.
`6. The method of claim 5 in which the progestin is
`norethindrone acetate.
`7. The method of claim 1 in which the daily amount of
`25 progestin is equivalent to 0.5- 1.5 mg of norethindrone
`acetate.
`8. The method of claim 1 in which the weight ratio is al
`least 1:50.
`9. The method of claim 1 in which the combination is
`administered for 24 days of the 28 day cycle.
`10. The method of claim 1 in which the estrogen is etbinyl
`estradiol.
`11. The method of claim 1 in which the progestin is
`norethindrone acetate.
`12. The method of claim 1 in which the daily amount of
`estrogen is up to 30 meg of ethinyl estradiol.
`
`Application of the compounds, compositions and methods 30
`of the present invention for the medical or pharmaceutical
`uses described can be accomplished by any clinical, medi(cid:173)
`cal, and pharmaceutical methods and techniques as are
`presently or prospectively known to those skilled in the art.
`It will therefore be appreciated that the various embodiments 35
`which have been described above are intended to illustrate
`the invention and various changes and modifications can be
`made in the inventive method without departing from the
`spirit and scope thereof.
`
`* * * * *
`
`Petitioner Exhibit 1005
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`