EXHIBIT 1001
`
`EXHIBIT 100 1
`
`

`

`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007704984B2
`
`(12) United States Patent
`Boissonneault
`
`(10) Patent No.:
`(45) Date of Patent:
`
`us 7,704,984 82
`Apr. 27, 2010
`
`(54) EXTENDED ESTROGEN DOSING
`CONTRACEPTlVE REGIMEN
`
`(75)
`
`lnveutor: Roger M. Boissonneault, Long Valley,
`NJ (US)
`
`(73) Assignee: Wa rner C ltilcott Company, L LC.
`Fajardo, PR (US)
`
`("') Notice:
`
`Subject to any disclaimer, the tem1 of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1382 days.
`
`(21) Appl. No.: 111112,290
`
`(22) Filed:
`
`Apr. 22, 2005
`
`(65)
`
`Prior Pu blica tion Data
`
`US 2006/024109 1 AI
`
`Oct. 26,2006
`
`(51)
`
`lot. C l.
`A6IK 31/56
`(2006.01)
`A61K 31/58
`(2006.01)
`....................................... 514/17 0: 514/843
`(52) U.S. Cl .
`(58) Field of C lassification Search ................ 514/ 170,
`514/843
`See application file for complete search history.
`
`(56)
`
`References C ited
`
`U.S. PATENT DOCUMENTS
`
`5/ 1990 Pasquale
`4,921,843 A
`4,962,098 A
`10/ 1990 Boissonneaull
`5,010,070 A
`4/ 199 1 Boissonneault
`1/ 1994 Ehrlich ct al.
`5,280,023 A
`5,5 10.341 A
`411996 Ehrlich et al.
`5,552,394 A
`9/ 1996 Hodgen
`5,747.480 A
`511998 Gast
`5,756,490 A
`5/ 1998 Lachnit el al.
`5,888.543 A
`3/ 1999 Gast
`5,898,032 A
`4/ 1999 Hodgen
`2/2000 Schmidt-Gollwitzer et al.
`6,027,749 A
`6,479,475 B1
`11/2002 Gast
`2004/0176336 Al* 9/2004 Rodriguez .................. 514/ 170
`
`FOREIGN PATENT DOCUMENTS
`wo 98/04268
`wo
`* 211998
`WO W02006/ 115871 A I
`1112006
`
`OTHER PUBLICATIONS
`
`J Oth ed." Hardman .JG, Limbird LE, and Gilman AG, Eds., McGraw(cid:173)
`Hill, 2001. t597-t 634 (pp. t597, 1618, 1623, and 1624 provided).•
`van De Waterbeemd H, Smith DA, Beaumont K. and Walker DK,
`"Property-based design: optimization of drug absorption and
`pha.nnacoki netics,"
`Journal of Med.icinal Chemistry, Apr.
`2001,44(9), 13 13-1333 ...
`Hillman Rs. Chapter 541-Iematopoictic Agents Growth Factors. Min(cid:173)
`erals, and Vitamins, "Goodman & Gilman's the Pharmacological
`Basis ofTherapeutics. l Oth ed." Hardman Jg. Limbird Lb, and Gil(cid:173)
`manAg, Eds., McGraw-Hill, 200 1, 1487-1 518 (pp. 1487, 1495, and
`1499 provided). •
`Mircette Study Group."An open-label. multicenter. noncomparative
`safety and efficacy study ofMicctte'~'". a low dose estrogen-progestin
`oral contraceptive"; American Joumal of Obslelrics and Gynecol(cid:173)
`ogy, Jul. 1998, vol. 179. No. 1. p. S2-S8.
`Gaspard. U. et al.. "New Forms ofHonnonal Contraception"; Jour(cid:173)
`nal de GJ,11ecologie. ObsJelriqueeJ8iologiedeal Reproduc1ion. May
`2000. vol. 29, No. 3, p. 288-291.
`European Patent Office, International Search Report for PCT/
`US2006/0 14367, Aug. 25, 2006.
`
`"' cited by examiner
`
`Primary Examiner- Brandon J Fetterolf
`Assistant Examiner- Paul Zarek
`(7 4) Allomey. Agent. or Finn- Fitzpatrick, Cella. Harper and
`Scinto
`
`(57)
`
`ABSTRACT
`
`A method of contraception that provides for sequentially
`administering to a female of child bearing age: (a) a first
`composition containing a progestin in an amount equivalent
`to about 0.3 to abou1 1.5 rug norethindrone acetate and an
`estrogen in an amotmt equivalent to about 5 to about 20 meg
`ofcthinyl estradiol for about 22to abou126 days; (b) a second
`composition containing an estrogen in an amount equivalent
`to about 5 to about 20 meg of eihinyl estradiol for about 2 to
`about 3 days and an optjonaJ third composition that is a
`placebo provided that (i) if estrogen administration is con(cid:173)
`tinuous then the first composition is administered for 25 to 26
`days, the second composition is administered for 2 to 3 days
`and no third composition is administered and (ii) if estrogen
`administration is not contil1uous then the first composition is
`administered for 22 to 24 days, the second composition is
`administered for 2 to 3 days and the third composition is
`administered for 1 to 4 days. The total cycle length is 28 days,
`with the first composition administered on day 1 of the men(cid:173)
`stntal cycle, defined as the firs t day ofmenslntal bleeding, or
`on the first Sunday after the first day of the menstmal cycle.
`
`Loose-Mitchell and Sta.ncel. Chapter 58- Estrogen and Progestins.
`"Goodman & Gilman's The Pharmacological Basis ofTherapeutics,
`
`9 C laims, No Drawings
`
`Petitioner Exhibit 1001
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`US 7,704,984 B2
`
`2
`mens with 23-25 consecutive days of hormone administra(cid:173)
`tion, followed by a 3-5 day hormone-free interval.
`U.S. Pat. No. 5,898,032 discloses an extended ora l contra(cid:173)
`ceptive regimen wherein estrogen and progestin are admin-
`istered in a combined dosage form. prelerably monophasi(cid:173)
`cally, for 60 to 110 consecutive days, followed by an
`administration free period of 3 to 10 days. The amount of
`estrogen and progestin administered daily are equivalent to
`about 5-35 meg of ethinyl estradiol and about 0.025 to I 0 mg
`of norethindrone acetate, respectively. In one particular
`embodimem, tile combined dosage form is administered for
`84 days followed by 7 pill free days. FoJJowing this particular
`regimen is said to result in four treatments and menstmal
`cycles dttring the year. However. extended oral contraceptive
`regimens tend to suffer from poor initial cycle control.
`Another disadvantage is that once breakthrough bleeding is
`under control, the user becomes functionally amenorrheic.
`This does not reasstu·e the user that she is not pregnant.
`One constant goal in the oral contraceptive art has been to
`reduce the bormone levels of such compositions wiibout
`reducing contraceptive efficacy and increasing undesired side
`effects. Since the risk is acute thrombosis (as opposed to
`ath erosclerosis), minimizing daily exposure of estrogen is a
`therapeutic goal. However, as estrogen doses decreased, tbe
`incidences of unwanted breakthrough bleeding or spotting
`have generally increased. TI1erefore, ti1ere remains a need for
`an oral contraceptive regimen that maintains contraceptive
`efficacy and provides adeqllate cycle control with a low daily
`dose of the estrogenic component.
`
`SUMMARY OF THE INVENTION
`
`1
`EXTENDE D ESTROGEN DOSING
`CONTRACEPTIVE REGIMEN
`
`BACKGROUND OF THE INVENTION
`
`5
`
`1. Field of the ltwention
`Tills invention is directed to an estrogellic/progestogenic
`contraceptive regimen with continuous and/or extended dos(cid:173)
`ing of the estrogenic component. The inventive regimen pro(cid:173)
`vides for low daily estrogenic hormone exposure without 10
`compromising contraceptive efficacy or cycle control. A con(cid:173)
`traceptive ki t that may be used to practice tbe method of the
`invention is also disclosed.
`2. Related Background Art
`Contraceptive compositions containing both estrogenic 15
`and progestogenic compounds are known to be effective in
`controlling ovulation and conception. The progestogenic
`component of the composition is primarily responsible for the
`contraceptive eil1cacy of the composition, while the estro(cid:173)
`genic component is included primarily to red uce undesired 20
`side effects, such as breaJ..:througb bleeding or spotting. It is
`thought that small amounts of estrogen help stabilize the
`endometrilLUl and allow cyclic withdrawal bleeding, similar
`to the natural menstrual cycle.
`·n1e earliest of these estrogenic/progestogenic contracep- 25
`tive compositions was administered monopbasically (fixed
`dose) and contained a relatively bigh level of estrogenic com(cid:173)
`ponent. U.S. Pat. No. 4,921,843 relates to the administration
`of an estrogen-only component from day 2 to day 7 of the
`menstrual cycle, followed by administration of a combination 30
`of estrogen and progestin from day 7 to day 28 of the men(cid:173)
`strual cycle. U.S. Pat. No. 5.280.023 and U.S. Pat. No. 5.510,
`341 describe the administration of an estrogen-only compo(cid:173)
`nentfor 5 to 14daysal lhe beginning of the cycle, fo llowed by
`23 to 14 days of an estrogenlgestagen combination. U.S. Pat. 35
`No.5, 756,490 discloses combination preparations with 23 or
`24 daily units of an estrogen and gestagen, and 4 to 10 daiJy
`units of estrogen only. Simi larly, U.S. Pat. No. 6,027,749
`discloses a n estrogen-only component administered for 5. 6,
`or 7 days. U.S. Pat. No. 5,552,394 discloses administration of 40
`tablets that contain both estrogen and progestin for 24 days
`followed by 4 days of placebo.
`U.S. Pat. No. 4.962,098 is directed to a multiphasic con(cid:173)
`traceptive regimen and describes a triphasic method of con(cid:173)
`traception using a progestin/estrogen combination in which 45
`the amount of estrogen is increased stepwise over the three
`phases wherein the first pbase is 4-7 days, the second pbase is
`5-8 days and the third phase is 7- 12 days. Prelerably, admin(cid:173)
`istration of the contraceptive compositions for the three
`phases combined will be 21 days followed by a 7 day placebo 50
`period. For all three phases, the progestin is 0.5 to 1.5 mg of
`norethindrone acetate, while abo ut 10 to 30 meg of ctllinyl
`estradiol is used in the flfst phase. about 20 to 40 meg of
`ethinyl estradiol is used in the second phase and 30 to 50 meg
`of ethinyl estradiol is employed in ihe third phase.
`U.S. Pat. No. 5,747.480 also discloses a multiphasic regj(cid:173)
`men wherein the progestin component is levonorgestrel. U.S.
`Pat. No. 5.888,543 discloses various regimens wherein a
`combination of progestin and estrogen are administered in a
`monophasic or multiphasic regimen (varied dose, e.g., bipha- 60
`sic or triphasic). In one embodiment. a combination of a
`progestin composition and an estrogen composition is admin(cid:173)
`istered such that the daily dosage of the second phase proges-
`tin is greater than the daily dosage of progestin in the first
`phase and the daily dosage of the second phase estrogen is 65
`greater than or equal to the daily dosage of estrogen in the first
`phase. U.S. Pat. No. 6,479,475 describes multiphasic rcgi-
`
`The present invention is directed to a method of contracep(cid:173)
`tion that comprises the steps of sequentially administering to
`a female of child-bearing age: (a) a first composition contain(cid:173)
`ing a progestin in an amotmt equivalent to about 0.3 to about
`1.5 mg norethindrone acetate and an estrogen in an amount
`equivalent to about 5 to 20 meg of ethinyl estradiol for about
`22 to about 26 days: (b) a second composition containing an
`esirogeJJ in an amount equivalent to about 5 to about 20 meg
`of ethinyl estradiol and substantially free of a progestin for
`about 2 to about 3 days; and (c)an optional third composition
`that is a placebo, wherein the sequential administration of the
`first composition, ti1e second composition and the optional
`third composition, when present. is perfom1ed on a daily
`basis over a 28 day cycle. If estrogen administration is con-
`tinuous during tbe cycle then the first composition is
`monopbasically administered for 25 to 26 days. the second
`composition is administered for 2 to 3 days and no third
`composition is administered, while if estrogen administration
`is extended. but not continuous. tl1en tl1e fLrst composition is
`administered for 22 to 24 days, tl1e second composition is
`administered for 2 to 3 days and the third composition is
`administered for I to 4 days. The sequential administration is
`55 begu11 on the Hrst day of the fema le's menstrua l cycle.
`One particular embodiment of this invention is directed to
`a method of contraception that provides for sequ entiaJJy
`administering to a female of child bearing age (a) a compo(cid:173)
`sition containing a progestin in an amount equivalent to about
`0.3 to about 1 .5 mg norethindrone acetate and an estrogen in
`an amount equivalent to about 5 to about 20 meg of etbinyl
`estradiol for about 25 or about 26 days; and (b) a composition
`containing an estrogen in an an1ount equivalent to about 5 to
`about 20 meg of ethinyl estradiol for about 3 to about 2 days
`for a total cycle length of28 days. No placebo is administered
`in this embodiment. The sequential administr<ttion of the first
`composition may be repeated the day following tl1e comple-
`
`Petitioner Exhibit 1001
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`US 7,704,984 B2
`
`3
`tion of the administration of the second composition to pro(cid:173)
`vide for continuous administration of estrogen.
`Yet another embodiment of this invention is directed to a
`method of contraception that provides for seqltentially
`administering to a female of childbearing age (a) a composi(cid:173)
`tion containing a progestin in an amount €.-qu ivalenr to about
`0.3 to about 1.5 mg norethindrone acetate and an estrogen in
`an amount equivalent to about S to about 20 meg ethinyl
`estradiol for about 22 to about 24 days; (b) a composition
`containing an estrogen in an amount equivalent to about 5 to tO
`about 20 meg ethinyl estradiol for about 2 to 3 days; and (c) a
`placebo tablet for about J to about 4 days (or a total cycle
`length of 28 days. 111is embodiment provides fo r extended,
`but not continuous, administration of estrogen. The sequen(cid:173)
`tial administration of the first composition may be repeated 15
`the day following the completion of the administration of the
`placebo to provide for continuous contraception.
`In preferred embodiments of the invention. the ammmt of
`estrogenic component remains the same in both phases of
`admi11istration, and the amo unt of progestin remains constan t 20
`during the first phase of administration. The invention is also
`directed to a kit for practicing the method of this invention.
`
`DETAJLED DESCRIPTION OF THE INVENTION
`
`By practicing the contraceptive method d.isclosed herein, a
`user advantageously improves control of meustm al bleediug
`while taking the contraceptive compositions of the invention.
`For the purposes of this invention. the designation "meg"
`refers to micrograms and "mg'· to m illigrams.
`ln a preferred embodiment. the amount of estrogen admin(cid:173)
`istered is equivaleUI to IS meg per day of ethinyl estradiol,
`while the amount of progestin administered is equivalent to
`1.0 mg norethindrone acetate per day duri ng the combined
`estrogen/progestin phase.
`The progestin may be selected. for example. from the
`group consisting of norethindrone acetate, drospirenone, tri(cid:173)
`megestone. norethindrone, levonorgestrel, desogestrel. 3-ke(cid:173)
`iodesogestrel, gestodene, demogestone, dydrogesterone,
`medrogestone. medroxy progesterone. esters and mixtures 40
`thereof and the like. The most preferred progestin is norethin(cid:173)
`drone acetate. The estrogen may be selected, for example,
`from the group consisting of ethinyl estradiol, 17 -~ -estradiol.
`conjugated estrogens, mestranol. estrone and esters, prodrugs
`and salts thereof. An exemplary ester is estradiol acetate. 45
`Preferred salts of estrone include, but are not limited to the
`sodium and piperate salt. For the conjugated estrogens. 1.25
`mg conjugated estrogens is equivalent to a daily dose of 15
`meg ethinyl estradiol. The most preferred estrogen is ethinyl
`estradiol The amount of progestin and estrogen employed in 50
`each phase w ill be that amount which is equivalent in potency
`to the ranges of norethindrone acetate and ethinyl estradiol,
`respectively, that are set fonh herein. Determination of
`equivalent potency is well understood and readily accom(cid:173)
`plished by those of ordinary skill in the art.
`The third composition, if present is a placebo. i.e .. a non(cid:173)
`steroidal component. The non-steroidal placebo may com(cid:173)
`prise an iron supplement. Suitable iron supplements include,
`for example, ferrous fumarate. ferrous sulfate, ferrous glu(cid:173)
`conate, iron polysaccharides, and mixtures thereof. 'fl1e pre- 60
`ferred iron supplement is ferrous fumarate, most preferably a
`dai ly placebo dosage will be equivalent to not more than
`abou t 75 mg ferrous fumarate.
`One goal of the extended estrogen dosing contraceptive
`regimen is to minimize daily exposure to estrogen from either 65
`exogenous or endogenous sources. Without wishing to be
`bound by theory, it is believed that continuous dosage oflow
`
`25
`
`4
`amounts of estrogen may suppress FSI-I (follicle-stimulating
`hormone) and minimize follicular recntitment and therefore
`minimize estrogen contlibution fi·om the developing follicle.
`The cyclic addition of a progestin component suppresses both
`5 Jeutenizing hormone and ovulation while maintaining the
`integrity of the endometriwn. Discontinuation of the proges(cid:173)
`tin provides a withdrawal bleed.
`The limitations of continuous low dose estrogen and
`progestin is irregular bleeding patterns due to a lack of an
`adeq uate withdrawal bleed. A lthough a nigher dose 24-day
`regimen provides an adequate witbd.rawa] bleed and fewer
`bleeding days, follicular suppression may not be optimal. The
`present invention provides in one embodiment that by extend-
`ing the estrogen/progestin dosing beyond 24 days (e.g., 25-26
`days) and utilizing estrogen alone for the rest of the cycle
`results in superior foll icular suppression, Jess endogenous
`estrogen and theretore a more predictable withdrawal bleed
`of fewer days. AJternatively, in yet another embodiment dos(cid:173)
`ing estrogen/ progestin for 22-24 days and eslrogeu alone for
`2-3 days with the addition of a placebo for the remainder of
`the cycle will allow follicular suppression while improving
`the reliability of a withdrawal bleed. These regimens allow
`for lower daily exposure to estrogen. while not compromising
`cycle control, and fewer days of cyclic withdrawal bleeding.
`If cyclic bleeding is predictable and a modest event, this
`nantral episode provides reassurance to reproductive women
`that they are not pregnant and the extended cycle monophasic
`30 continuo us dosing described in U.S. Pat. No. 5,898,032 pro(cid:173)
`vides linle o r no advantage.
`The composi lions used in this invention are administered
`using a suitable daily dosage form. Tablets, pills. capsules,
`and caplets are exemplary dosage fonns. Suitable carriers
`35 with whicb ll1e compositions can be administered include
`lactose, starch, cellulose derivatives and the like used in suit(cid:173)
`able amounts. Lactose is a preferred carrier. Mixtures of
`carriers, e.g. lactose, microcrystalline cellulose and starch,
`may also be used. ln general. any pharmaceutically-accept(cid:173)
`able additive which does not interfere with the function of the
`active components can be used in one or more of the compo(cid:173)
`sitions. -n,ese additives include conventional additives, e.g.,
`fillers, colorants, polymeric binders. and the like.
`The terms "method" and "kit" are used herein to encom(cid:173)
`pass any drug delivery system via the use of which the inven(cid:173)
`tion outlined above can be effectively administered to human
`females. The contraceptive kit of this invention is a package
`containing the daily dosages of the compositions lor practic(cid:173)
`ing the method of this invention. Various types of packages
`for holding contraceptives are well known and it is contem-
`plated that any such packaging may be used or altered for use
`in the practice of the present invention. For example, a single
`cycle package of the present invention for use in continuous
`55 estrogen dosing would preferably include about 25 to about
`26 monophasic daily dosages of the firs t composition and
`abou t 2 to about3 daily dosages of the second composition,
`with a total of 28 dosages. A single cycle package of the
`present invention for use in extended. but not continuous,
`estrogen dosing would preferably include about 22 to about
`24 daily dosages of the first composition. about 2 to 3 daily
`dosages of the second composition and 1 to 4 daily dosages of
`the third composition, with a total of28 dosages. The kit will
`also include instntctions and/or indicia indicating that the first
`dai ly dosage of the first composition should be administered
`on the first day of the menstrua l cycle, which is defi ned as the
`
`Petitioner Exhibit 1001
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`5
`first day of menstrual bleeding, or on the first Sunday after the
`first day of the menstrual cycle.
`
`6
`
`-continued
`
`US 7,704,984 B2
`
`EXAMPLES
`
`The foUowing examples are used to explain the invention
`in more detail. The dosage units are formulated convention(cid:173)
`ally using tablets. pills, coated tablets, and the like.
`
`Example 1
`
`Continuos Estrogen Contraceptive Regimen
`
`5
`
`Composition
`
`22
`
`C
`
`23
`c
`
`24
`c
`
`Day
`
`25
`
`E
`
`26
`
`E
`
`27
`
`p
`
`28
`
`p
`
`Oay I is first day of bleeding.
`C = 1.0 milligrams Norethindrone Acetate and 15 rnicrogroms Et:binyl Estrtl-
`10 diol
`E • t5 micrograms Etbinyl Estradiol
`P =Placebo
`
`2
`
`c
`
`9
`
`c
`
`c
`
`8
`c
`
`Composition
`
`Composition
`
`Composition
`
`c
`
`tO
`c
`
`Day
`
`4
`
`c
`
`Day
`
`11
`c
`Day
`
`18
`c
`
`5
`
`c
`
`12
`c
`
`t9
`c
`
`6
`
`c
`
`13
`c
`
`7
`
`c
`
`14
`c
`
`21
`c
`
`t5
`
`20
`
`25
`
`30
`
`While the invention has been described above wit"h refer(cid:173)
`ence to specific embodiments thereof, it is apparent that many
`changes. modifications, and variations can be made without
`departing from the inventive concept disclosed herein.
`Accordingly, it is intended to embrace all such changes,
`modifications, and variations that fall within the spirit and
`broad scope of the appended claims. All patent applications,
`patents. and other publications cited herein are incorporated
`by reference in their entirety.
`What is claimed is:
`l. A method of contraception comprising the steps of
`sequeotiaJiy administering to a female of child-bearing age:
`(a) a first composition containing a progestin in an amount
`equivalent to about 0.3 to about 1.5 mg norethindrone
`acetate wherein the progestin is selected from norethin(cid:173)
`drone acetate or norethindrone and 5 to 15 meg of ethi(cid:173)
`nyl est"radiol for 24 days;
`(b)a second composition containing 5 to 15 meg ofethinyl
`estradiol and substantially free of a progestin for 2 days;
`and
`(c) a third composition that is a placebo,
`wherein the sequential administration of the first compo(cid:173)
`sition, the second composition and the third composi(cid:173)
`tion, is perfom1ed on a daily basis over a 28 day cycle.
`2. 1l1e method according to claim 1, wherein the sequential
`administration is repeated beginning the day after completion
`of the 28 day cycle.
`3. The method according to claim 1, wherein the progestin
`in the first composition is norethindrone acetate.
`4.111e method according to claim3. wherein the amount of
`norethindrone acetate in tbc first composition is about I mg.
`5. 111e method according to claim 1. wherein the placebo
`contains about 75 mg offerrous fumarate.
`6. The method according to claim 4. wherein the amount of
`elhinyl estradiol in the first and second composition is the
`san1e.
`7. A method of contraception comprising the steps of
`sequentially administering to a fema le of child bearing age:
`(a) a fi rst composition containing about 0.3 to about 1.5 mg
`norethindrone acetate and 5 to 15 meg etbinyl estradiol
`for 24 days:
`(b) a second composition containing 5 to 15mcg of ethinyl
`estradiol and substantially free of a progestin for 2 days;
`(c) a t"b.ird composition that is a placebo for 2 days.
`wherein the sequential administration of the first compo(cid:173)
`sition, tl1e second composition and the third composition
`is performed on a daily basis over a 28 day cycle.
`8. Tl1e method according to claim 7, wherein tl1e first
`composition contains about 1 mg of norethindrone acel'ate.
`9. The method according to claim 7, wherein the amount of
`ethi.nyl estradiol in tl1e first and second composition is the
`same.
`
`* * * * *
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`t5
`c
`
`22
`
`c
`
`t6
`c
`
`23
`c
`
`t7
`c
`
`24
`
`c
`
`Day
`
`25
`
`c
`
`26
`
`E
`
`20
`c
`
`27
`
`E
`
`28
`
`E
`
`Composition
`
`Day I is finlt day ofb1ecding.
`C = 1.0 milligrams Norethindrone Acetate and 15 micrograms Ethil1yl Estrn·
`diol
`E • 15 micrograms Etbinyl Estmdiol
`
`Example 2
`
`Extended Estrogen Contraceptive Regimen
`
`Day
`
`4
`c
`Day
`
`11
`c
`Da
`
`18
`c
`
`c
`
`10
`c
`
`t7
`c
`
`2
`c
`
`9
`c
`
`16
`c
`
`s
`c
`
`t2
`c
`
`19
`c
`
`6
`c
`
`13
`c
`
`20
`c
`
`7
`c
`
`14
`c
`
`21
`c
`
`Composition
`
`Composition
`
`Composition
`
`c
`
`8
`c
`
`15
`c
`
`Petitioner Exhibit 1001
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`