EXHIBIT 1021
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`EXHIBIT 102 1
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`

`

`Europalsches Patentamt
`
`European Patent Office
`
`Office european des brevets
`
`@ Publication number:
`
`0 253 607
`A1
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`@
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 87306174.1
`
`@ Int. Cl.4: A61 K 31/565
`
`@ Date of filing: 13.07.87
`
`@ Priority: 15.07.86 US 885971
`
`@ Date of publication of application:
`20.01.88 Bulletin 88/03
`® Designated Contracting States:
`AT BE CH DE ES FR GR IT Ll LU NL SE
`
`@ Applicant: AMERICAN HOME PRODUCTS
`CORPORATION
`685, Third Avenue
`New York, New York 10017(US)
`
`@ Inventor: Upton, Gertrude Virginia
`208 Hermitage Drive
`Radnor Pennsylvanla(US)
`® Representative: Brown, Keith John Symons et
`al
`c/o John Wyeth & Brother Limited Patent
`and Trademark Department Huntercombe
`Lane South
`Taplow Maidenhead Berkshire SL6 OPH.(GB)
`
`® Combination dosage form for premenopausal women.
`
`@ Disclosed herein is a method of providing hor(cid:173)
`monal replacement therapy and contraception for a
`pre-menopausal woman, which comprises adminis(cid:173)
`tering to a pre-menopausal woman In need thereof a
`combination dosage form of an estrogen selected
`from
`0.5--2.0 mg. of 17,8-estradiol,
`0.008.0.030 mg. of ethinyl estradiol, and
`0.015.0.060 mg. of mestranol;
`and a progestogen selected from
`0.025.0.100 mg. of levonorgestrel,
`0-010.0.070 mg. of gestodene,
`0.025-0.100 mg. of desogestrel,
`0.025-0.100 mg. of 3-ketodesogestrel, and
`"""'
`C:C
`0.085.0.35 mg. of norethindrone,
`I' said combination dosage form being administered
`0 for 23-25 days beginning at day one of the men(cid:173)
`U) strual cycle, followed by 2-5 pill-free or blank pill
`M days, for a total of 28 days in the administration
`ll) cycle. The preferred dosage form of the invention is
`N a combination of 1 mg. of 17 ,8-estradiol and 0.050 or
`0 0.075 mg. of levonorgestrel. The preferred admin(cid:173)
`A. istration cycle of the invention is administration of
`W the combination dosage form for the first 24 days of
`the menstrual cycle and no dosage form for the last
`4 days of the menstrual cycle.
`
`•
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`Xetox Copy Centre
`
`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
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`COMBINATION DOSAGE FORM FOR PRE-MENOPAUSAL WOMEN
`
`The subject invention provides hormonal re(cid:173)
`placement therapy and contraceptive protection for
`the pre-menopausal woman in need thereof. Such
`therapy ~nd contraceptive protection is provided by
`a combination dosage form of the invention which
`comprises a low dose of an estrogen combined
`with a very low dose of a progestogen. A preferred
`combination dosage form of the invention com(cid:173)
`prises 0.5·2.0 mg. of 17tl·estradiol and 0.025·0.100
`mg. of levonorgestrel. The combination dosage
`form of. the invention is administered for the first
`23-26 days of the menstrual cycle, followed by 2·5
`pill-free or blank pill days, for a total o~ 28 days in
`the administration cycle. The preferred administra·
`tion cycle is 24 days of the combination dosage
`form and 4 days of no dosage form.
`Pre-menopause is defined as the time around
`40 years of age when a woman can reasonably be
`said to be approaching menopause (the last men·
`strual period) or the time when a woman feels the
`approach of menopause by experiencing pre(cid:173)
`menopausal irregularities in her menstrual cycle or
`other hypoestrogenic symptoms.
`The woman over forty is in a transitional period
`in which her hormone levels are waning; she still
`ovulates and yet she experiences many of the
`symptoms of the hypoestrogenlc woman, insom·
`nia,hot flushes, irritability, etc. The fact that these
`women are still menstruating has led to the uni(cid:173)
`formed attitude that her complaints are psychoso·
`matic in origin.
`The climacteric is marked by many changes
`due to the natural aging process; all of which are
`modified by individual life-styles. Both natural and
`surgical menopause appear to be associated with
`adverse changes in metabolic parameters and in
`hormone
`levels. For example,
`the metabolic
`change in the blood lipid profile of the post·meno·
`pausal woman may lead to the development of
`athersclerosis, hypertension and coronary heart
`disease. See Notelovitz M, Graig SK, Rappaport V,
`et a!;
`"Menopausal status associated with
`in(cid:173)
`creased inhibition of blood coagulation," Am J Ob·
`stet Gynecol 141 :149, (1981 ); Notelovitz M, Greig
`HBW, "Natural estrogen and anti-thrombin Ill activ·
`ity in postmenopausal women," J Reprod Mad
`16:87 (1976); Nielsen FH, Honore E,Kristoffersen K,
`et al, "Changes in serum lipids during treatment
`with
`norgestrel,
`estradiol-valerate
`and
`cycloprogynon. R Acta Obstet Gynecol Scand
`56:367 {1977) and Paterson MEL, Sturdee OW,
`Moore B, "The effect of various regimens of hor(cid:173)
`mone
`therapy
`on
`serum
`cholesterol
`and
`triglyceride concentrations
`in postmenopausal
`women," Br J Obstet Gynecol 87:552 (1980). Ad-
`
`5
`
`15
`
`20
`
`2s
`
`30
`
`verse changes in hormonal levels of the post(cid:173)
`menopausal woman are associated with en(cid:173)
`dometrial and breast cancer and with osterporosis.
`See Gambrell AD Jr. Bagnell CA, Greenblatt RB,
`"Role of estrogens and progesterone in the etiol·
`ogy and prevention of e.ndometriai cancer: Re(cid:173)
`view," Am J Obstet Gynecoi 146:696 (1983); Gam(cid:173)
`brell AD Jr, "The prevention of endometrial cancer
`in postmenopausal women with progestogen,".
`10 Maturitas 1 :107 (1978); and Nachtigal! LE, Nach·
`tigali RH, Nachtigali AD, et ai, "Estrogen replace·
`ment therapy: I. A 1 O·year prospective study in· the
`relationship
`to osteoporosis," Obstet Gynecoi
`53:277, (1979).
`The years after 40 witness an ever increasing
`number of anovulatory cycles, leaving a woman still
`menstruating but exposed to variable periods of
`unopposed estrogen. It is impossible to predict
`which cycles will be ovulatory or anovulatory be-
`cause of the absence of any consistent pattern.
`Thus, the pre-menopa~sal woman also needs con(cid:173)
`stant contraceptive protection. If one considers the
`mortality rate in the aging woman due to late
`this contraceptive need becomes of
`childbirth,
`paramount importance. Therefore, in consideration
`of the appropriate hormone therapy for the pre(cid:173)
`menopausal woman, attention must be focused on
`the effects of such therapy on metabolic param·
`eters as well as on reproductive target organs. In
`the pre-menopausal woman it is necessary that
`such therapy also be contraceptive.
`In a first aspect, this invention provides a meth·
`od of providing hormonal replacement therapy and
`contraception for a pre-menopausal woman, which
`comprises administering
`to a pre-menopausal
`woman in need thereof a combination dosage form
`of an estrogen selected from
`0.5·2.0 mg. of 17.8-estradiol,
`0.008-0.030 mg. of ethinyl estradiol, and
`O.Q15·0.060 mg. of mestranol;
`and a progestogen selected from
`0.025·0.1 00 mg. of levonorgestrel,
`0.01 Q-0.70 mg. of gestodene,
`0.025-0.100 mg. of desogestrel,
`0.025-0.100 mg. of 3-ketodesogestrel, and
`0.085·0.35 mg. of norethindrone,
`said combination dosage form being administered
`for 23·26 days beginning at day one of the men·
`strual cycle, followed by 2·5 pill-free or blank pill
`days, for a total of 28 days in the adminsitration
`cycle.
`In a second aspect, this invention provides a
`combination dosage form for hormonal replace(cid:173)
`ment therapy and contraception for a pre-meno(cid:173)
`pausal woman, comprising a combination of an
`
`. •
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`35
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`45
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`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
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`estrogen selected from
`0.5--2.0 mg. of 17 p-estradiol
`0.008-0.030 mg. of ethinyl estradiol, and
`O.Q15-Q.060 mg. of mestranol;
`and a progestogen selected from
`0.025-o.100 mg. of levonorgastrel,
`0.010-Q.070 mg. of gestodene,
`0.025-Q.100 mg. of desogestrel. and
`0.025-Q.100 mg. of 3-ketodesogestrel, and
`0.085-Q.35 mg. of norethindrone,
`said combination dosage form baing administered
`for 23 - 26 days beginning at day one of the
`menstrual cycle, followed by 2-5 pill-free or blank
`pill days, for a total of 28 days in the administration
`cycle.
`In the third aspect the invention provides the
`use of a composition comprising an estrogen se(cid:173)
`lected from
`0.5-2.0 mg. of 17 p-estradiol
`0.008-0.030 mg. of ethinyl estradiol, and
`O.G15-Q.060 mg. of mestranol;
`and a progestogen selected from
`0.025-Q.100 mg. of levonorgestrel,
`0.010-Q.070 mg. of gestodene,
`0.025-Q.100 mg. of desogestrel,
`0.025-Q.100 mg. of 3-ketodesogestrel, and
`0.085-Q.35 mg. of norethindrone.
`for the manufacture of a dosage form for providing
`hormonal replacement therapy and contraception
`for a pre-menopausal woman by administration of
`the dosage form for 23 to 26 days beginning at day
`one of the menstrual cycle, followed by 2 to 5 pill(cid:173)
`free or blank pill days, for a total of 28 days in the
`administration cycle.
`A fourth aspect of the invention provides a
`pack for providing hormonal replacement therapy
`and contraception for a pre-menopausal woman
`which pack comprises 23-26 dosage forms each
`comprising an estrogen selected from
`(a) 0.5-2.0 mg. of 17,S-estradiol
`0.008-0.030 mg. of ethinyl estradiol, and
`0.015-Q.OSO mg. of mestranol;
`and a progestogen selected from
`0.025-D.1 00 mg. of levonorgestrel,
`0.010-Q.70 mg. of gestodene,
`0.025-D.100 mg. of desogestrel,
`0.025-0.100 mg. of 3-ketodesogestrel, and
`0.085-D.35 mg. of norethindrone
`(b) 2 to 5 blank pills or other indications to
`indicate that the daily administration of the 23 to 26
`dosage forms should be followed by 2 to 5 pill free
`or blank pill days.
`For all aspects of the invention the preferred
`estrogen is 17 ,s-estradiol and the preferred pro(cid:173)
`gestogen is levonorgestrel. For all aspects of the
`invention a preferred dosage range of the estrogen
`component is:
`0.75-1.50 mg. of 17,8-estradiol,
`
`0.012-0.025 mg. of ethinyl estradiol, and
`0.025-Q.050 mg. of mestranol; and
`a preferred dosage range of the progestogen com(cid:173)
`ponent is:
`0.035-Q.085 mg. of levonorgestrel,
`0.015-0.060 mg. of gestodene,
`0.035-o.085 mg. of desogestrel,
`0.035-D.085 mg. of 3-ketodesogestrei, and
`0.010-Q.30 mg. of norethindrone.
`For all aspects of the invention the preferred es(cid:173)
`trogens are 17 ,S-estradiol, ethinyl estradiol and
`mestranol; and
`the preferred progestogens are
`levonorgestrel, gestodene, desogestrel and 3-
`ketodesogestrel. 17 ,B-estradiol and levonorgestrel
`are particularly preferred. Gestodene is also a par(cid:173)
`ticularly preferred progestogen. A particularly pre(cid:173)
`ferred combination dosage form for all aspects of
`the invention Is a combination in which the es(cid:173)
`trogen is in a dose of 1 mg. of 17 .B-estradiol or an
`equivalent dose of ethinyl estradiol or mestranol
`and the progestogen is in a dose of 0.050 mg. of
`levonorgestrel or an equivalent dose of gestodene,
`desogestrel or 3-ketodesogestrel. A further particu(cid:173)
`larly preferred combination dosage form for both
`aspects of the invention is a combination In which
`the estrogen is in a dose of 1 mg. of 17,8-estradiol
`or an equivalent dose of ethlnyl estradiol or
`mestranol and the progestogen is in a dose of
`0.075 mg. of levonorgestrel or an equivalent dose
`of gestodene, desogestrel, or 3-ketodesogestrel. A
`preferred course of administration for all aspects of
`the invention is administration of the combination
`dosage form of the invention for the first 24 days of
`the menstrual cycle and no dosage form Q.e. plll-
`free) or a blank dosage form for the last 4 days of
`the menstrual cycle. A further preferred course of
`administration for all aspects of the invention is
`administration of .the combination dosage form for
`the first 23 days of the menstrual cycle and no
`dosage form (i.e. pill-free) or a blank dosage form
`for the last 5 days of the menstrual cycle. The
`preferred doses equivalent to 1 mg. of 17,8-es(cid:173)
`tradiol are, approximately: ethinyl estradiol O.Q15
`mg. and mestranol 0.030 mg. The preferred doses
`equivalent to 0.050 mg. of levonorgestrel are ap(cid:173)
`proximately: gestodene 0.035 mg., desogestrel and
`3-ketodesogestrel 0.050 mg., and norethindrone
`0.175 mg. The preferred doses equivalent to 0.075
`mg.
`of
`levonorgestrel
`are,
`approximately:
`gestodene 0.052 mg., desogestrel and 3-
`ketodesogestrel 0.075 mg., and norethindrone 025
`mg. Such equivalent doses may vary depending
`upon the physiological effect desired and the assay
`method used.
`An especially preferred method of the invention
`comprises administering
`to a pre-menopausal
`woman in need thereof a combination dosage form
`of 1 mg. of 17 ,8-estradiol and 0.050 mg. of levonor-
`
`s
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`10
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`15
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`20
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`2s
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`30
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`35
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`40
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`45
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`so
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`55
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`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
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`gestrel or 1 mg. of 17 .B·estradiol and 0.075 mg. of
`levonorgestrel for 23-26 days beginning at day one
`of the menstrual cycle, followed by 2-5 pill-free or
`blank-pill days, for a total of 28 days in the admin·
`istration cycle. An especially preferred combination
`dosage form of the invention for providing hor·
`monal replacement therapy and contraception for a
`pre-menopausal woman comprises a combination
`dosage form of 1 mg. of 17 .B-estradiol and 0.050
`mg. of levonorgestrel or 1 mg. of 17 .B·estradioi and
`0.075 mg. of levonorgestrel, said combination dos·
`age form being administered for 23·26 days begin·
`ning at day one of the menstrual cycle, followed by
`2·5 pill·free or blank-pill days, for a total of 28 days
`in the administration cycle. For all aspects of the
`invention, the preferred cycle of administration is
`administration of the combination dosage form for
`the first 24 days of the menstrual cycle and admin·
`istration of no dosage form or a blank dosage form
`for the last 4 days of the menstrual cycle. Or,
`administration of the combination dosage form for
`the first 23 days of the menstrual cycle and no
`dosage form or a blank dosage form for the last 5
`days is also preferred. A preferred dose of ethinyl
`estradiol equivalent to the preferred dose of 1 mg.
`of 17.8-estradiol is O.G15 mg. The equivalent pre·
`ferred dose of mestranol is 0.030 mg. The pre·
`ferred equivalent doses of desogestrel and 3·
`ketodesogestrel which are equivalent to the ·pre·
`ferred doses of levonorgestrel, namely, 0.050 mg.
`and 0.075 mg. are also 0.050 mg. and 0.075 mg.
`The equivalent preferred doses of gestodene to
`0.050 mg. and and 0.075 mg. of levonorgestrel are
`0.035 mg. and 0.052 mg.
`It is to be understood that in this specification
`and the accompanying claims norgestrel may be
`used in place of levonorgestrel, but at twice the
`stated dose of levonorgestrel. The accompanying
`claims should be construed accordingly. Norgestrel
`is a racemic compound while levonorgestrel is one
`of the optically active isomers. Levonorgestrel is
`particularly preferred.
`The progestogen levonorgestrel is well known
`and has been marketed in oral contraceptive for·
`mulations (at doses of 0.15 mg. and higher) for
`many years. Its chemical name is (·)· 13-ethyl-17·
`hydroxy-18,1 9-dinorpregn-4-en-20-yn-3-one. Nor·
`gastral's common name is 17 a·ethynyl-1 8-homo·
`19-nortestosterone. Gestodene, deogestrel, and 3·
`ketodesogestrel are newer progestogens in various
`stages of clinical development and use. The new
`compound, ge.stodene, differs from norgestrel by a
`double bond in
`the 15 position and
`is pro·
`gestationally active per se, whereas desogestrel is
`believed to be inactive as the parent molecule ·and
`is thought to undergo two metabolic steps for pro·
`gestational activity. Desogestrel is believed to be
`metabolized
`first to the biologically active 313-
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`hydroxydesogestrel with estrogenic/androgenic ac(cid:173)
`tivity and then to 3·ketodesogestrel, which has pro(cid:173)
`gestogenic activity; it differs from norgestrel by a
`methylene group at position 11. Norethindrone's
`chemical name is 17 -hydroxy-19-norpregn-4-en-20-
`yn-3-one. It is. also known as 19-norethisterone or
`norethisterone. Norethindrone acetate may be used
`in place of norethindrone, and hence the term
`"norethindrone" in the accompanying claims is to
`be understood as referring to either the free alcohol
`or its acetate.
`17.B·estradiol is the most potent naturally oc(cid:173)
`curring estrogen in mammals. Its chemical name is
`estra-1,3,5(1 O)·triene-3,17-diol. 17/3-estradiol (or .B·
`estradiol) is its common name. Ethinyl estradiol
`and mestranol are both synthetic estrogens which
`have an ethinyl group at the 17 position of the
`estradiol ring structure. Mestranol additionally has a
`methoxy group rather than a hydroxy group at the
`3 position of the estradiol ring structure. Ethinyl
`estradiol and mestranol are used
`in oral
`contraceptive-formulations. The composition of
`such marketed oral contraceptives is shown in Ta·
`ble 15-2 on page 454 In Chapter 15 "Fertility
`Control and its Complications" by Bruce R. Carr
`and James E.Griffin in Williams Textbook ~ En·
`docrinology, seventh edition, (Jean D.Wilson M.D.
`and Daniel W.Foster M.D. fY'/.8. Saunders Com·
`pany, Philadelphia, 1985).
`An example of a pack which may be used in
`the fourth aspect of the invention or for providing
`the dosage forms for use by the patient in other
`aspects of the invention is a blister pack type
`product as is commonly used with oral contracep-
`tive products. Such product would normally com(cid:173)
`prise the appropriate number of dosage tablets ina-(cid:173)
`sealed blister pack in a cardboard, paperboard or
`plastic sleeve with a protective cover or box. Each
`combination dosage tablet blister container may be
`numbered or otherwise marked for the first 23-26
`days of the m'enstrual cycle, [as, for example,
`prescribed by the patient's physician}. The remain-
`ing 2·5 (pill·free) days of the 28 day administration
`cycle would contain blank-pills or unfilled blisters or
`other marking devices to assist the patient in fol·
`lowing the prescribed administeration cycle. The
`combination estrogen and progestogen dosage
`form of the invention is preferably provided as a
`tablet, caplet or capsule in a manner known in the
`art. Similarly a blank pill is preferably a tablet,
`caplet or capsule containing no active hormonal
`agents. Other oral or parenteral dosage prepara·
`tions or packages may be provided as known in
`the art.
`
`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
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`Claims
`
`1. The use of a composition comprising an
`estrogen selected from
`0.5-2.0 mg. of 17 P-estradiol
`0.008-Q.030 mg. of ethinyl estradiol, and
`O.D15-0.060 mg. of mestranol;
`and a progestogen selected from
`0.025-0.100 mg. of levonorgestrel,
`0.010-Q.070 mg. of gestodene,
`0.025-Q.1 00 mg. of desogestrel,
`0.025-Q.100 mg. of 3-ketodesogestrel, and
`0.085-Q.35 mg. of norethindrone,
`for the manufacture of a dosage form for providing
`hormonal replacement therapy and contraception
`tor a pre-menopausal woman by administration of
`the dosage form for 23 to 26 days beginning at day
`one of the menstrual cycle, followed by 2 to 5 pill(cid:173)
`free or blank pill days, for a total of 28 days in the
`administration cycle.
`2. The use as claimed in Claim 1 in which the
`estrogen is 17 ,8-estradiol.
`3. The use as claimed in Claim 1 or 2 in which
`the progestogen is levonorgestrel.
`4. The use as claimed in Claim 1 or 2 in which
`the progestogen is gestodene, desogestrel or 3-
`ketodesogestrel.
`5. The use as claimed in Claim 1 in which the
`dosage form comprises an estrogen selected from:
`0.75·1.50 mg. of 17,8-estradiol,
`0.012·0.025 mg. of ethinyl estradiol. and
`0.025·0.050 mg of mestranol; and
`a progestrogen selected from:
`0.035-0.085 mg. of levonorgestrel,
`0.015-0.060 mg. of gestodene,
`0.035-Q.085 mg. of desogestrel,
`0.035-Q.085 mg. of 3-ketodesogestrel, and
`0.10-0.30 mg of norethindrone.
`6. The use as claimed in Claim 1 in which the
`estrogen is in a dose of 1 mg. of 17,8-estradiol or
`an equivalent dose of ethinyl estradiol or mestranol
`and the progestogen is in a dose of 0.050 mg. of
`levonorgestrel or an equivalent dose of gestodene,
`desogestrel or 3-ketodesogestrel.
`7. The use as claimed in Claim 1 in which the
`estrogen is in a dose of 1 mg. of 17,8-estradiol or
`an equivalent dose of ethinyl estradiol or mestranol
`and the progestogen is in a dose of 0.075 mg. or
`levonorgestrel or an equivalent dose. of gestodene,
`desogestrel or 3·ketodesogestrel.
`8. A pack for providing a hormonal replace(cid:173)
`ment therapy and contraception for a pre-meno(cid:173)
`pausal woman which pack comprises
`(a) 23 to 26 dosage forms each comprising
`an estrogen selected from:
`0.5-2.0 mg. of 17 ,8-estradiol
`0.008-0.030 mg. of ethinyl estradiol, and
`0.015-0.060 mg. of mestranol:
`
`and a progestogen selected from
`0.025-Q.100 mg. of levonorgestrel,
`0.01 O-Q.70 mg. of gestodene,
`0.025-Q.100 mg. of desogestrel
`0.025-Q.100 mg. of 3-ketodesogestrel, and
`0.085-Q.35 mg. of norethindrone
`
`and
`
`(b) 2 to 5 blank pills or other indications to
`indicate that the daily administration of the 23 to 26
`dosage forms should be followed by 2 to 5 pill free
`or blank pill days.
`9. A pack as claimed in Claim 8 in which the
`estrogen selected is 171!-estradiol.
`10. A pack as claimed in Claim 8 or 9 in which
`the progestogen selected is levonorgestrel.
`11 . A pack as claimed in Claim 8 in which the
`estrogen is selected from:
`0.75-1.50 mg. of 17,8-estradiol,
`0.012-Q.025 mg. of ethinyl estradiol, and
`0.025-Q.050 mg. of mestranol; and
`the progestogen is selected from:
`0.035-Q.085 mg. of levonorgestrel,
`0.015-0.060 mg. of gestodene,
`0.035-o.085 mg. of desogestrel,
`0.035-Q.OBS mg. of 3-ketodesogestrel, and
`0.10·0.30 mg. of norethindrone.
`12. A pack as claimed in Claim 8 in which the
`estrogen is in a dose of 1 mg. of 17 ,B·estradiol or
`an equivalent dose of ethinyl estradiol or mestranol
`and the progestogen is in a dose of 0.050 mg. of
`levonorgestrel or an equivalent dose of gestodene,
`desogestrel or 3·ketodesogestrel.
`13. A pack as claimed in Claim 8 in which the
`estrogen is in a dose of 1 mg. of 17,8-estradiol or
`an equivalent dose of ethinyl estradiol or mestranol
`and the progestogen is In a dose of 0.075 mg. of
`levonorgestrel or an equivalent dose of gestodene,
`desogestrel or 3-ketodesogestrel.
`14. A pack as claimed In any one of Claims 8
`to 13 which comprises 24 dosage forms and 4
`blank pills or other indications to indicate thaf no
`dosage form or a blank pill is admin'lstered for the
`last 4 days of the menstrual cycle.
`15. A pack as claimed in any one of Claims 8
`to 13 which comprises 23 dosage forms and 5
`blank pills or other indications to indicate that no
`dosage form or a blank pill is administered for the
`last 5 days of the menstrual cycle.
`16. A pack according to Claim 8 comprising 24
`dosage forms each comprising 1 mg. of 17,s-es,
`tradiol and 0.50 mg. or 0.075 mg. levonorgestrel
`and 4 blank pills or other indications to indicate that
`no dosage form or a blank pill is administered for
`the last 4 days of the menstrual cycle.
`17. A pack according to Claim 8 comprising 23
`dosage forms each comprising 1 mg. of 17t!-es(cid:173)
`tradiol and 0.50 mg. or 0.075 mg. of levonorgestrel
`
`s
`
`10
`
`1s
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`so
`
`55
`
`5
`
`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`9
`
`0 253 607
`
`10
`
`and 5 blank pills or other indications to indicate that
`no dosage form or a blank pill is administered for
`the last 5 days of the menstrual cycle.
`
`Claims for the following Contracting States: ES,
`GR. AT
`
`5
`
`8. A process for preparing a pack for providing
`a hormonal replacement therapy and contraception
`for a premenopausal woman which process com·
`prises associating
`(a) 23 to 26 dosage forms each comprising
`an estrogen selected from:
`0.5-2.0 mg. of 17.B=estradiol
`0.008-0.030 mg. of ethinyl estradiol, and
`O.Q15-0.060 mg. of mestranol;
`and a progestogen selected from
`0.025·0.1 00 mg. of levonorgestrel,
`0.010-0.70 mg. of gestodene,
`0.025-0.100 mg. of desogestrel
`0.025-0.100 mg. of 3-ketodesogestrel, and
`-0.085-0.35 mg. of norethindrone
`
`with
`
`10
`
`15
`
`20
`
`1. The use of a composition comprising an
`estrogen selected from
`0.5-2.0 mg. of 17,8-estradiol
`0.008-0.030 mg. of ethinyl estradiol, and
`0.015-0.060 mg. of mestranol;
`and a progestogen selected from
`0.025-0.100 mg. of levonorgestrel,
`0.010-0.070 mg. of gestodene,
`0.025-0.100 mg. of desogestrel,
`0.025·0.100 mg. of 3-ketodesogestrel, and
`0.085-0.35 mg. of norethindrone,
`for the manufacture of a dosage form for providing
`hormonal replacement therapy and contraception
`for a pre-menopausal woman by administration of
`the dosage form for 23 to 26 days beginning at day
`one of the menstrual cycle, followed by 2 to 5 pill·
`free or blank pill days, for a total of 28 days in the
`administration cycle.
`2. The use as claimed in Claim 1 in which the
`estrogen is 17 ,8-estradiol.
`3. The use as claimed in Claim 1 or 2 in which
`the progestogen is levonorgestrel.
`4. The use as claimed in Claim 1 or 2 in which
`the progestogen is gestodene, desogestrel or 3·
`ketodesogestrel.
`5. The use as claimed in Claim 1 in which the
`dosage form comprises an estrogen selected from:
`0.75-1.50 mg. of 17,8-estradiol,
`0.012-0.025 mg. of ethinyl estradiol, and
`0.025-Q.050 mg of mestranol; and
`a progestrogen selected from:
`0.035-0.085 mg. of levonorgestrel,
`O.Q15-0.060 mg. of gestodene,
`0.035-Q.085 mg. of desogestrel,
`0.035-0.085 mg. of 3-ketodesogestrel, and
`0.10-0.30 mg of norethindrone.
`6. The use as claimed in Claim 1 in which the
`estrogen is in a dose of 1 mg. of 17,8-estradiol or
`an equivalent dose of ethinyl estradiol or mestranol
`and the progestogen is in a dose of 0.050 mg. of
`levonorgestrel or an equivalent dose of gestodene,
`desogestrel or 3-ketodesogestrel.
`7. The use as claimed in Claim 1 in which the
`estrogen is in a dose of 1 mg. of 17,8-estradiol or
`an equivalent dose of ethinyl estradiol or mestranol
`and the progestogen is in a dose of 0.075 mg. or
`levonorgestrel or an equivalent dose of gestodene,
`desogestrel or 3-ketodesogestrel.
`
`(b) 2 to 5 blank pills or other indications to
`indicate that the daily administration of the 23 to 26
`dosage forms should be followed by 2 to 5 pill free
`or blank pill days.
`9. A process as claimed in Claim 8 in which
`the estrogen selected is 17 .B-estradiol.
`1 O.A process as claimed in Claim 8 or 9 in
`25 which the progestogen selected is Jevonorgestrel.
`11.A process as claimed in Claim 8 in which
`the estrogen ·is selected from:
`0.75-1 .50 mg. of 17,8-estradiol,
`0.012-0.025 mg. of ethinyl estradiol, and
`0.025-0.050 mg. of mestranol: and
`the progestogen is selected from:
`0.035·0.085 mg. of levonorgestrel,
`0.015·0.060 mg. of gestodene,
`0.035-0.085 mg. of desogestrel,
`0.035-0.085 mg. of 3-ketodesogestrel, and
`0.10-0.30 mg. of norethindrone.
`12.A process as claimed in Claim 8 in which
`the estrogen is in a dose of 1 mg. of 17,8-estradiol
`or an equivalent dose of ethinyl estradiol or
`40 mestranol and the progestogen is in a dose of
`0.050 mg. of levonorgestrel or an equivalent dose
`of gestodene, desogestrel or 3-ketodesogestrel.
`13.A process as claimed in Claim 8 in which
`the estrogen is in a dose of 1 mg. of 17,8-estradiol
`or an equivalent dose of ethinyl estradiol or
`mestranol and the progestogen is in a dose of
`0.075 mg. of levonorgestrel or an equivalent dose
`of gestodene, desogestrel or 3-ketodesogestrel.
`14.A process as claimed in any one of Claims
`8 to 13 which comprises 24 dosage forms and 4
`blank pills or other indications to indicate that no
`dosage form or a blank pill is administered for the
`last 4 days of the menstrual cycle.
`15. A process as claimed in any one of Claims
`8 to 13 which comprises 23 dosage forms and 5
`blank pills or other indications to indicate that no
`dosage form or a blank pill is administered for the
`last 5 days of the menstrual cycle.
`
`30
`
`35
`
`45
`
`so
`
`ss
`
`6
`
`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`

`11
`
`0 253 607
`
`12
`
`16. A process according to Claim 8 comprising
`24 dosage forms each comprising 1 mg. of 17 ~­
`estradiol and 0.50 mg. or 0.075 mg. levonorgestrel
`and 4 blank pills or other indications to indicate that
`no dosage form or a blank pill is administered for
`the last 4 days of the menstrual cycle.
`17. A process according to Claim 8 comprising
`23 dosage forms each comprising 1 mg. of 17/J(cid:173)
`estradiol and 0.50 mg. or 0.075 mg. of levonor-
`gestrel and 5 blank pills or other indications to
`indicate that no dosage form or a blank pill is
`administered for the last 5 days of the menstrual
`cycle.
`
`s
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`55
`
`7
`
`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`

`

`A\\\ Eu~opean Patent
`:J!!)J Off1ce
`
`EUROPEAN SEARCH REPORT
`
`Appllea11on number
`
`EP 87 30 6174
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation of document with indication. where appropriate,
`otnrievantp~es
`
`Cat~gory
`
`Relevant
`to claim
`
`CLASSIFICATION OF THE
`APPLICA TJON (Int. CI.A)
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`(PLUNKETT et
`EP-A-0 136 011
`al.)
`* Page 19, line 1 - page 22, line
`6; claims 1- 15 *
`---
`UNLISTED DRUGS, vol. 26, no. 10,
`October 1974, page 162q,
`Chatham, New Jersey, US;
`"Sophia- A"
`
`---
`
`UNLISTED DRUGS, vol . 271 no. 9,
`September 1975, page 145d,
`Chatham, New Jersey, US;
`"Medicon"
`
`---
`UNLISTED DRUGS, vol . 25, no. 10,
`October 1973, page 160a,
`Chatham, New Jersey, US;
`"Microgynon"
`
`---
`UNLISTED DRUGS, vol. 27, no. 12,
`December 1975, page 194g,
`Chatham, New "'J'ersey, US;
`"Menophase"
`
`---
`UNLISTED .DRUGS, vol. 34, no. 2,
`February 1982, page 29f,
`Chatham, New Jersey,
`US;
`11Trionetta 11
`
`---
`
`-I-
`
`1-17
`
`A 61 K 31/565
`
`1-17
`
`1-17
`
`1- 17
`
`1- 17
`
`1- 17
`
`TECHNICAL FIELDS
`SEARCHED (Int. CI.AJ
`
`A 61 K
`
`·"':J
`
`Pl-of-rett
`THE HAGUE
`
`Date of completion of the MarCh
`21-10-1987
`
`Examiner
`
`! BRINKMANN C.
`
`CATEGORY OF CITED DOCUMENTS
`
`T : theory or principle underlying the invention
`~
`a
`E : earlier patent document, but published on. or
`X : particularly retevant if taken alone
`after the filing date
`~ Y : particularly relevant if combined with another
`0 : document cited in the application
`document of the same category
`L : document cited for other reasons
`~ A : technological background
`& : 'memtier'oili-.e'samepatent'iamily, corresponding
`...
`0 : non-written disclosure
`~ P : intermediate document
`document
`w~----~~~~~~----------------------~~----------------------------~
`
`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
`
`

`

`European Patent
`Office
`
`EUROPEAN SEARCH REPORT
`
`Applicat•on number
`
`•
`
`Category
`
`A
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation of document with indication, where appropriate,
`of relevant paaaages
`
`UNLISTED DRUGS, vol. 26, no. 11,
`November 1974, page 170b,
`Chatham, New Jersey, US; "
`WL- 20 11
`
`Ret.¥ ant
`to claim
`
`1- 17
`
`EP 87 30 6174
`
`Page 2
`CLASSIFICATION OF THE
`APPLICATION (Int. Cl.4)
`
`TECHNICAL FIELDS
`SEARCHED (Int. Cl.4)
`
`Examiner
`BRINKMANN C.
`
`I
`
`Place of search
`THE HAGUE
`
`Date of completion of the search
`21- 10- 1987
`
`CATEGORY OF CITED DOCUMENTS
`
`T : theory or principle underlying the invention
`E : earlier patent document. but published on. or
`after the tiling date
`X : particularly relevant if taken alone
`0 : document cited In the application
`Y : particularly relevant if combined with another
`document of the same category
`L : document cited tor other reasons
`... ~ A : technological background
`&·:· memtleroTitie"siriwt patent tamny, c~rresponding
`o : non-written disclosure
`2 P : intermediate document
`document
`w ~---------~---~--~---------------------------------------------------------------------------~
`
`Petitioner Exhibit 1021
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
`
`