United States Patent
`
`I9
`
`Vorys
`
`FOLLICULAR PHASE ESTROGEN OR
`PROCESTIN WITH PHYSIOLOGIC
`ESTROGEN/PROGESTIN
`LUTEAL PHASE
`DRUG DELIVERY SYSTEM
`REPLACEMENT
`
`Inventor
`
`Nichols
`
`336
`Columbia
`Vorys
`Ave Columbus Ohio 43209
`AppI No 69275
`
`Filed
`
`Aug 24 1979
`
`Related U.S Application
`
`Data
`
`Division
`doned
`
`mt CL3
`U.S Cl
`
`of 5cr No 865851 Dcc 30
`
`1977
`
`aban
`
`AOIN 45/00
`
`A61K 31/56
`424/2413
`424/238
`206/533
`
`Field of Search
`
`424/238
`
`240
`
`4292315
`
`Sep 29 1981
`
`the
`
`follicular phase
`tered Depending
`
`on
`
`no
`
`exogenous
`the clinical and/or
`
`steroid
`
`is adminis
`
`physiologic
`
`situation of
`
`patient
`
`or estrogen
`progestin
`embodiment
`
`and
`
`progestin
`
`in
`
`bination
`
`cal
`
`success
`
`estrogen/progestin
`of the method
`
`only upon
`
`cule
`
`administered
`
`unopposed
`is then administered In the preferred
`an
`phase follows with low dose administration
`early luteal
`of combination
`estrogen/progestin mid luteal estrogen
`dose
`is administered
`adequate to
`pituitary FSH and LH and
`to maintain
`the
`suppress
`reduced dosage of com
`endometrium and terminally
`is administered The clini
`not
`and formulation
`depends
`potency of the progestin mole
`the biologic
`and
`the dose
`but also depends
`upon
`of administration
`
`of exogenous
`temporal
`relationship
`estrogen progestin and combination
`estrogen/proges
`any FDA approved
`tin As
`or progestin in pharmacologically appropriate
`in accordance with
`and
`
`consequence
`
`synthetic
`
`estrogen
`
`is suitable for formulation
`
`dosage
`the present
`
`invention Menstrual
`
`regulation
`
`effective
`
`contraception
`
`References
`Cited
`U.S PATENT DOCUMENTS
`
`3409721
`
`3957982
`
`11/1968
`
`5/1976
`
`Applezweig
`Lachnit-Fixson
`
`424/238
`
`424/238
`
`Attorney
`
`Primary ExamineElbert
`Roberts
`Agent or FirmKenyon
`ABSTRACF
`
`Kenyon
`
`method formulation and steroid drug delivery sys
`tem for the administration
`
`of sex steroids for menstrual
`The invention
`
`is useful
`
`in
`
`cycle
`
`regulation
`
`is disclosed
`
`clinical applications
`ment of menstrual
`
`for pregnancy
`dysfunction Progestin
`
`and
`treat
`spacing
`and estrogen
`in
`treatment
`sex
`cycle mimicking
`in the normal menstrual cycle The
`is divided
`cycle
`into arbitrary
`and
`follicular and luteal phase segments beginning
`with the Onset of menstruation In the early segment
`of
`
`are administered
`
`steroid hormones
`
`steroid treatment
`
`discrete
`
`pituitary dysrhythmia rather
`
`than
`
`endogenous
`
`estrogen
`
`suppression
`
`to the adverse endocrine
`
`and metabolic
`
`cycle
`is achieved
`by hypothalamic-
`sustained FSH LH
`reduced exposure
`effects of high
`
`dose estrogen
`
`and progestin
`
`administered
`
`concurrently
`
`the adminis
`Upon discontinuation
`is accomplished
`of
`invention prompt FSH and subse
`tration of the present
`quent LH recovery
`ensue providing for an appropriate
`return of ovulation
`and appropriate
`menstruation
`in the
`patient The method
`prior to drug normal ovulating
`formulation
`to take physio
`further allow the physician
`
`and
`
`measures
`corrective
`in menstrual
`logic
`patients who may or may not seek
`as hypoestrogen
`
`present
`
`eueslrogen
`
`or hyperestrogen
`
`dysfunction
`and
`
`contraception
`
`ovulation
`
`dysfunction
`
`or anovulatory
`
`20 Claims
`
`Drawing
`
`DY OFCYCU
`
`PaInflfVs Exhibit
`
`Cee Na 12Y292JAPTJE
`
`PTX 112
`
`WC_LPO4O 5821
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`

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`U.S Patent
`
`Sep 29 1981
`
`Sheet
`
`of
`
`4292315
`
`FIG
`
`FIG
`
`PREOVULATORY
`
`-J
`
`WC_LP0405822
`
`DAY OF CYCLE
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2015, Pg. 2
`
`

`
`U.S Patent
`
`Sep 29 1981
`
`Sheet
`
`of
`
`4292315
`
`FIG
`
`Ij
`
`FIG.4
`
`Cd
`
`DAY OF CYCLE
`
`WC_LP0405823
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`WC Ex. 2015, Pg. 3
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`

`
`U.S Patent
`
`Sep 29 1981
`
`Sheet
`
`of
`
`4292315
`
`18
`
`xT
`
`61L1A
`
`P.eoc Qr
`
`25
`
`FIG
`
`Oq.y .57QQ
`
`.05
`
`.02
`
`.35
`
`I.e
`
`GES7Vjy
`
`11 iI
`
`14
`
`ZI
`
`ze
`
`WC_LP0405824
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2015, Pg. 4
`
`

`
`U.S Patent
`
`Sep 29 1981
`
`Sheet
`
`of
`
`4292315
`
`WC_LP0405825
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`WC Ex. 2015, Pg. 5
`
`

`
`U.S Patent
`
`Sep 29 1981
`
`Sheet
`
`of
`
`4292315
`
`FIG.7
`
`2OmIU
`
`DAY OF CYCLE
`
`FIG.8
`
`DAY OF CYCLE
`
`WC_LP0405826
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2015, Pg. 6
`
`

`
`U.S Patent
`
`Sep 29 1981
`
`Sheet
`
`of
`
`4292315
`
`FIG
`
`FIG 9A
`
`FIG 9C
`
`WC_LP0405827
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`WC Ex. 2015, Pg. 7
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`

`
`4292315
`
`and progestin while previously
`estrogen
`been discontinued
`of associated
`because
`
`allowed
`cancer of the
`
`has
`
`endometrium
`The administration
`
`of these
`
`sex steroid
`
`exogenous
`has been associated with the development
`formulations
`In 1956 when Rock
`of adverse side effects in patients
`Pinkus et
`combined
`trials of
`began clinical
`and
`of estrogen
`the progestin 19 nortestosterone
`considered
`their study
`and metabolic
`
`dosage
`
`for
`
`only
`
`evaluation
`
`consequences
`of the metabolic
`
`contraceptive
`
`objectives
`
`cursory endocrinologic
`and made only preliminary
`fate of
`the exogenous
`tered Subsequent
`both mild and serious
`
`and progestin
`estrogen
`have
`however
`authors
`reported
`side effects resulting from combi
`oral estrogen
`and
`sequential
`The mild side effects include
`
`adminis
`
`progestin
`
`nausea
`
`ad-
`vom
`
`15
`
`nation
`
`and
`
`ministration
`
`FOLLICULAR PHASE ESTROGEN OR
`PROGESTIN WITH PHYSIOLOGIC
`ESTROGEN/PROGESTIN
`LUTEAL PHASE
`DRUG DELIVERY SYSTEM
`REPLACEMENT
`
`This is
`division of application
`Dec 30 1977 now abandoned
`
`Ser No 865851
`
`filed
`
`BA
`
`CKGROUND OF THE INVENTION
`
`The following
`specification describes my invention
`system The invention
`new steroid drug delivery
`and formulation
`new method
`for menstrual
`useful
`
`10
`
`of
`
`is
`
`cycle
`
`regulation
`
`menstrual
`
`is
`
`to achieve
`and
`ovulation
`control
`to treat
`dysfunction More particularly my invention
`follicular-luteal sex steroid replacement which may
`be adapted to the specific presenting
`clinical state of the
`patent Thus
`individual
`the method
`the invention
`placement of
`of clinical states
`
`for sex steroid re-
`
`lassitude weight gain fluid retention
`iting fatigue
`The more
`and headache
`
`serious
`
`side effects
`
`chloasma
`
`of menstrual
`
`is useful
`
`in the management
`irregularity menstrual
`
`dysfunction ovulation
`pain primary dysmenorrhea
`syndrome The method
`and premenstrual tension
`useful
`sex steroid drug delivery
`system for preg-
`where
`sex steroids are widely used
`
`as
`
`spacing
`
`nancy
`day
`
`is also
`
`to-
`
`metabolic
`
`resulted
`
`for undesirable
`
`administered
`
`present
`
`bolic
`
`and endocrine
`
`clinical endocrine and
`Opportunities
`side effects which have
`from exoge-
`nous steroid dosages
`in prior art contra-
`and
`ceptive methods
`are reduced by the
`formulations
`The hepatic morphologic
`invention
`meta-
`adverse consequences
`from sex
`are reduced by steroid adminis-
`steroid treatment
`cycles
`invention Future
`tration in accordance with the present
`ovulation
`disturbance
`in patients
`administered
`
`roids for menstrual
`
`contraception
`
`purposes is also mini-
`
`sex ste-
`
`were
`
`in liver
`
`function chloestatic
`
`20
`
`disease
`
`changes
`thromboembolic
`alteration in carbohydrate
`lipid metabolism hypertension modular
`hyperplasia
`the liver and carcinoma of the endometrium
`By 1970 the adverse effects of high level dosages of
`combination
`were
`
`jaundice
`and
`
`of
`
`frequently
`gen i.e over
`
`doses
`
`of estro
`
`adverse
`
`side effects
`
`also noted liver
`
`invariably
`
`associ
`
`thyroid
`
`globulin
`
`transfuren
`
`cerulo
`
`beta
`
`estrogen/progestin
`contraceptives
`25 more widely reported Thromboembolic
`disease was
`more
`associated with larger
`0.05 mgm Other
`the liver were
`particularly
`involving
`tumors or nodular hyperplasia were
`30 ated with high dose estrogen/progestin
`administration
`of time two years or more liver pro-
`for long periods
`estrogen in
`tein synthesis
`was affected
`by exogenous
`bind-
`the serum proteins
`creasing
`transcortin
`ing globulin TE binding
`35 plasmin pre-beta
`lipoproteins
`IGg
`otensinogen
`related coagulation
`and IX
`VIII
`To reduce adverse
`and endocrine
`metabolic
`40 quences work in the prior art sought
`and progestin
`dosage of both the estrogen
`component
`the combination
`sex steroid birth control pill For exam-
`
`macroglobulen
`factors i.e VII
`
`angi
`lipoproteins
`and prothrombin
`and probably II
`
`conse
`
`to decrease
`
`the
`
`of
`
`norethynodrel
`
`the progestin
`pie the pill
`combining
`and the estrogen mestranol
`45 was
`subsequently
`and estrogen
`19-nortestosterone
`
`first
`
`introduced
`
`redesigned
`in 1960 and
`
`content
`
`introduced
`
`in 1963
`
`in 1957
`with
`lower progestin
`1964 Norethindrone
`progestin was
`with the estrogen mestranol Dosage
`reduced
`these steroids were
`
`levels of the
`
`pill combining
`in 1963
`and 1975
`1967
`The later identification
`of more
`biologically
`potent
`progestin molecules allowed the prior art
`to reduce the
`
`manages
`
`in
`
`rational
`
`physiologic
`
`manner
`
`and
`
`combined
`
`jiwBLEMS OF THE rRIOR
`
`50
`
`In the prior art
`
`the combination
`
`cyclic
`
`used
`
`in
`
`diacetate
`
`cally potent
`60 were
`
`and/or
`
`progestins
`
`were
`
`in
`
`but
`
`administered
`synthetic
`with the estrogen
`l9-nortestosterone
`
`65 and
`
`ethinyldiol
`
`only acted
`
`as oral progestin
`
`and/or
`dosage of synthetic
`progestin
`estrogen
`combination
`birth control pills Thus when norgestrel
`both potent
`55 and ethinyldiol
`were
`progestins
`in 1968
`and 1969
`combination
`introduced
`respectively
`allowed
`reduced
`pills formulated with these progestin
`estrogen As more biologi
`dosage of progestin
`the progestins
`identified
`lower daily dosage
`not only administered
`also allowed
`of
`the
`reduced dosage
`concurrently-
`estrogen Also in accordance
`approach of the prior art
`reduction
`such as norethynodrel
`compounds
`were
`which
`diacetate
`not
`identified
`but also had some associ
`Other
`
`ated
`
`inherent
`
`activity
`
`mized
`
`In addition
`
`and formulation
`
`allows
`
`rational
`
`invention
`
`the present
`method
`provides
`for the delivery
`of steroid drugs which
`decrease
`in sex
`of exogenous
`estrogen
`cycle management The method mini-
`steroid menstrual
`rnizes both the dose and days of administration
`of exog-
`enous estrogen
`and minimizes the days of combination
`and
`exogenous
`estrogen
`progestin
`cycles The invention
`ment
`provides adequate men-
`and physiologic
`of men-
`correction
`clinical problems
`formulation
`
`in sex steroid treat-
`
`strual cycle
`
`control
`
`strual dysfunction
`
`in diverse
`
`current
`
`estrogen/progestin
`
`that no
`
`adequately
`
`and sequential
`hormone
`drugs by oral
`effects has been known
`
`dosage
`
`recent
`
`available
`
`steroid dos-
`
`ages
`
`in tablet
`
`form each
`
`are
`
`norgestrel
`
`ethynodiol
`
`diac-
`
`administration
`of sex steroid
`to achieve contraceptive
`since about 1957
`survey of currently
`for oral contraception
`lists some twenty-four corn-
`formulations Chart Hormone
`available
`mercially
`Content of Currently Available
`Oral Contraceptives
`43216 March
`Ross
`Laboratories Columbus Ohio
`1976 These
`cornbina-
`formulations
`administer
`either
`tion of both estrogen
`and progestin
`day for twenty or twenty
`one days following menstrua-
`tion or provide microdose tablet of progestin
`alone
`in continuous
`fashion
`Such contraceptive
`dosages
`formulated from synthetic
`estrogens mestranol and
`and synthetic
`ethinyl estradiol
`progestins
`norethindrone norethindrone acetate
`and norethynodrel
`
`etate
`
`Sequential
`
`administration
`
`of
`
`progestins
`
`estrogen
`have
`
`increased
`
`substitute
`oral
`and maxi
`
`androgen activity
`
`WC_LP0405828
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2015, Pg. 8
`
`

`
`mum anti-estrogen
`toserone
`
`activity
`
`is norgestrel
`
`The most potent
`19 fortes
`which is significantly
`
`potent
`
`than
`
`norethindrone
`
`4292315
`
`progestin
`more pharmacologically
`of
`which because
`
`its biologic
`
`allowed the for
`
`pill marketed
`
`potency
`combination
`low dose
`mulation of
`the trademark Lo/Ovral
`under
`with
`daily estrogen
`dose reduced to under 0.05 mgrn and finally to as low
`as 0.03 mgm for twenty-one
`days in daily combination
`No progestm other
`with
`dosage
`reduced progestin
`can be administered
`low 10
`than norgestrel
`in comparable
`doses of progestin
`and estrogen without
`poor contin
`
`pharmacologic
`serious menstrual disarray and exceedingly
`
`uation
`rates
`Of the prior art combination pills many reproduction
`from 15
`the safest
`Lo/Oral
`consider
`endocrinologists
`metabolic and endocrine
`Weaker
`
`such
`
`standpoint
`as northindrone and noreth
`formulated with low dose
`
`pill
`
`progestins
`indrone acetate
`were
`also
`latter formulations
`estrogen in combination pills These
`levels however were
`dose
`in several
`and unpredictable
`breakthough
`bleeding
`in 40 to 50% of the cases Because
`their acceptance has been minimal
`fact
`Hence because of the prior art approach in develop
`ing new and more
`steroid molecules
`potent
`of the various
`combination
`characteristic
`
`ing
`
`associated with 20
`
`uterine bleed
`
`of this clinical
`
`principal
`
`25
`
`contraceptive
`
`the
`
`is required
`
`wit
`
`contraception
`when
`
`ministered
`
`estrogen
`
`to adapt
`
`norgestrel
`
`of
`
`the enterohepatic
`
`circulation
`
`of estrogen
`because
`from exogenous
`provides little metabolic rest
`estrogen
`by the liver
`and results in an altered protein synthesis
`This affects metabolic consequences
`in carbohydrate
`test hyper
`metabolism decreased
`glucose tolerance
`and lipid metabo
`tension
`increased
`angiotensinogen
`in Fredrickson Class
`IV hyper
`
`lism i.e elevation
`ha and
`
`triglycerides
`
`of cholesterol
`in Fredrickson Class
`
`lipidemias
`Concurrent
`cell membrane
`permeability
`combination with progestin
`
`progestin
`
`administration
`
`affects
`
`target
`
`Exogenous
`
`estrogen
`
`in
`
`is transported
`
`into the cell
`
`receptor
`
`site at
`
`rate
`
`progestin
`
`to the cytosol
`greater
`estrogen
`in the presence of
`and concentration thus
`estrogen
`effect on liver cell pro
`has more profound
`Thus in the combina
`and cell replication
`tein synthesis
`is administered
`tion birth control pills where
`estrogen
`results an unremit
`concurrently with progestin there
`by the liver as well
`ting abnormal
`of proteins
`capabilities of the liver
`as alteration
`and met
`the endocrine
`dos
`
`synthesis
`
`in the excretory
`
`Another
`
`approach to prevent
`
`abolic
`
`abnormalities
`
`associated
`
`with combination
`
`employed
`
`progestin
`
`solely
`
`injectible
`delivery
`longlasting
`in side effects includ
`
`resulted
`
`age of estrogen/progestin
`One such method
`was
`system which however
`follicular and corpus
`of abnormal
`ing the development
`and unpredictable
`luteum phases of the menstrual cycle
`low
`progestin method provides
`bleeding Another
`in the form of
`the mini-pill
`dose of progestin
`
`which
`
`progestins
`
`and lower tract
`to prevent pregnancy
`acts on the cervix
`Small continued microdoses of several
`norethindrone and
`particularly
`tempted in this manner but each
`fohlicular
`and
`abnormal
`with breakthrough
`bleeding
`the menstrual cycle The
`and corpus luteum phases
`of
`the
`administered
`fate of the corpus luteum in patients
`is in one-third of the patients
`and in the remaining
`
`norgestrel
`been associated
`
`were
`
`at
`
`has
`
`normal
`
`in func
`
`40
`
`While the solo
`
`side
`
`dosage of progestin
`of
`effects
`contraceptive
`
`reduced estrogen
`
`pills the
`chaos
`and
`
`the
`
`in the market
`is that
`steroid
`formulations
`today
`on the potency of the pro
`design of each
`is predicated
`used in the combination with its inher
`gestin molecule
`To 30
`reduced dosage of estrogen
`eat ability to allow
`administered less
`the more potent
`the
`progestin
`in combination with the progestin
`estrogen
`to achieve effective
`and menstrual cycle
`is ad
`control However
`less potent
`progestirl
`reduced
`of 35
`with
`in combination
`dosage
`to adverse metabolic effects men
`results Of the lower dose combi
`strual cycle
`disruption
`0.3 mgm
`nation pills Lo/Ovral combining
`0.03 mgm for
`with
`low dose
`ethinyl
`estradiol
`char-
`the best overall performance
`days has
`This formulation as does all other combina
`acteristics
`uniform and unremitting
`tion pills however provides
`in combination with pro
`dosage of exogenous
`pharam
`gestin during the twenty-one
`day drug cycle
`principle which
`for the
`is contraphysiologic
`of menstrual dysfunction
`management
`The prior art also unsuccessfully
`attempted
`of estrogen
`and progestin
`tial administration
`steroids
`In
`about 1967 several drug companies marketed an estro
`which provided
`for
`formulation
`cycle
`gen sequential
`estrogen followed
`days of unopposed
`dosage
`by five or seven days of combination
`and pro
`estrogen
`group of clinical and metabolic side effects
`of estrogen
`characteristic
`as
`developed
`sequential
`result of the large
`estro-
`dose of unopposed
`exogenous
`by this formulation The adverse ef
`administered
`gen
`eukorrhea
`fluid retention
`weight gain
`pregnancies Re
`unexpected
`ovulation
`escape
`has been reported to be asso
`cently estrogen
`sequential
`of the endometrium
`ciated with abnormal morphology
`lesions and carcionoma
`premalignant
`Because
`
`twenty-one
`
`cological
`
`estrogen
`
`of sixteen
`
`gestin
`
`fects
`
`included
`
`and
`
`sequen
`
`45
`
`50
`
`55
`
`60
`
`suggesting
`endometrium
`
`of such
`
`side effects
`
`sequential
`market
`
`formulations
`
`have
`
`been
`
`removed
`
`of
`
`the
`
`estrogen
`from the
`
`In these
`
`steroid
`
`formulations
`
`estrogen
`
`is believed
`
`that
`
`dosage
`and progestin it
`combination
`of the
`component
`estrogen
`sequential pill when given for sustained
`
`of
`
`combined
`the large dose
`
`65
`
`and
`estrogen
`periods of time
`
`mini-pill
`tion and in one-third abnormal
`third absent
`
`dependent
`was associated with menstrual cycle
`method
`receiving
`In patients
`severe menstrual derangement
`bleeding
`that breakthrough
`it was estimated
`mini-pill
`and
`occurred in approximately 40 to 50% of the patients
`than 25% in
`was less
`rate for patients
`the continuation
`one year Thus
`progestin
`long term clinical use either
`menstrual cycle
`regulation
`the prior art neither success
`In sum in most instances
`present nor the adverse met
`fully reduced the estrogen
`sex steroid
`with oral
`associated
`consequences
`for contraception Rather
`administration
`set of clinical endocrine
`new and different
`produced
`and metabolic adverse consequences
`four combination
`
`alone
`
`is unsatisfactory
`
`as
`
`contraceptive
`
`for
`
`for
`
`or
`
`abolic
`
`each variation
`
`Out of
`
`formulations
`
`twenty-
`cur
`
`estrogen/progestin
`
`reproduction endocrinologists
`available
`rently
`ally agree that only Lo/Ovral
`closely satisfies
`and metabolic need of
`the oral contra
`cal endocrine
`patient However
`for menstrual dysfunction
`
`ceptive
`
`inappropriate
`
`this
`
`formulation
`
`design
`
`is
`
`patients
`
`gener
`the clini
`
`OBJECTIVES OF THE PRESENT
`
`INVENTION
`
`The follicular-luteal
`
`sex steroid replacement
`
`and drug
`
`system of the present
`delivery
`of the clinical
`the reduction
`bolic side effects associated with the administration
`is to reduce
`not only by
`sex steroids Another
`
`invention
`
`has
`
`endocrirtologic
`
`as its object
`and meta
`of
`
`object
`
`WC_LP0405829
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2015, Pg. 9
`
`

`
`amount but also by the number
`of days administered
`administered
`during the cycle the exogenous
`estrogen
`This allows maximum target organ rest of hypothala
`and liver
`from exogenous
`mus pituitary
`is to reduce the dosage
`of progestin
`progestins may be em
`biologic
`potent
`as the potent progestin norgestrel
`to reduce
`number
`of days
`the
`is adminis
`
`further
`
`object
`
`that moderately
`
`estrogen
`
`so
`
`ployed as effectively
`Another
`
`object
`
`is
`
`that progestin
`the drug cycle
`throughout
`estrogen Another
`concomitant with exogenous
`to reduce the amount
`of exogenous
`objective
`estrogen
`with any or all moderately
`syn
`potent
`low concentration
`to an
`
`tered
`
`is
`
`administered
`
`thetic
`
`progestins
`irreducibly
`control
`while preserving menstrual cycle
`system of the invention minimizes 15
`Thus the delivery
`ad
`clinical endocrine
`and metabolic
`the undesirable
`associated with the administration
`
`4292315
`
`hypermenorrhea
`20 amenorrhea
`
`al-Prolution
`
`strual
`
`tension
`
`menometrorrhagia
`oligomehorrhea
`of progesterone withdraw
`in presence
`100 mgm I.M dysmenorrhea
`pre-men
`and for ovulation
`pain For the euestro
`in which the fol
`gen and hyperestrogen
`clinical states
`and steroid supplementation
`licular-luteal drug delivery
`system of the invention
`for contraception
`applied
`when done on
`long term basis the contraceptive
`cation of the invention minimizes the adverse
`
`is
`
`appli
`endocrine
`
`10
`
`and metabolic
`
`or estrogen
`
`administered
`
`effects of excessive
`exogenous
`estrogen
`in combination with progestin
`concentration
`the
`of estrogen
`
`at
`
`allowing for increased
`end organ cytosol
`art combination
`
`receptor
`
`as compared
`
`to the prior
`
`estrogen/progestin
`
`oral contraception
`
`verse
`
`consequences
`of high dose exogenous
`tive days each treatment
`
`systems
`dosage
`For treatment
`
`of and/or
`
`sex steroid delivery
`
`tients in the hypoestrogen
`
`presenting
`
`state
`
`invention
`
`provides
`
`sex steroid
`
`to pa
`the present
`and/or
`
`estrogen
`
`cycle
`
`period
`
`for too many consecu
`and increases
`the target
`treatment
`
`after each
`
`20
`
`states as
`
`recovery
`organ estrogen
`cycle which is far too short
`
`in the prior art combination
`
`dosage cycles
`The present
`formulation
`
`which
`
`permits
`both the amount
`
`invention
`
`new sex steroid
`also provides
`for therapeutic menstrual cycle
`
`regulation
`return to ovulation reduces
`prompt
`of and length
`
`of
`
`time
`
`which
`
`exogenous
`
`estrogen
`
`is administered
`
`cycle reduces
`and progestin
`
`the length
`
`of
`
`time
`
`are administered
`
`i.e hypothalamus
`release
`
`dotropins
`
`administration
`
`synthetic
`
`estrogen
`
`gestin
`nous
`
`during
`
`drug delivery
`supplementation
`ammenorrhea
`rhea oral contraception
`breakthrough
`bleeding
`ratios of exogenous
`to inappropriate
`or due
`to inadequate
`progestin
`unopposed
`priming and minimizes escape
`endogenous
`estrogen
`and
`its subsequent withdrawal during the cycles
`of
`steroid ad
`only and low dose contraceptive
`is seen with prior art combination
`as
`
`replacement
`system for such clinical
`amenorrhea
`hypomenor
`second
`
`estrogen7-
`
`estrogen
`
`oral
`
`ary
`
`progestin
`
`ministration
`
`invention
`
`modifications
`
`the
`
`sex
`
`and their current
`estrogen/progestin
`The present
`is dependent more
`upon
`steroids adminis
`of exogenous
`temporal
`relationship
`of the patients
`tered to the endogenous
`hormones
`pres
`of the ex
`clinical state and to interrelationships
`the steroid administration
`steroids throughout
`ogenous
`potency of the particular
`than to the absolute
`cycle
`and
`steroid administered Hence any synthetic
`estrogen
`can be used in accordance with the invention
`dose dura
`
`enting
`
`progestin
`
`if the temporal
`
`25
`
`30
`
`35
`
`tion of administration
`
`and/or
`
`progestin
`
`40
`
`alent
`
`set
`
`forth
`
`estrogen
`
`during
`during the drug
`exogenous
`estrogen
`during the drug
`together
`the end organ and cellular
`cycle lengthens
`recovery
`from exogenous
`estrogen minimizes hypothala
`period
`on CNS
`mic and pituitary sustained
`supression relies
`and pituitary dysrhythmia of gona
`than total sustained
`rather
`suppres
`the follicular phase of the drug cycle mini-
`Sian during
`mixes the dose and the length of time of synthetic
`pro
`uses adequate amounts
`of exoge
`and progestin
`en
`to suppress
`FSH and LH for approximately seven days
`dogenous
`the corpus luteum phase of the drug cycle ad-
`to
`or progestin
`ministers exogenous
`an arbitrary
`and estrogen
`follicular
`phase
`corpus luteum phase in the treat
`to create
`progestin
`cycle with adequate but not excessive
`exogenous
`and progestin
`the integrity of the 45
`to maintain
`estrogen
`endometrium
`
`create
`
`ment
`
`Further
`
`the present
`
`invention
`
`does not
`as results with pres
`and provides
`formulations
`
`excessively
`
`suppress gonadotropins
`
`ent
`
`sex steroid oral dosage
`
`more
`pharmacologic
`flexibility
`Hence the drug dosage
`the present
`invention
`
`of
`
`system and treatment
`accomplishes
`forth above
`as set
`through
`objectives
`ments which may be more particularly
`adapted for the
`and hyperestrogen
`hypoestrogen
`euestrogen
`
`method
`
`50
`
`its therapeutic
`embodi
`
`various
`
`clinical
`
`states of
`
`the presenting
`
`patient
`
`such
`
`55
`
`sys
`
`synthetic
`
`estrogen
`
`relative
`interrelationships
`and ratio of exogenous
`are approximately biologically
`equiv
`and variations
`the inven
`of
`thereof
`The invention
`may be
`currently FDA
`and
`
`to examples
`tion as hereinafter
`
`estradiol
`
`synthetic
`and any of
`
`gestins
`
`norgestrel
`
`tate ethyriodiol
`
`diocetate
`
`In contrast
`
`which
`
`adapted to be employed with either
`estrogen mestranol
`approved
`the FDA approved
`pro
`synthetic
`norethindrone norethindrone ace
`and norethynodrel
`formulations
`to prior art steroid dosage
`dose
`uniform daily
`administer
`
`ethinyl
`
`of combined
`
`the drug administration
`
`steroids throughout
`exogenous
`cycle the present
`segments of
`accordingly provides
`
`invention
`
`presenting
`
`separately
`patients menstrual
`
`drug administration
`
`treats discrete
`cycle and
`like
`
`cycle
`
`wise having discrete
`which are temporally
`Thus
`an arbitrary
`steroid administration
`
`exogenous
`related to the presenting
`
`steroid characteristics
`
`cycle
`
`delivered
`
`upon
`Depending
`sex steroid delivery
`the appropriate
`clinical state
`tem in accordance with the invention
`
`is selected
`
`for
`
`administration
`
`for treatment management
`of the menstrual
`
`cycle Further
`
`unlike
`
`therapeutic
`and regulation
`combination
`
`the
`
`delivered
`
`and
`
`progestin
`
`sex steroids 60
`
`invention
`
`is useful
`
`estrogen
`by the prior art
`the present
`of hypothalmic-pituitary
`physiology
`and its clinical manifestations
`
`in the correction
`
`of menstrual
`
`dysfunction
`
`Thus
`
`in addition
`
`roid contraception
`
`strogen
`
`presenting
`
`spacing
`
`and oral ste
`
`to pregnancy
`uses for the euestrogen
`and hypere-
`the method
`and
`for
`
`clinical states
`
`65
`
`mulation
`
`of
`
`the invention
`
`is useful
`
`for the treatment
`
`of
`
`menstrual
`
`irregularity
`
`as
`
`for example menorrhagia
`
`superim
`cycle
`over
`the endoge
`exogenously
`poses
`men
`nous
`hormone
`characteristic
`strual cycle The invention
`separate arbitrary
`provides
`for the follicular and corpus lu
`steroid characteristic
`cycle Hence in the inven
`of the menstrual
`and
`an arbi
`follicular steroid phase
`steroid phase
`sex steroid drug
`comprise
`cycle In turn each
`have
`and luteal may itself
`tinct steroid characteristics
`The first half of the inventions arbitrary
`end
`hypothalamus
`phase
`organs
`endometrium and liver from both estrogen
`
`dosages
`of
`
`the
`
`presenting
`
`discrete
`
`i.e follicular
`phase
`segments with dis
`
`follicular
`
`pituitary
`and proges
`
`teum phases
`
`tion an arbitrary
`
`trary luteal
`
`administration
`
`rests the
`
`WC_LP0405830
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2015, Pg. 10
`
`

`
`4292315
`
`tin The second
`
`half of
`
`cyte
`
`exogenous
`
`follicular
`the arbitrary
`phase
`hormone and the pituo
`exposes hypothalamic
`releasing
`on
`to primary doses depending
`the presenting
`of exogenous
`doses of
`clinical state
`estrogen
`progestin but never
`
`or small
`
`to estrogen/progestin
`and
`
`together Endogenously
`estrogen
`progestin
`follicular phase about one day
`seen only in the normal
`THe corpus
`luteum phase
`to ovulation
`in the
`of
`combined
`dosage
`
`prior
`
`treatment
`
`cycle
`
`increases
`
`trogen/progestin
`
`gradually
`
`but
`
`quires
`
`estrogen
`
`in its
`
`are
`
`es
`re
`
`in its early stage
`and progestin
`adequate exogenous
`middle stage to suppress pituitary FSH and LII and to
`maintain the integrity of the endometrium The terminal
`portion of the corpus luteum phase may reduce the dose
`to allow for FSH
`of combination
`estrogen/progestin
`endometrial with
`and
`prompt
`of the steroid adminis
`
`LII
`
`recovery
`drawal
`
`and their relationship with ovula
`and days of the cycle
`tion and menstruation are indicated
`as the axis against
`which the ranges of FSH LH and estrogen
`are plotted
`plots daily blood levels of LH and
`FIG separately
`FSH and estrogen
`normal ovula
`and progesterone
`for one
`and
`same
`the
`cycle
`patient
`patient
`cycles during which the patient
`two further
`prior art combination
`administered
`estrogen/proges
`tin sex steroid contraceptive The suppressive
`effect of
`the hormone levels
`such prior art administration
`upon
`
`in
`
`in
`
`is
`
`tory
`
`through
`
`after successive
`FIG
`
`cycles
`
`is apparent
`
`alone
`
`effects of
`upon LH
`normal
`and
`
`is compared
`
`distribution
`
`the
`
`present
`
`estrogen
`
`distribution
`
`10
`
`15
`
`20
`
`25
`
`the
`endogenous
`similarly depicts
`of progestin
`prior art administration
`FSH estrogen
`and progesterone
`through
`successive
`drug cycles
`FIG depicts
`of examples of the pres
`formulations
`of
`and in distribution
`both in daily dose
`ent
`invention
`admin
`and progestin
`the exogearius
`synthetic
`estrogen
`the menstrual cycle The distribu
`istered throughout
`exogenous estrogen
`tion of
`the administered
`synthetic
`to the normal serum endogenous estrogen
`normal ovulatory menstrual cy
`found in
`in FIG
`cle heretofore
`depicted
`Also in comparison with examples of
`and
`invention
`the
`endogenous
`FIG depicts
`steroid contraceptives including
`and distribution
`
`formulations
`
`of
`
`level
`
`the cycle
`
`several prior art dosage
`the daily dosage
`of combination
`for
`and the now
`
`initiate
`
`cessation
`
`bleeding
`
`upon
`in one drug cycle
`
`tered
`
`Because
`
`the invention
`
`establishes
`
`and dis
`
`tinct steroid administration
`
`characteristic
`
`cycle
`
`terminal
`
`fourteen
`
`sequential
`
`various
`
`other
`
`the
`
`in
`
`alone mini-pill
`
`separate
`for each of
`steroid admin
`follicular and luteal phase of an arbitrary
`can be adapted
`istration cycle the administration
`euestrogen or hyperestro
`to either
`the hypoestrogen
`of
`patient by the administration
`gen clinical presenting
`during the sec
`either unopposed
`or progestin
`estrogen
`embodi
`ond half of the follicular phase
`In its preferred
`corpus luteum retains
`fixed ratio of
`ment the arbitrary
`then FSH LH sup
`estrogen/progestin first low dose
`as endometrial maintenance
`as well
`doses
`pressive
`decrease of estrogen
`doses and
`finally
`progestin The arbitrary
`corpus luteum about
`days of the steroid administration
`is designed for
`cycle
`men
`proper endometrium maturation and predictable
`in the ovulatory menstrual
`strual
`function
`just as is seen
`
`the
`invention
`provides
`present
`and steroid drug delivery
`the dose and days of administration
`gen in oral sex steroid treatment
`days of combination
`exogenous
`in oral sex steroid treatment
`cycles minimizing hepatic
`distortion metabolic and endocrine ad
`from oral
`steroid
`treatment
`sex
`consequences
`cycles and minimizing future ovulation
`administered oral
`sex steroids
`
`treatment
`
`system minimizing
`estro
`of exogenous
`cycles minimizing the
`and .progestin
`
`estrogen
`
`35
`
`40
`
`disturbance
`
`in
`
`for menstrual 45
`
`cycle
`Thus
`method
`
`morphologic
`
`verse
`
`patients
`
`through
`mulations the progestin
`30 defunct
`estrogen
`FIG depicts
`luteal
`formulations
`
`examples of follicular
`also
`invention
`
`comparison
`
`exogenous
`
`administration
`
`formulations
`
`examples
`
`using
`
`against
`
`estrogen
`
`of
`present
`of
`in terms of daily
`distribution
`dosage
`the cycle and total drug
`steroids
`through
`in one cycle with prior art combination
`of the
`the same steroid components
`background of endogenous
`
`ment
`
`of menstrual
`
`steroid
`
`cycle dysfunction In addition the present
`method
`
`for sex steroid oral
`
`replacement
`method
`
`invention
`
`is
`
`in the manage
`for oral
`sex
`
`of menstrual
`
`oligomenonhea
`and
`method
`
`pri- 50
`ovu
`for
`
`in
`
`estro-
`
`60
`
`level
`
`against
`
`irregularity
`in the management
`replacement
`i.e hypermenorrhea
`menorrhagia
`dysfunction
`mary amenorrhea
`amenorrhea
`lation pains primary dysmenorrhea
`oral sex steroid replacement
`in pregnancy
`spacing
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG depicts
`the blood levels and relationships
`of LH FSH estra
`normal ovulatory menstrual cycle
`by radioimmu
`as measured
`diol 17B and progesterone
`no exogenous
`steroids
`noassay in
`patient
`receiving
`FIG depicts
`range of endogenous
`normal
`gen FSH and LH serum levels throughout
`the normal
`menstrual cycle
`In FIG
`the estrogen
`is depicted
`of FSH and LH levels
`for comparison
`background
`one ovulatory menstrual cycle The cycle
`is 65
`through
`divided into preovulatory follicular
`and post-ovula
`by the LH peak
`luteum segments divided
`tory corpus
`occurs The occurrence
`at which
`of menses
`ovulation
`
`distribution
`in serum FSH LII
`FIG depicts
`the daily alteration
`estradoil 17B and progesterone found in Euestrogenic
`Fol
`normal ovulatory patient who was administered
`Formulation of
`Luteal
`licular Progestin
`Replacement
`for approximately one year Note
`FSH LH estradiol
`of endogenous
`of total suppression
`in contrast with FIG and FIG
`17B and progesterone
`
`the invention
`
`the lack
`
`depicts
`
`alteration
`
`administered
`
`trogenic
`
`Progestin
`
`vention
`
`FIG
`the daily
`in endogenous
`FSH LH estradoil 17B and progesterone
`in hypoes
`patient who was
`Follicular
`Formulation of the in
`Luteal
`Replacement
`for one year in illustration of the necessity
`of the Follicular
`in the administration
`patient selection
`
`for
`
`Luteal
`
`Replacement
`
`Formulations
`
`for the oral
`
`unitary
`
`dispenser
`
`Estrogen/Progestin
`invention
`of the present
`FIGS and 9a9c depict
`tablet package
`of steriod tablets during
`drug (cid:224)dminis
`administration
`formu
`tration cycle of the follicular
`luteal
`replacement
`the invention Daily tablets are formulated
`lations of
`and assembled in
`such
`as
`package
`for orderly
`
`the
`
`one
`
`depicted
`and
`
`dosage
`invention
`
`interrelationships
`
`administration
`
`in daily
`in accordance with the
`
`DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`In accordance with the present
`invention pharmaco
`overdoses of combination
`estrogen
`synthetic
`logic
`are associated with the adverse side
`progestin which
`
`WC_LP0405831
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2015, Pg. 11
`
`

`
`effects jroduced
`
`hormone
`
`administra
`
`4292315
`
`10
`
`by the exogenous
`are substantially
`tion of prior art systems
`administration
`contrast
`to the contraphysiologic
`of exogenous
`rest periods
`
`unreirtting
`
`reduced
`
`In
`
`estrogen
`
`of an
`
`and
`
`to the
`
`dosage
`daily
`and nominal
`progestin
`inadequate
`end organs from exogenous
`the follicular-luteal
`the prior art
`mimicks
`the hormone
`
`steroids
`
`characteristic
`
`of
`
`replacement