EXHIBIT 1004
`
`
`
`EXHIBIT 1004EXHIBIT 1004
`
`

`
`(12) United States Patent
`Boissonneault et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006667050Bl
`US 6,667,050 Bl
`Dec.23,2003
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) C HEWABLE ORAL CONTRACEPTIVE
`
`(56)
`
`References C ited
`
`(75)
`
`Inventors: Roger M. Boissonneault, Long Valley,
`NJ (US); Tina M. deVries, Long
`Valley, NJ (US)
`
`(73) Assignee: Galen (Chemicals) Limited,
`Dunlaoghaire (IE)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/879,028
`
`(22) Filed:
`
`.Jun. 12, 2001
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of applicatioo No. 09!286,908, filed oo
`Apr. 6, 1999.
`
`(51)
`
`Int. C l.7
`
`. ...... ........... ...... .... . . ........... ...... . A61K 47/00
`
`(52) U.S. C l .. ...................... 424/439; 424/400; 424/440;
`424/441; 424/464; 424/484; 424/489; 514/841;
`514/843
`
`(58) Field of Search ................................. 424/400, 439,
`424/440, 441, 464, 484, 489; 514/84],
`843
`
`U.S. PATENT DOCUMENTS
`
`Suschi rzky et al.
`Rutherford et al.
`Suscbitzky ct al.
`Fuchs ct al.
`Reel et al.
`Valentine
`Alexander et al.
`Gori nskyt
`Mizumoto ct al.
`Gast ........................... 5 14/ 170
`
`6/ 1976
`3,960,9 J I A
`4,036,983 A
`7/1977
`4,038,413 A
`7/1977
`1/ 1979
`4,136, 162 A
`4/ 1985
`4,512,986 A
`4,684,534 A
`8/1987
`5,135,744 A
`8/ 1992
`J0/ 1996
`5,569,456 A
`5,576,014 A
`11/ 1996
`5,747,480 A * 5/1998
`• cited by examiner
`Primary Examiner- Timrman K. Page
`Assistnnt Exnminer--Charesse Evans
`(74) Attorney, Agent, or Firm-Akin,
`Hauer & Feld, L.L.P.
`
`Gump, Strauss,
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a chewable, palatable oral
`contraceptive tablet, comprising an oral contraceptive agent,
`a cbewable carrier suitable for human consumption, aud not
`comprising a ferrocene compound, as well as use o( these
`tablets in a met bod of human female oral cootraccptioo, and
`in a method of enhancing compliance with a human fema le
`oral contraceptive regimen.
`
`60 Claims, No Drawings
`
`Petitioner Exhibit 1004
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`
`US 6,667,050 Bl
`
`1
`CHEWABLE ORAL CONTRACEPTIVE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This is a continuation-in-part of U.S. patent application
`Ser. No. 09/286,908, filed Apr. 6, 1999.
`
`STATEMENT REGARDING FEDERALLY
`SPONSORED RESEARCH OR DEVELOPMENT
`
`Not Applicable.
`
`REFERENCE TO MICROFICHE APPENDIX
`
`Not Applicable.
`
`BACKGROUND OF THE INVENTION
`
`2
`to conceal, they are not necessarily easy to ingest. Access to
`water to facilitate contraceptive pill taking remains a prob(cid:173)
`lem. Most medications are typically stored in a medicine
`cabinet and therefore are likely to be near a water source. On
`tbc contrary, oral contraceptive pills arc often carried oo the
`person and a source of water is not always available wben
`it is time to take the oral contraceptive pill. Additionally, a
`certain segment of the patient population will have trouble
`swallowing pills, irrespective of access to water.
`The present invention provides an improved oral contra(cid:173)
`ceptive tablet. T11e technology encompassed in the invention
`involves a chewable, palatable ora l contraceptive tablet that
`has appropriate size and hardness for blister packaging and
`compliant use.
`
`BRIEF SUMMARY OF THE INVENTION
`
`5
`
`10
`
`15
`
`One aspect of the present invention relates to a chewable,
`palatable oral contraceptive tablet, comprising an oral con-
`20 traceptive agent, a chewable carrier suitable for human
`consumption, and not comprising a fcrroccne compound.
`Another aspect of this invention relates to a method of
`human fema le oral contraception, the method comprising
`providing a chewable, palatable oral contraceptive tablet
`25 comprising a contraccptively effective amount of an oral
`contracept ive agent, and a chewable carrier suitable for
`human consumption, and not comprising a ferrocene
`compound, and administering the iablei to a human female.
`Yet another aspect of this invention relates to a method of
`30 enhancing compliance with a human female oral contracep(cid:173)
`tive regimen involving oral contraceptive tablets, the
`method comprising providing chewable, palatable oral con(cid:173)
`traceptive tablets comprising a contraceptively effective
`amount of an oral contraceptive agent, and a chewable
`35 carrier suitable for human consumption, and not comprising
`a ferrocene compound, and administering tbe tablets to the
`human female in accordance with the contraceptive regi(cid:173)
`men.
`
`l11e present invention genera lly relates to an ora l contra(cid:173)
`ceptive delivery system, and in particular an oral contracep(cid:173)
`tive delivery system involving novel alternate dose forms to
`improve compliance.
`The efficacy of oral contraceptives tends to be particularly
`patient compliance dependent, largely due to the lack of a
`disease state or symptoms to remind a human female patient
`(sometimes referred to simply as "patient" or ·'woman") to
`take a pill. The single most signilicant reason for failure with
`oral contraceptives is use, rather than method, fail ure. That
`is, unless the contraceptives are used according to the
`prescribed regi men, the contraceptives can fail to effectively
`help a patient avoid pregnancy. Further, in order to be most
`effective in preventing pregnancy and maintaining men(cid:173)
`strual cycle control, proper compliance wilh ao oral contra(cid:173)
`ceptive dosage regimen requires that the oral contraceptives
`be taken at about the same time each day.
`Various attempts have been made to improve patient
`compliance with contraceptive regimens. for example, it bas
`been suggested that progestin rods can be inserted subder(cid:173)
`mally. This procedure has been described, for example, in
`U.S. Pat. No. 5,756,115. 1bis technique bas the significant
`disadvantage o( requiri ng a surgical incision, a procedure 40
`Lhat is highly disfavored by a relatively large segment of the
`paticot population.
`As another example, it bas been suggested that DEPO(cid:173)
`PROVERA® (Pbarmacia, Inc.) mcdroxyprogestcronc
`acetate can be injected subcutaneously every tbree months.
`This technique bas been described, for example, in U.S. Pat.
`No. 4,639,439. This procedure bas the disadvantage of
`requiring ao injection via hypodermic needle, which is also
`a procedure that is disfavored by many patients.
`In many cases, the patient prefers to carry the cootracep-
`tive pills on ber person as a matter of lifestyle or personal
`discretion. This is especiaJiy true for younger patients, and
`it is not uncommon for sucb patients to exchange pills.
`Members of this population tend to view portable packaging 55
`of the pills, immediate access to the pills, and ease of pill use
`as significant beoe6ts.
`Prior proposed solutions to the compl iance problem have
`tended to focus primarily or exclusively on optimizing
`compliance packaging, rather than on changes to the dosage 60
`form. It bas been suggested that instead of being packaged
`in vials, contraceptive pills can be packaged in 21 or 28 day
`blister packages. It bas also been suggested that the size of
`these packages can be reduced to improve portability and
`confidentiality.
`Although oral contraceptive pills provided in a small
`blister package are somewbat more convenient to carry and
`
`45
`
`50
`
`BRfEF DESCRWfiON OF THE SEVERAL
`VIEWS OF T l IE DRAWINGS
`
`Not Applicable.
`
`DETAILED DESCRIPTION OF TI-JE
`INVENTION
`
`The present invention relates to chewable, palatable oral
`contraceptive tablets for administering .an oral contraceptive
`agent to human females. The tablets of this invention may
`simply be chewed, and therefore are easy for a patient to
`ingest, even in tbe absence of a liquid. The oral contracep(cid:173)
`tive agent form ulation of this invention improves dosage
`regimen compliance, and thereby enhances the desired con(cid:173)
`traceptive effect of the oral contraceptive. This invention
`also includes methods for administering the oral contracep(cid:173)
`tive formulations to a woman.
`
`Definitions
`
`Tbe articles " a" and "an" arc used blerein to refer to one
`or more than one (i.e., to at least one) of the grammatical
`objects of the article. By way of example, ''an element"
`mcaos one element or more tban one e lement.
`Tbe term '·oral contraceptive agent," as used herein, refers
`to any compound or combination of compounds which,
`65 when administered orally, prevents pregnancy.
`The term "estrogen," as used herein, refers to any natural
`or synthetic compound which exhibits ao effect on the
`
`Petitioner Exhibit 1004
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`
`US 6,667,050 Bl
`
`3
`female reproductive organs in a manner similar to the na tural
`female hormone estrogen. Examples of an estrogen include,
`but arc not limited to, ethi nyl estradiol, estradiol, estradiol
`valerate, and estradiol acetate.
`
`4
`levonorgest rel, e thynodio l d iace ta te, norgestre l,
`norgcstimatc, gcstodcnc, d rospircnonc, trimcgcstone,
`levodesogestrel, gestodyne, and nesterone. Preferably, the
`progestin is norethindrone.
`
`5
`
`The term "progestin," as used herein, refers any natural or
`synthetic compound which exhibits a progestational effect
`on the female reproductive organs. Examples of a progestin
`include, but are not limited to, norethindrone, norethindrone
`acetate, desogestrel, levonorgesLrel, ethynodiol diacetate, 10
`norgestrel, norgestima te, gestodene, drosp irenone,
`trimegestooc, levodesogestrel, gestodyne and nesterone.
`
`The term "palatable," as used herein, means thattbe table t
`of tbis invention bas a taste, mouth feel, chewability, texture,
`aroma, and lack of grittiness and bad aftertaste that makes
`the tablet agreeable to a woman to chew.
`
`The dosage of the oral contracept.ive agent employed
`would tend to be that conventionally used in the art for the
`particular oral contraceptive agent selected. 'Tbe proportion
`of the oral contraceptive agent in the tablet may be a
`pharmaceutically effective trace amou_nt to about 10% by
`weight. Thus, the quantity of oral cootraceptivc agent per
`tablet may be varied as desired, typically abou t LO micro(cid:173)
`grams to abou t 5 milligrams, but tbc lower and upper
`dosages may be reduced or increased. Examples of approxi·
`15 mate dosage ranges of oral contraceptive agents in milli·
`grams per tablet are summarized in Table 1.
`
`TABLE 1
`
`Examples of Dose Range,; o[ Oral Contraceptive Agents (rnilligmms per tablet)
`
`Description Examples
`
`Broad
`
`Intermediate
`
`Preferred
`
`Pt"Ogestin
`
`Estrogen
`
`Norethindrone,
`Norethindrone acetate
`Desogestrel
`Levonorgestrel
`Ethynodiol diacetate
`Norgestrel
`Norgestintate
`Gestodene
`Drospirenone
`T nmegestone
`J;thinyl l,_.tradiol,
`Estradiol
`Estradiol valerate
`Estradiol acetate
`
`0.25 to 2.0
`0.1 to 2.5
`0.25 to 2.0
`0.1 to 2.5
`0.05 to 0.5
`0.1 to 0.3
`0,025 to J.S
`0.025 LO 1.0
`0.75 to J.25
`0.5 to 2.5
`0.05 to 3.0
`0.05 to 2.0
`0.15 to 0.35
`0.1 to 0.5
`0.05 to 0.10
`0.03 to O.J5
`2.0 to 4.0
`1.0 tO 5.0
`0.05 to 0.5
`0.1 to 0.3
`O.Ql to 0.075 0.015 to 0.05
`0.5 to 4.0
`1 to 3
`0.5 to 5.0
`1.5 to 3.5
`0.5 to 5.0
`1.5 to 3.5
`
`0.4 to 1.5
`0.4 to 1.5
`0.1 to 0.2
`0.05 to 0.6
`0.9 to 1.1
`0.1 to 1.2
`0.18to 0.25
`0.06 lO 0.075
`2.5 to 3.5
`O.lto 0.2
`0.020 to 0.050
`1.5 to 2.5
`}.9 to 3.0
`1.8 to 3.0
`
`A tablet is "chewable," as used herein, such that when the
`tablet is chewed, it breaks into smaller pieces that can be
`swallowed. 'Ibis is in contrast to gum, for example, which
`does not break imo smaller pieces when chewed.
`
`Description of the Inven tion
`
`The first aspect of the invention relates to a chewable,
`palatable oral conLraceptivc tablet comprising an oral coo(cid:173)
`Lraceptive agen t, a chewable carrier suitable fo r human
`consumption and not comprising a ferrocene compound.
`The tablet of this invention expressly does not contain a
`ferrocene compound. Ferrocenc compounds are used in the
`Lreatment of anemia and it should not be assumed that all
`patients desiring an oral contraceptive agent are anemic.
`Administering fcrroccne compounds when they arc no t
`needed can lead to iron poisoning. Additionally, ferroceoe
`compounds may not be palatable when chewed.
`
`In principle, virtually any oral contracep tive agent used in
`human medicine could be employed in accordance with the
`principles of the present invention. The oral contracept ive
`agent may be an estrogen, a progestin, or a combination of
`an estrogen and a progestin. In one embodiment, the oral
`contracept ive agent is an estrogen selected from the group
`coosL'>ting of ethioyl estradiol, estradiol, estradiol valerate,
`and estradiol acetate. Preferably, the estrogen is ethinyl
`estradiol.
`
`In one preferred embodiment, the tablet comprises estro·
`gen in tbe form of ethinyl estradiol io an amoun t of about lO
`micrograms to about 75 micrograms. In another preferred
`40 embodiment, the tablet comprises progestin in the form of
`norethindrone in an amount of about 0.1 milligram to about
`2.5 milligrams.
`The invention also includes a tablet in which the oral
`contraceptive agent is a combination of an estrogen and a
`45 progestin. Preferably, tbe estrogen is ethinyl estradiol and
`the progestin is norethindrone. !o a mo re preferred
`embodiment, the amount of etbinyl estradiol in the tablet is
`about 10 micrograms to about 75 m icrograms and the
`amount of no rethi ndrone in the tablet is about O. l milligram
`50 to about 2.5 milligrams.
`The tablets of this invention can be used in conjunction
`with an oral contraceptive regimen. Tbe regimen can com·
`prise administering tablets on a daily basis for multiple
`consecutive days. As such, throughout the duration of the
`regimen the amoliD t of oral contraceptive agent in the oral
`contraceptive tablets may remai n constant, thereby compris(cid:173)
`ing a uniphasic regimen. Additionally. the amount of oral
`contraceptive agent in the oral contraceptive tablets may
`vary throughout the duration of the regimen, thereby com(cid:173)
`prising a multiphasic regimen. In tablets comprising an
`60 estrogen and a progestin, the ratio of the estrogen to the
`progestin can be constant Lhroughout the duration of the
`regimen. Additionally, the ratio of the estrogen to the proges·
`tin in the oral contraceptive tablets can vary throughout the
`regimen.
`It is also pOS.'iible 10 form placebo tablets which otherwise
`correspond in composition to the tablet of the present
`invention but are free of tbe oral contraceptive agent.
`
`55
`
`In another embodiment, the oral contraceptive agent is a 65
`progestin selected from
`tbe group consis t ing of
`nore thindrone, nore thindrone acetate, desogcstrel,
`
`Petitioner Exhibit 1004
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`
`US 6,667,050 Bl
`
`6
`
`TABLE 2-continued
`
`Sweetener and Flavor Amounts Used in Chewable Oral
`Contraceptive Fommlations
`
`lugre-
`dient
`Type
`
`Examples
`
`Broad
`
`llllermcdiate
`
`l'•·eferred
`
`Flavor
`Spearmint
`Agent Winter·
`green
`Wild berry O.J to3%
`
`0.5 to 5%
`0.5 to 5%
`
`lto3%
`Jto3%
`
`J.5 to 2.5%
`J.5 to 2.5%
`
`0.2101%
`
`0.3 to 0.5%
`
`5
`
`10
`
`5
`The oral contracep tive agent may be present in a carrier
`e ither in a dissolved or a uniformly suspended s tate. A
`carrier comprises all but the active oral contraceptive agen t
`or agents and includes an inactive ingredient or a combina(cid:173)
`tion of one or more inactive ingredients. The carrier imparts
`chewable and palatable characteristics to the tablet and must
`be suitable for human consumption, that is, free of harmful
`amounts of any toxins or components that are adverse to
`humans. All ingredients in the carrier should be generally
`recognized as safe (GRAS), as determined by the Food and
`Drug Administration (FDA) or the Flavor and Extract Manu(cid:173)
`facturers' Association (FEMA). The carrier selected for tbe
`invention must be chewable and should oot confer a d~s­
`agreeable taste to the tablet. Thus, the carrier itself must be 15
`palatable. The primary ingredient of a carrier is one or more
`diluents. Non-limiting examples of diluents that can be used
`in accordance with this invention include microcrystalli ne
`cellu lose, corn starch, modilied starch, calcium carbonate,
`dicalcium phosphate, and poly-alco bol sugars such as 20
`dextrose, mannitol, sorbitol, xylitol, lactose, sucrose, and
`fructose. Many other diluents or other ingredjents suitable as
`components of carriers for a chewable, palatable oral con(cid:173)
`traceptive tablet are available and would be well known to
`those skilled in the art in view of the present disclosure.
`
`25
`
`Optionally, a color agent may be added to aid in tablet
`identification and to enhance tbe visual appearance of the
`tablet. A visually pleasing color enhances patient acceptance
`and thereby compliance with an oral contraceptive regimen.
`The color agent may be any that are well known to those in
`the tablet-making art i n view of the present disclosure, and
`could be used in any amount to impart the desired color.
`The tablet can be manufactured by standard pharmaceu-
`tical techniques of solid dose formulation, such as granula(cid:173)
`tion and compression. These processes are well known to
`those skilled in the art of making tablets (See Lieberman,
`Lachman, and Schwartz, Pharmaceutical Dosage Fom1s,
`Volume 1, New York, 1989). During the granulation process,
`In anot her aspect of the invention, the tablet optionally
`other ingredients typically used in tablet formulation fo r
`further comprises at least one of a flavor agent, a sweetener,
`human consumption can be included, such as binders,
`and a color agent. A flavo r agen t can be used to enhance the
`lubricants, anti-adherents, glidants, disintegrants and fillers
`30 or other optional ingredients that do not adversely affect
`taste of the tablet, making the tablet more palatable than a
`tablet without a flavor agen t. Spray dried flavor agents are
`chewability or palatability of the tablet or its active oral
`preferred because they arc easy to incorporate into a chew(cid:173)
`contraceptive agent iogrcdicnt(s).
`able tablet. Non-limiting examples of preferred flavor agents
`Binders aid the formation of granulaLed particles of active
`impart the following flavors: strawberry, wild berry,
`35 oral contraceptive agents and carrier ingredients. Noo(cid:173)
`spearmint, wintergreen, black cherry, orange, orange cream,
`Jjmiting examples of binders include glucose, acacia, guar
`and lemon. The flavoring agents are readily available from
`gum, gelatin, simple syrup, sucrose, sorbitol, s tarch, alginic
`acid , alginate salts, polyeLhylcoe glycol,
`many commercial sources. Exemplary compounds suitably
`polyvi nylpyrrolidone, polymetbacryla tes, pregelatinized
`used in preparing flavors are listed in G. Burdock, Ed.,
`40 starch, and celluloses such as methylcellulose, sodium
`Fenaroli 's Ha ndbook of Flavor Ingredients, 3"" edition,
`carboxymethylcell ulose, hydroxypropylmethylcell ulose,
`Volumes I and II, CRC Press, New York, 1995. Other flavors
`bydroxypropylceUulose, and etbylceUulosc. A solution of
`and flavoring agen ts suitable for the tablet would be weU
`binder is prepared (concentrations dependent on the particu(cid:173)
`known to those skilled in the art in view of the present
`lar binder used), and the binder solution is mixed with the
`d isclosure.
`A sweetener can also be used to enhance to taste of the 45 other excipients to form tbe wet granulation. A binder sucb
`as polyvinylpyrrolidone (Povidone) is typically used in a
`tablet, mak'ing the tablet more palatable than a tablet without
`solution of about 3% to about 15% by weight and is added
`to the other tablet ingredients resulting in a fi nal formu lation
`a sweetener. Sweeteners include natural sugars and artificial
`concentration of about 2% to about 5%. Similarly, cellulose
`sugar substitutes. Non-limiting examples of sweeteners that
`derivatives are typically used in granulating solutions of
`can be used in accordance with this invention include
`about 5% to aboutlO% by weight and concentrations would
`aspartame, sucralose, xylitol, sorbitol, mannitol, dextrose,
`be known to one skilled in the art of making tablets usi ng
`sucrose, and fructose. Non-limiting examples of the amoun t
`wet granulation in view of the present disclosure.
`of flavor agents or sweeteners that can be used in the tablet
`Disintegrants facilitate break'1lp of the tablet af1er admin-
`composition of tbe present invention are listed in Table 2.
`55 istrat ion during chewing. Non-limiting examples of disin te(cid:173)
`The amounts in Table 2 are given as percentage of the total
`grants include crospovidone, croscarmellose sodium,
`tablet weight.
`starches, corn starch, potato starch, modified corn starch,
`sodium starch glycolate, and pregelati nized starch. Disinte(cid:173)
`graots can be included in the tablet formu lation in amounts
`60 generally les.s than about 25% of the tablet weight, prefer-
`ably less than about 20%, and more preferably about 1 to
`about 20% (natural starches such as corn or potato starch),
`about 5 to about 10% (pregelatini?..Cd starch), and about 3 to
`8% (modified com starch). Crospovidone and croscarmel(cid:173)
`lose sodium are used at levels of about 5% or lower.
`As a Hnal s tep in tbe manufacture of the tablet, a lubricant,
`an anti-adherent, and a glidaot can be added to tbe tablet
`
`50
`
`TABLE 2
`
`Sweetener and Flavor Amounts Used in Chewable Oml
`Contraceptive Fom1ulations
`
`lngre·
`dient
`Type
`
`Examples
`
`Broad
`
`lntcrmed.iatc
`
`Preferred
`
`Sweet-
`ener
`
`Aspartan1e 0.02to 1.0% 0.02% to 0.2%
`Sucralose O.QJ to 0.5% O.OJ% to 0.1%
`
`0.03% to 0.05%
`0.02 to 0.04%
`
`65
`
`Petitioner Exhibit 1004
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`
`US 6,667,050 Bl
`
`7
`granulation. A lubricant facilitates tablet manufacture by
`reducing friction in the tablet die during compression and
`eject ion. An anti-ad herent prevents the tablet from slicking
`to the tablet punch and die wall. A glidant improves flow
`characteristics of the granulation. Non-limiting examples of 5
`a lubricant include stearates, such as magnesium, calcium,
`and sodium stearates, stearic acid, hydrogenated vegetable
`oils, waxes, talc, boric acid, sodium benzoate, sodium
`acetate, sodium chloride, DL-leucine, sodium oleate,
`sodium Iaury! sulfate, magnesium Iaury! sulfate, and CAR- 10
`BOWAX® (Union Carbide Cbemicals & Plastics Technol(cid:173)
`ogy Corp.) polyethylene glycols. Non-limiting examples of
`an anti-adherent include talc, corn starch, colloidal silicon
`dioxide, DL-Jeucine, sodium Iaury! sulfate, and metallic
`stearates. Non-limiting examples of a glidant include talc, 15
`corn starch, and colloidal silicon dioxides sucb as CAB-0 -
`SIL® (Cabot Corp.), SYLOID® (W.R. Grace & Co.), and
`AEROSIL® (Degussa). Some ingredients, such as talc, can
`contribute to the fom1ulation with combined functions,
`acting as a lubricant, and an an ti-adherent, and a glidant.
`A lubricant is typically included in lbe tablet formulation
`in amounts less tban about 10% of the tablet weight,
`preferably less than abou t 6%, and more preferably about
`0.25 to about 2% (stearates, stearic acid, hydrogenated
`vegetable oil), about1 to about5% (talc, waxes, DL-Ieucine, 25
`CARBO WAX®, sodium Iaury! sulfate), abou t 1to abou t 2%
`(magnesium Iaury! sulfate) and about4to about 6% (sodium
`chloride, sodium o leate, sodium benzoate, sodium acetate).
`Anti-adherents are typically included in the tablet formu (cid:173)
`lation in amounts generally less than about 15% of the tablet 30
`weight, preferably less than about 12%, and more preferably
`about 3 to about 10% (cornstarch, DL-leucine), about 1 to
`about 5% (talc), abou t 0.1 to about 0.5% (colloidal silicon
`dioxide) and less than about 1% (sodium Iaury! sulCate,
`metallic stcarates).
`Aglidant is typically included in the tablet formulation in
`amouots generally less than about 15% of the tablet weight,
`preferably less than about 12%, and more preferably less
`than about 5 to about 10% (corn starcb), abou t 0.1 to about 40
`0.5% (CAB-0-SIL®, SYLOID®), about l to about 3%
`(AEROSIL®), and about 5% (talc).
`The chewable tablet generally is not coated wi th a film or
`sugar coating. However, tbin tablet coatings of a type known
`to those skilled in making coated tablets can be used.
`In one preferred embodiment of the invention, the oral
`contracep tive agent comprises norethindrone and e thioyl
`estradiol, the carrier comprises dicalcium phosphate, lactose
`monohydrate, and maltodextrin, and the tablet further com(cid:173)
`prises sucralose, a flavor agent, sodi.um starch glycolate, so
`povidone, and magnesium stearate.
`The overall size of the tab.let may be any tablet size tba t
`incorporates the desired contraceptively effective amount of
`tbe oral contraceptive agent and the carrier and is still
`chewable and palatable. In a preferred embodiment, the size ss
`of the tablet is small, on the order of about 50 milligrams to
`about 300 milligrams. More preferably, the tablet weight is
`about 70 milligrams to about 120 milligrams, and most
`preferably, the table t weight is about 90 milligrams to about
`110 milligrams. A smaller tablet is more portable than a 60
`larger tablet and therefore more appealing to patients pre(cid:173)
`ferring to carry oral contraceptive pills on their person,
`particularly in blister packaging. Further, smaller tablets arc
`more likely than larger tablets to be accepted as chewable.
`Therefore, smaller tablets are more likely to enhance a 65
`patient's compliance with an oral contraceptive regimen.
`The shape of the tablet of the present invention is not critical.
`
`8
`The hardness of the table t may be any hardness tha t
`allows for tablet formation and tha t is still palatable and
`cbewable. O ne aspect of the invention includes a tablet
`having a hardnes.~ sufficient for blister packaging while still
`remaining palatable and chewable. Blister packaging is
`common in the art of oral contraceptive tablet dispensing. In
`a preferred embodiment, the tablet of the invention has a
`hardness of about 5 kilopond (kp) to about 15 kp, and
`preferably about 7 kp to about 12 kp.
`Another aspect of this invention relates to a method of
`human female oral contraception comprising providing a
`chewable, palatable oral contraceptive tablet comprising a
`contraceptively cticctive amount of an oral contraceptive
`agent, and a chewab.le carrier suitable for human
`consumption, and not comprising a ferrocene compound,
`and administering the tablet to a buman female. 'The tablet
`is the tablet described above, and typically and preferably, a
`number of such tablets as part of a contraceptive regimen.
`The tablet can be administered to the woman in a variety
`20 of ways. Typically, the table t is administered once daily. The
`tablet routinely contains a contraceptively active amount of
`an oral contraceptive agent, and some tablets used in a
`regimen may be a placebo. The placebo tablets are admin-
`istered on days where the oral contraceptive agent is not
`required. As such, the woman is administered a tablet every
`day to help mai ntain the contraceptive regimen of taking a
`daily tablet. For example, a dosage regimen may utilize
`about 21 to about 63 days of tablets containing the oral
`contraceptive agent followed by about 3 to about 7 days of
`tablets comprising a placebo. Preferably, the regimen entails
`administering tablets for total o( about 24 to about 32 days,
`wherein tablets containing lbe oral contraceptive agent are
`administered for about 21 to about 25 days, followed by
`about 3 to abou t 7 days of placebo tablets not contai ning tbe
`contraceptive. In one preferred embodiment, the tablets are
`administered fo r a total of about 28 days.
`A<; explai ned above, the contraceptive dosage in the
`tablets can be uniphasic or multiphasic.
`Another aspect of this invention relates tO a method o(
`enhancing compliance wit h a human female oral contracep(cid:173)
`tive regimen involving oral contraceptive tablets, the
`method comprising providing chewable, palatable oral con(cid:173)
`traceptive tablets comprising a contracep tively effective
`45 amount of an oral contraceptive agent, and a chewable
`carrier suitable for buman consumption, and not comprising
`a ferrocene compound, and administering the tablets to the
`human female in accordance with the contraceptive regi(cid:173)
`men.
`In connecrion with this aspect of tbe invention, each tablet
`of the regimen preferably comprises a daily dosage of the
`oral contraceptive agent. As sucb, daily administration of
`one of the tablets would be part of the regimen. Tbe
`chewable, palatable oral contraceptive of this invention
`allows the woma n the convenience of i~ngesting the tablet in
`a manner tha t does not require taking the tablet with liquid,
`without chewing it. Therefore, the woman can take the tablet
`each day at a time and place that is suitable to her lifestyle.
`Ingesting the tablets at the same time of day on a daily basis
`enhances compliance with any given contracep tive regimen.
`The regimen can comprise any number of days of admin(cid:173)
`istration of the tablets to the woman. In one preferred
`embodiment, the regimen comprises providing about 21 to
`about 63 tablets, each tablet comprising the daily dosage of
`the oral contraceptive agent, followed by abou t 3 to about 7
`tablets, each comprising a placebo. Preferably, a total of
`about 24 to about 32 tablets are administered daily, wherein
`
`35
`
`Petitioner Exhibit 1004
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`
`US 6,667,050 Bl
`
`9
`about 21 to about 25 tablets each comprising the oral
`contraceptive agent are administered, followed by about 3 to
`about 7 tablets each comprising a placebo. In one preferred
`embodiment, a total of about 28 tablets is administered.
`The amount of the oral contraceptive agen t through the 5
`duration of the regimen can remain constant or can be varied
`for tablets cootaining an oral contraceptive agent (rather
`than placebo tablets without an oral contraceptive agent). l n
`one embodiment, the amount of the oral contraceptive agent
`is present in the same amount in the oral contraceptive 10
`tablets of the regimen, thereby comprising a uniphasic
`regimen. In another embodiment, the amou nt of the oral
`contraceptive agent is present in varying amounts in the oral
`contraceptive tablets of the regimen, thereby comprising a
`multiphasic regimen. In tablets comprising an estrogen and 15
`a progestin, the ratio of the estrogen to the progestin can be
`constant throughou t the duration of the regimen.
`Alternatively, the ratio of the estrogen to the progestin in the
`tablets can vary th roughout the regimen.
`Any number of the tablets may be dispensed in any type 20
`of packaging commonly used in the art of tablet dispensing.
`Blister packages are often and preferably used for dispens(cid:173)
`ing oral contraceptives. Blister packages are generally small
`and portable, usually and preferably containing the number
`of tablets requked for a month of dosing. Many patients 25
`desiring oral contraceptive tablets find this method of dis(cid:173)
`pensing convenient. ln a preferred embodiment, the tablets
`for the ora l contraceptive regimen of this invention are
`dispensed in a blister package. The packaging is preferably
`in the form of a 28-daily dosage units blister package 30
`comprising about 2lto about 25 tablets comprising the oral
`contraceptive agent and the remaining respective abou t 7 to
`about 3 tablets comprising a placebo.
`A tablet made in accordance with the present invention 35
`may simply be chewed. This substantially reduces the exist(cid:173)
`ing barriers to compliance. The use of a chewable, palatable
`tablet in accordance with the present invention eliminates
`the need to incorporate liquid to facilitate swallowing and
`makes oral contraceptives mo re agreeable for patients who 40
`have ditliculty or reluctance to swallowing tablets. The
`chewable, pa latable tablets of this invention have a tablet
`size and hardness suitable for use in blister packaging and
`arc synergistic with the existing design and intent of oral
`contraceptive package portability and convenience. 45
`1bcrefore, the oral contraceptive formu lations of this
`invention, administered according 10 this invention, provide
`a method of enhancing compliance with a human female
`oral contraceptive regime