1
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`CIVIL NO 11 5048 and 122928
`
`WARNER CHILCOTT CO LLC
`
`Plaintiff
`
`TRANSCRIPT OF PROCEEDINGS
`
`TRIAL
`
`vs
`
`LUPIN LTD and LUPIN
`PHARMACEUTICALS INC
`
`Defendants
`WARNER CHILCOTT CO LLC
`Plaintiff
`
`vs
`WATSON LABORATORIES INC
`
`Defendant
`
`Trenton New Jersey
`October 7 2013
`
`B E F O R E
`
`THE HONORABLE
`UNITED STATES DISTRICT COURT JUDGE
`
`JOEL A PISANO
`
`to Section 753 Title 28 United States
`Pursuant
`Code the following transcript
`is certified to be
`an accurate record as taken stenographically in the
`above entitled proceedings
`
`SJoanne M Caruso CSR CRR
`Official Court Reporter
`9083342472
`
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`JOANNE M CARUSO CSR CRR OFFICIAL COURT REPORTER
`
`TRENTON NJ
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 1
`
`

`
`Barnhart
`
`Direct
`
`50
`
`THE COURT Miss Breen is that what you like to be
`
`MS BORG BREEN Caryn BorgBreen It’s a hyphenated
`
`called
`
`name
`
`THE COURT Yes I know that I didn’t know if you
`
`wanted both
`
`MS BORG BREEN
`
`It’s actually my husband’s last
`
`name
`
`THE COURT
`
`How are you
`
`MS BORG BREEN
`I’m doing pretty well your Honor
`At this time Lupin would call its first witness Dr Kurt T
`Barnhart
`
`THE COURT Dr Barnhart
`
`MS BORG BREEN
`
`He is a board certified obstetrician
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`1 2 3 4 5 6 7 8 9
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`and gynecologist who will be presenting testimony on behalf of
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`Lupin supporting prior art
`
`Permission to approach
`
`THE COURT Sure
`B A R N H A R T sworn
`THE COURT Good morning sir
`
`K U R T
`
`THE WITNESS
`
`Good morning
`
`Can I clarify two important things before we start
`
`THE COURT Wait until Miss BorgBreen gets back
`
`What have you given here
`
`MS BORG BREEN
`
`We have two binders of exhibits and
`
`JOANNE M CARUSO CSR CRR OFFICIAL COURT REPORTER TRENTON NJ
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 2
`
`

`
`Barnhart
`
`Cross
`
`227
`
`A
`
`Q
`
`A
`
`Yes often in scientific
`
`Cartoon
`
`That’s a word we use scientifically all the time to show
`
`it’s not data it’s an example
`
`Q
`
`A
`
`Q
`
`A
`
`Q
`
`A
`
`Q
`
`Cartoon was the word you used sir
`
`That was the word I used
`
`Let’s talk about
`
`the 050 patent now
`
`Can we have DTX 3 and four Mr Brooks
`
`You discussed this yesterday as well correct
`
`I did
`
`Can we have column two lines 47 through 49
`
`Which DTX is this I’m sorry
`
`DTX 384
`
`Do you see that at column two lines 47 through 49 it
`
`says The present
`
`invention relates to chewable palatable
`
`1 2 3 4 5 6 7 8 9
`
`10
`
`11
`
`12
`
`13
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`14
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`15
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`16
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`oral contraceptive tablets for administering an oral
`
`17
`
`18
`
`19
`
`20
`
`contraceptive agent to human females
`
`A
`
`Q
`
`That’s correct
`
`And the inventor stated and now I’m at column three
`
`lines 55 through 60 In principle virtually any oral
`
`21
`
`contraceptive agent used in human medicine could be employed
`
`22
`
`in accordance with the principles of
`
`the invention
`
`The oral
`
`23
`
`contraceptive agent may be an estrogen a progestin or
`
`24
`
`25
`
`combination of an estrogen and a progestin
`
`Do you see that sir
`
`JOANNE M CARUSO CSR CRR OFFICIAL COURT REPORTER TRENTON NJ
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 3
`
`

`
`Warner Chilcott v. Lupin Ltd., et al.,
`C.A. 11-05048 (JAP) (TJB)
`Warner Chilcott v. Watson Labs.,
`C.A. 12-2928 (JAP) (TJB)
`
`DTX 384
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 4
`
`

`
`US 6,667,050 B1
`
`1
`CHEWABLE ORAL CONTRACEPTIVE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`a continuation-in-part of U.S. patent application
`This
`Ser. No. 09/286,908, filed Apr. 6, l999.
`
`STATEMENT REGARDING FEDERALLY
`SPONSORED RESEARCH OR DEVELOPMENT
`
`Not Applicable.
`
`REFERENCE TO MICROFICI-IE APPENDIX
`
`Not Applicable.
`
`BACKGROUND OF THE INVENTION
`
`The present invention generally relates to an oral contra-
`ceptive delivery system, and in particular an oral contracep-
`tive delivery system involving novel alternate dose forms to
`improve compliance.
`The efficacy oforal 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 significant reason for failure with
`oral contraceptives is use, rather than method, failure. 'l‘hat
`is, unless the contraceptives are used according to the
`prescribed regimen, the contraceptives can fail to cllectively
`help a patient avoid pregnancy. Further, in order to he most
`effective in preventing pregnancy and maintaining men-
`strual cycle control, proper compliance with an oral contra-
`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 has
`been suggested that progestin rods can be inserted subdcr-
`mally. This procedure has been described, for example, in
`U.S. Pat. No. 5,756,115. This technique has the significant
`disadvantage of requiring a surgical incision, a procedure
`that is highly disfavored by a relatively large segment of the
`patient population.
`As another example, it has been suggested that DEPO-
`PROVERA® (Pharmacia,
`Inc.) medroxyprogcstcronc
`acetate can be injected subcutaneously every three months.
`This technique has been described, for example, in U.S. Pat.
`No. 4,639,439. This procedure has the disadvantage of
`requiring an injection via hypodermic needle, which is also
`a procedure that is disfavored by many patients.
`In many cases, the patient prefers to carry the contracep-
`tive pills on her person as a matter of lifestyle or personal
`discretion. This is especially true for younger patients, and
`it
`is not uncommon for such patients to exchange pills.
`Members of this population tend to view portable packaging
`of the pills, immediate access to the pills, and ease ofpil] use
`as significant benelits.
`Prior proposed soltttions to the compliance problem have
`tended to focus primarily or exclusively on optimizing
`compliance packaging, rather than on changes to the dosage
`form. It has been suggested that instead of being packaged
`in vials, contraceptive pills can be packaged in 21 or 28 day
`blister pat:l<agc$. It has also been suggested that the size of
`these packages can he reduced to improve portability and
`confidentiality.
`Although oral contraceptive pills provided in a small
`blister package are somewhat more convenient to carry and
`
`2
`to conceal, they are not necessarily easy to ingest. Access to
`water to facilitate contraceptive pill taking remains a prob-
`lem. Most medications are typically stored in a medicine
`cabinet and therefore are likely to be near a water source. On
`the contrary, oral contraceptive pills are often carried on the
`person and a source of water is not always available when
`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-
`ceptive tablet. The technology encompassed in the invention
`involves a chewable, palatable oral contraceptive tablet that
`has appropriate size and hardness for blister packaging and
`compliant use.
`BRIEF SUMMARY OF THE INVENTION
`
`One aspect of the present invention relates to a chewable,
`palatable oral contraceptive tablet, comprising an oral con-
`traceptive agent, a chewable carrier suitable for human
`consumption, and not comprising a ferrocene compound.
`Another aspect of this invention relates to a method of
`human female oral contraception, the method comprising
`providing a chewable, palatable oral contraceptive tablet
`comprising a contraceptively effective amount of an oral
`contraceptive agent, and a chewable carrier suitable for
`human consumption, and not comprising a
`ferrocene
`compound, and administering the tablet to a human female.
`Yet another aspect of this invention relates to a method of
`enhancing compliance with a human female oral contracep-
`tive regimen involving oral contraceptive tablets,
`the
`method comprising providing chewable, palatable oral con-
`traceptive tablets comprising a contraceptively effective
`amount of an oral contraceptive agent, and a chewable
`carrier suitable for human consumption, and not comprising
`a fcrroccne compound, and administering the tablets to the
`human female in accordance with the contraceptive regi-
`men.
`
`BRIEF DESCRIPTION OF TI-IE SEVERAL
`VIEWS OF THE DRAWINGS
`
`Not Applicable.
`DETAILED DESCRIPTION OF THE
`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 the absence of a liquid. The oral contracep-
`tive agent formulation of this invention improves dosage
`regimen compliance, and thereby enhances the desired con-
`traceptive effect of the oral contraceptive. This invention
`also includes methods for administering the oral contracep-
`tive formulations to a woman.
`
`Definitions
`
`The articles “a” and "an” are used herein 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”
`means one element or more than one element.
`
`The term “oral contraceptive agent," as used herein, refers
`to any compound or combination of compounds which,
`when administered orally, prevents pregnancy.
`The term “estrogen,” as used herein, refers to any natural
`or synthetic compound which exhibits an effect on the
`
`5
`
`10
`
`15
`
`30
`
`35
`
`40
`
`45
`
`SD
`
`55
`
`60
`
`(S5
`
`|PR2015-00682
`Mylan v. Warner Chilcott
`WC Ex. 2023, Pg. 5
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 5
`
`

`
`US 6,667,050 B1
`
`3
`female reproductive organs in a manner similar to the natural
`Female hormone estrogen. Examples of an estrogen include,
`but are not limited to, ethinyl estradiol, estradiol, estradiol
`valerate, and estradiol acetate.
`
`4
`levonorgestrel, ctbynodiol diacetatc, norgestrel,
`norgestimate, gestodene, drospirenone,
`trimegestone,
`levodesogestrel, gestodyne, and nesteronc. Preferably, the
`progestin is norethindrone.
`
`The term “progestin," as used herein, refers any natural or
`synthetic compound which exhibits a progestational etfect
`on the female reproductive organs. Examples of a progestin
`include, but are not limited to, norethindrone, norethindrone
`acetate, dcsogestrel,
`levonorgestrel, ethynocliol diacetate,
`norgestrel, norgestimate, gestodene, drospirenone,
`trimegestone, levodesogestrel, gestoclyne and nesterone.
`'lhe term “palatable,” as used herein, means that the tablet
`of tltis invention has a taste, mouth feel, chewability, texture,
`aroma, and lack of grittincss and bad aftertaste that makes
`the tablet agreeable to a woman to chew.
`
`The dosage of the oral contraceptive agent employed
`would tend to be that conventionally used in the art for the
`particular oral contraceptive agent selected. The proportion
`of the oral contraceptive agent
`in the tablet may be a
`pharmaceutically ellcctive trace amount to about 10% by
`weight. Thus, the quantity of oral Contraceptive agent per
`tablet may be varied as desired, typically about 10 micro-
`grams to about 5 milligrams, but
`the lower and upper
`dosages may be reduced or increased. Examples of approxi-
`mate dosage ranges of oral contraceptive agents in milli-
`grams per tablet are summarized in Table 1.
`
`10
`
`15
`
`TABLE 1
`
`Examples of Dose Ranges of Oral Contraceptive Agents (milligmms Er tablet:
`
`Description
`Progcstin
`
`Preferred
`Intermediate
`Broad
`Examples
`0.4 to 1.5
`0.25 to 2.0
`0.1 to 2.5
`Nnrethirtdrone,
`0.4 to 1.5
`0.25 to 2.0
`0.1 to 2.5
`Norcthindrone acetate
`0.] to 0.2
`0.1 to 0.3
`0.05 to 0.5
`Dcsogestrel
`0.05 to 0.6
`0.025 to 1.0
`0.025 to 1.5
`Levonorgestrcl
`0.9 to 1.1
`0.75 to 1.25
`0.5 to 2.5
`Ethynodiol diacemte
`0.] to 1.2
`0.05 to 2.0
`0.05 to 3.0
`Norgcstrcl
`0.18 lo 0.25
`0.15 to 0.35
`0.1 to 0.5
`Nurgestirnatc
`0.06 to 0.075
`0.05 to 0.10
`0.03 to 0.15
`Gestodene
`2.5 to 3.5
`2.0 to 4.0
`1.0 to 5.0
`Drospirenone
`0.1 to 0.2
`0.1 to 0.3
`0.05 to 0.5
`'l‘n'megt.-stone
`0.020 to 0.050
`0.015 to 0.05
`0.01 to 0.075
`Ethinyl Estradiol,
`1.5 to 2.5
`1 to 3
`0.5 to 4.0
`lilstradiol
`1.9 to 3.0
`1.5 to 3.5
`0.5 to 5.0
`Etradiol valcrate
`
`
`
`31.5 to 3.50.5 to 5.0llstradiol acetate 1.8 to 3.0
`
`Estrogen
`
`A tablet is “chcwable," as used herein, such that when the
`tablet is chewed, it breaks into smaller pieces that can be
`swallowed. This is in contrast to gum, for example, which
`does not break into smaller pieces when chewed.
`
`Description of the Invention
`
`The first aspect of the invention relates to a chewable,
`palatable oral contraceptive tablet comprising an oral con-
`traceptive agent, a chewable carrier suitable for human
`consumption and not comprising a [crrocene compound.
`The tablet of this invention expressly does not contain a
`ferrocene compound. Ferroccue compounds are used in the
`treatment of anemia and it should not be assumed that all
`patients desiring an oral contraceptive agent are anemic.
`Administering ferrocenc compounds when they are not
`needed can lead to iron poisoning. Additionally, ferrocene
`compounds may not be palatable when chewed.
`
`In principle, virtually any oral contraceptive agent used in
`human medicine could be employed in accordance with the
`principles of the present invention. The oral contraceptive
`agent may be an estrogen, a progestin, or a combination of
`an estrogen and aprogestin. in one embodiment, the oral
`contraceptive agent is art estrogen selected from the group
`consisting of ethinyl estradiol, cstradiol, estradiol valcrale,
`and estradiol acetate. Preferably,
`the estrogen is ethinyl
`estradiol.
`
`In another embodiment, the oral contraceptive agent is a
`progestin selected from the group consisting of
`norethindrone, norethindronc acetate, dcsogcstrel,
`
`40
`
`45
`
`50
`
`55
`
`I50
`
`65
`
`In one preferred embodiment, the tablet comprises estro-
`gen in the fonn of ethinyl estradiol in an amount of about 10
`micrograms to about 75 micrograms. In another preferred
`embodiment, the tablet comprises progcstin in the form of
`norcthindronc 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
`progestin. Preferably, the estrogen is ethinyl estradiol and
`the progestin is norethindrone.
`in a more preferred
`embodiment, the amount of ethinyl estradiol in the tablet is
`about 10 micrograms to about 75 micrograms and the
`amount of norethindrone in the tablet is about 0.1 milligram
`to about 2.5 milligrams.
`The tablets of this invention can be used in conjunction
`with an oral contraceptive regimen. The regimen can com-
`prise administering tablets on a daily basis for multiple
`consecutive days. As such, throughout the duration of the
`regimen the amount of oral Contraceptive agent in the oral
`contraceptive tablets may remain constant, thereby compris-
`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-
`prising a multiphasic regimen.
`ln tablets comprising an
`estrogen and a progestin, the ratio of the estrogen to the
`progestin can be constant throughout 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 possible to form placebo tablets which otherwise
`correspond in composition to the tablet ot‘
`the present
`invention but are [rec of the oral contraceptive agent.
`
`|PR2015-00682
`Mylan v. Warner Chilcott
`WC Ex. 2023, Pg. 6
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 6
`
`

`
`US 6,667,050 B1
`
`5
`’ll1e oral contraceptive agent may be present in a carrier
`either in a dissolved or a uniformly suspended state. A
`carrier comprises all but the active oral contraceptive agent
`or agents and includes an inactive ingredient or a combina-
`tion of one or more inactive ingredients. The carrier imparts
`chewable and palatable characteristics to tl1e 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-
`facturers’ Association (FEMA). The carrier selected for the
`invention must" be chewable and should not confer a dis-
`agreeable taste to the tablet. Thus, the carrier itself must be
`palatable. The primary ingredient of a carrier is one or more
`dilucnts. Non-limiting examples of diluents that can be used
`in accordance with this invention include microcrystalline
`cellulose, corn starch, modified starch, calcium carbonate,
`clicalcium phosphate, and poly-alcohol sugars such as
`dextrose, mannitol, sorbitol, xylitol, lactose, sucrose, and
`fructose. Many other diluent.-5 or other ingredients suitable as
`components of carriers for a chewable, palatable oral con-
`traceptive tablet are available and would be well known to
`those skilled in the art in view of the present disclosure.
`
`In another aspect of the invention, the tablet optionally
`further comprises at least one of a flavor agent, a sweetener,
`and a color agent. Allavor agent can be used to enhance the
`taste of the tablet, making the tablet more palatable than a
`tablet without a flavor agent. Spray dried flavor agents are
`preferred because they are easy to incorporate into a chew-
`able tablet. Non-limiting examples o[ preferred llavor agents
`impart
`the following flavors: strawberry, wild berry,
`spearrnint, wintergrcen, black cherry, orange, orange cream,
`and lemon. The flavoring agents are readily available from
`many commercial sources. Exemplary compounds suitably
`used in preparing flavors are listed in G. Burdock, Ed.,
`Fenaroli’s Handbook of Flavor Ingredients, 3”’ edition,
`Volumes I and II, CRC Press, New York, l995. Other flavors
`and flavoring agents suitable for the tablet would be well
`known to those skilled in the art in view of the present
`disclosure.
`
`A sweetener can also be used to enhance to taste of the
`
`tablet, making the tablet more palatable than a tablet without
`a sweetener. Sweeteners include natural sugars and artificial
`sugar substitutes. Non-limiting examples of sweeteners that
`can be used in accordance with this invention include
`aspartame, sucralose, xylitol, sorbitol, rnttnnitol, dextrose,
`sucrose, and fructose. Non-limiting examples ofthe amount
`of llavor agents or sweeteners that can be used in the tablet
`composition of the present invention are listed in Table 2.
`The amounts in Table 2 are given as percentage of the total
`tablet weight.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4!]
`
`50
`
`TABLE 2
`Sweetener and Flavor Amounts Used in Chewable Oral
`Corttmceptive Formulations
`
`60
`
`Ingre-
`client
`Btamples
`Type
`Swcct- Aspartame
`cner
`Sucralose
`
`lnten-nediate
`Broad
`0.02 to 1.0% 0.02% to 0.2%
`[LU] to 0.5% [l.D1‘.7:) to U.1'.’a
`
`Preferred
`0.03770 to 0.05%
`U.U2 to U.D4‘.'E:
`
`6
`
`TABLE 2-continued
`Sweetener and Flavor Amottnls Used in Chewable Ornl
`Contmccptivc Fon-nulntions
`
`Ingre-
`dient
`Type
`
`Exttmplcs
`
`Brttatl
`
`lnlcnnctlitttc
`
`Preferred
`
`Spearmint
`Flavor
`Agent Wintet-
`green
`Wild berry
`
`0.5 to 5%
`0.5 to 5%
`
`0.1 to 3%
`
`1 to 3%
`1 to 3%
`
`0.2 to 1%
`
`1.5 to 2.5%
`1.5 to 2.5%
`
`0.3 to 0.5%
`
`Optionally, a color agent may be added to aid in tablet
`identification and to enhance the visual appearance of the
`tablet. Avisually 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-maJ~:ing art in 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 tecbniques of solid (lose formulation, sttch as granula-
`tion and compression. These processes are well known to
`those skilled in the art of making tablets (See Lieberman,
`Lachman, and Schwartz, Pltarrtracerttical Dosage Forms,
`Volume 1, New York, 1989). During the granulation process,
`other ingredients typically used in tablet formulation for
`human consumption can be included, such as binders,
`lubricants, anti-adherents, glidants, disintegrants and fillers
`or other optional ingredients that do not adversely afi'cct
`chewability or palatability of the tablet or its active oral
`contraceptive agent ingredient(s).
`Binders aid the formation of granulated particles of active
`oral contraceptive agents and carrier ingredients. Non-
`limiting examples of binders include glucose, acacia, guar
`gum, gelatin, simple syrup, sucrose, sorbitol, starch, alginic
`acid, alginate salts, polyethylene glycol,
`polyvinylpyrrolidone, polymcthacrylates, pregelatinizcd
`starch, and celluloscs such as methylcellulose, sodium
`carboxymcthylcellulosc, hydroxypropylmethylcellulose,
`hydroxypropylcellulose, and ethylcellulose. A solution of
`binder is prepared (concentrations dependent on the particu-
`lar binder used), and the binder solution is mixed with the
`other excipicnts to form the wet granulation. A binder such
`as polyvinylpyrroliclone (Povirlone) is typically used in a
`solution of about 3% to about 15% by weight and is added
`to the other tablet ingredients resulting in a final formulation
`concentration of about 2% to about 5%. Similarly, cellulose
`derivatives are typically used in granulating solutions of
`about 5% to about 10% by weight and concentrations would
`be known to one skilled in the art of making tablets using
`wet granulation in view of the present disclosure.
`Disintegrants facilitate brealntp of the tablet after admin-
`istration during chewing. Non-limiting examples of disinte-
`grants include crospovidone, croscarmcllosc sodium,
`starches, corn starch, potato starch, motlilietl corn starch,
`sodium starch glycolate, and prcgelatinized starch. Disinte-
`grants can be included in the tablet formulation in amounts
`generally less 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% (prcgelatinizccl starch), and about 3 to
`8% (modified corn starch). Crospovidonc and croscarmcl-
`lose sodium are used at levels of about 5% or lower.
`
`As a final step in the manufacture of the tablet, a lubricant,
`an anti-adluerent, and a glidant can be added to the tablet
`
`|PR2015-00682
`Mylan v. Warner Chilcott
`WC Ex. 2023, Pg. 7
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 7
`
`

`
`US 6,667,050 B1
`
`7
`granulation. A lubricant facilitates tablet manufacture by
`reducing friction in the tablet die during compression and
`ejection. An anti-adherent prevents the tablet from sticking
`to the tablet punch and die wall. A glidant improves flow
`characteristics of the granulation. Non-limiting examples of
`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-lcucine, sodium oleate,
`sodium lauryl sulfate, magnesium lauryl sulfate, and CAR-
`BOWAX® (Union Carbide Chemicals & Plastics Technol-
`ogy Corp.) polyethylene glycols. Non-limiting examples of
`an anti-adherent include talc, corn starch, colloidal silicon
`dioxide, DL-lcucine, sodium lauryl sulfate, and metallic
`stearates. Non-limiting examples of a glidant include talc,
`corn starch, and colloidal silicon dioxides such as CAB-0-
`SIL® (Cabot Corp.), SYLOlD® (W.lZ. Grace EL Co.), and
`AEROSlI..® (Dcgussa). Some ingredients, such as talc, can
`contribute to the formulation with combined functions,
`acting as a lubricant, and an anti-adherent, and a glidant.
`Alubricanl is typically included in the tablet formulation
`in amounts less than about 10% of the tablet weight,
`preferably less than about 6%, and more preferably about
`0.25 to about 2% (stearates, stearic acid, hydrogenated
`vegetable oil), about 1 to about 5% (talc, waxes, DL-lcucine,
`CARBOWAX®, sodium lauryl sulfate), about 1 to about 2%
`(magnesium lauryl sulfate) and about 4 to about 6% (sodium
`chloride, sodium oleate, sodium benzoate, sodium acetate).
`Anti-aclherents are typically included in the tablet formu-
`lation in amounts generally less than about 15% of the tablet
`weight, preferably less than about 12%, and more preferably
`about 3 to about 10% (cornstarch, DL-lcucine), about 1 to
`about 5% (tale), about 0.1 to about 0.5% (colloidal silicon
`dioxide) and less than about 1% (sodium lauryl sulfate,
`metallic stearates).
`Aglidant is typically included in the tablet formulation in
`amounts 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 starch), about 0.1 to about
`0.5% (CAB-O-S1L®, SYLOlD®), about
`1
`to about 3%
`(AEROSIL®), and about 5% (tale).
`The chewable tablet generally is not coated with a film or
`sugar coating. 1-lowcvcr, thin 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
`contraceptive agent comprises noretltirtdrone and ethinyl
`estradiol, the carrier comprises dicalcium phosphate, lactose
`monohydrate, and maltodextrin, and the tablet further com-
`prises sucralose, a flavor agent, sodium starch glycolate,
`povidone, and magnesium stearatc.
`The overall size of the tablet may be any tablet size that
`incorporates the desired contraceptively effective amount of
`the oral contraceptive agent and the carrier and is still
`chewable and palatable. In a preferred embodiment, the size
`of the tablet is small, on the order of about 50 milligrams to
`about 300 milligrams. More preferably, the tablet weight is
`about 70 milligratns to about 130 milligrams, and tnosl
`preferably, the tablet weight is about 90 milligrams to about
`110 milligrams. A smaller tablet
`is more portable than a
`larger tablet and therefore more appealing to patients pre-
`ferring to carry oral contraceptive pills on their person,
`particularly in blister packaging. Further, smaller tablets are
`more likely than larger tablets to be accepted as chewable.
`Therefore, smaller tablets are more likely to enhance a
`patient’s compliance with an oral contraceptive regimen.
`The shape ofthe tablet of the present invention is not critical.
`
`1U
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`8
`'l‘he hardness of the tablet may be any hardness that
`allows for tablet formation and that is still palatable and
`chewable. One aspect of the invention includes a tablet
`having a hardnes sufiicient 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
`Another aspect of this invention relates to a method of
`human female oral contraception comprising providing a
`chewable, palatable oral contraceptive tablet comprising a
`contraceplively effective amount of an oral contraceptive
`agent, and a chewable carrier suitable for human
`consumption, and not comprising a ferrocene compound,
`and administering the tablet to a human 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
`of ways. Typically, the tablet 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 maintain 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 of about 24 to about 32 days,
`wherein tablets containing the oral contraceptive agent are
`administered for about 21 to about 25 days, followed by
`about 3 to about 7 days of placebo tablets not containing the
`contraceptive. In one preferred embodiment, the tablets are
`administered for a total of about 28 days.
`As explained above,
`the contraceptive dosage in the
`tablets can be uniphasic or multiphasic.
`Another aspect of this invention relates to a method of
`enhancing compliance with a human female oral contracep-
`tive regimen involving oral contraceptive tablets,
`the
`method comprising providing chewable, palatable oral con-
`traceptive tablets comprising a contraccptivcly clIcctivc
`amount of an oral contraceptive agent, and a chewable
`carrier suitable for human consumption, and not comprising
`a ferrocene compound, and administering the tablets to the
`human female in accordance with the contraceptive regi-
`men.
`
`In connection with this aspect of the invention, each tablet
`of the regimen preferably comprises a daily dosage of the
`oral contraceptive agent. As such, daily administration of
`one ol'
`the tablets would be part of the regimen. The
`chewable, palatable oral contraceptive of this invention
`allows the woman the convenience ofingesting the tablet in
`a manner that 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.
`lrtgcsling the tablets at the same time of day on a daily basis
`enhances compliance with any given contraceptive regimen.
`The regimen can comprise any number of days of admin-
`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 about 3 to about 7
`tablets, each comprising a placebo. Preferably, a total ol'
`about 24 to about 32 tablets are administered daily, wherein
`
`|PR2015-00682
`Mylan v. Warner Chilcott
`WC Ex. 2023, Pg. 8
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2023, Pg. 8
`
`

`
`US 6,667,050 B1
`
`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.
`'.lhe amount of the oral contraceptive agent through the
`duration ofthe regimen can remain constant or can be varied
`for tablets containing an oral contraceptive agent (rather
`than placebo tablets without an oral contraceptive agent). In
`one embodiment, the amount of the oral contraceptive agent
`is present
`in the same amount
`in the oral contraceptive
`tablets of the regimen,
`thereby comprising a uniphasic
`regimen. In another embodiment, the amount of the oral
`contraceptive agent is present in varying amounts in the oral
`contraceptive tablets of the regimen, thereby comprising a
`rnultiphasic regimen. In tablets comprising an estrogen and
`a progestin, the ratio of the estrogen to the progestin can be
`constant
`throughout
`the duration of the regimen.
`Alternatively, the ratio of the estrogen to the progestin in the
`tablets can vary throughout the regimen.
`Any number of the tablets may be dispensed in any type
`of packaging commonly used in the art of tablet dispensing.
`Blister packages are often and preferably used for dispens-
`ing oral contraceptives. Blister packages are generally small
`and portable, usually and preferably containing the number
`of tablets required for a month of dosing. Many patients
`desiring oral contraceptive tablets find this method of dis-
`pensing convenient. In a preferred embodiment, the tablets
`for the oral contraceptive regimen of this invention are
`dispensed in a blister package. 'l'hc packaging is preferably
`in the form of a 28-daily dosage units blister package
`comprising about 21 to about 25 tablets comprising the oral
`contraceptive agent and the remaining respective about 7 to
`about 3 tablets comprising a placebo.
`A tablet made in accordance with the present invention
`may simply be chewed. This substantially reduces the exist-
`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 more agreeable for patients who
`have difticnlty or reluctance to swallowing tablets. The
`chewable, palatable tablets of this invention have a tablet
`size and hardness suitable for use in blister packaging and
`are synergistic with the existing design and intent of oral
`contra