Warner Chilcott Company v. Lupin Atlantis Holdings et. al.

8/21/2019 Warner Chilcott Company v. Lupin Atlantis Holdings et. al.

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IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF MARYLAND

WARNER CHILCOTT COMPANY, LLC,

Union St., Road 195, Km. 1.1

Fajardo, Puerto Rico

Plaintiff,

v.

LUPIN ATLANTIS HOLDINGS SA

Mhlentalstrasse 28200 Schaffhausen

Schaffhausen, Switzerland

LUPIN LTD.

B/4 Laxmi Towers,

Bandra Kurla Complex, Bandra (E),

Mumbai 400 051 India

LUPIN PHARMACEUTICALS, INC.

111 S. Calvert Street,

21st Floor,Baltimore, MD 21202

Baltimore City

Defendants.

C.A. No. _________________

COMPLAINT FOR PATENT INFRINGEMENT


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Plaintiff Warner Chilcott Company, LLC, by its undersigned attorneys, brings this

action against Defendants Lupin Atlantis Holdings SA; Lupin Ltd.; and Lupin

Pharmaceuticals, Inc. (collectively Lupin), and hereby alleges as follows:

THE PARTIES

1. Plaintiff Warner Chilcott Company, LLC (Warner Chilcott) is a limitedliability company organized and existing under the laws of Puerto Rico, having offices at

Union St., Road 195, Km 1.1, Fajardo, Puerto Rico.

2. Upon information and belief, Defendant Lupin Limited (Lupin Ltd.) is acorporation organized and existing under the laws of India.

3. Upon information and belief, Defendant Lupin Atlantis Holdings SA (LupinAtlantis) is a wholly-owned subsidiary of Lupin Ltd., and is a corporation organized and

existing under the laws of Switzerland.

4. Upon information and belief, Defendant Lupin Pharmaceuticals, Inc. (LupinPharmaceuticals) is a wholly-owned subsidiary of Lupin Ltd. and is a corporation

organized and existing under the laws of the Commonwealth of Virginia. Lupin

Pharmaceuticals has a principal place of business located at 111 S. Calvert Street, 21st

Floor, Baltimore, MD 21202.

5.

Upon information and belief, Lupin Ltd. has engaged in continuous and

systemic contacts with the United States by, among other things, filing with the United

States Food and Drug Administration (FDA) Abbreviated New Drug Applications

(ANDAs) to sell various products in the United States. Upon information and belief,


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Lupin Ltd. manufactures generic drug products for sale and use in the United States,

including in this judicial district.

6. Upon information and belief, Lupin Ltd., Lupin Atlantis, and LupinPharmaceuticals are agents of each other with respect to the development, regulatory

approval, marketing, sale and/or distribution of generic pharmaceutical products. Upon

information and belief, Lupin Ltd. and Lupin Pharmaceuticals, through their affiliate,

agent, and alter-ego Lupin Atlantis, filed the ANDA with FDA that is at issue in this

patent infringement suit. Upon information and belief, the acts of Lupin Atlantis

complained of herein were done and are being done with the cooperation, participation,

and assistance of, and at least in part for the benefit of, Lupin Ltd. and Lupin

Pharmaceuticals.

JURISDICTION AND VENUE

7. This is an action for patent infringement arising under the patent laws of theUnited States, 35 U.S.C. 271(e)(2) and 21 U.S.C. 355. This Court has subject matter

jurisdiction over this action based on 28 U.S.C. 1331 and 1338(a).

8. This Court has personal jurisdiction over Lupin Pharmaceuticals by virtue of,at least, its principal place of business in Baltimore, MD.

9.

This Court has personal jurisdiction over Lupin Atlantis at least under

Federal Rule of Civil Procedure 4(k)(2).

10. This Court has personal jurisdiction over Lupin Ltd. at least under FederalRule of Civil Procedure 4(k)(2).


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11. Venue is proper in this Court under 28 U.S.C. 1391 and 1400(b).COUNT I: CLAIM FOR INFRINGEMENT OF THE 050 PATENT

12. Warner Chilcott LLC is the holder of New Drug Application (NDA) No.203667 for Minastrin24 Fe, which contains the active ingredients ethinyl estradiol and

norethindrone acetate. Minastrin24 Fe was approved by FDA on May 8, 2013, and is

indicated for use by women to prevent pregnancy. Minastrin24 Fe is sold as a 28-day

oral contraceptive regimen that includes 24 chewable tablets comprising 1.0 mg

norethindrone acetate and 0.020 mg ethinyl estradiol, and 4 chewable ferrous fumarate

tablets (placebo).

13. U.S. Patent No. 6,667,050 (the 050 Patent) entitled Chewable OralContraceptive was lawfully issued by the United States Patent and Trademark Office on

December 23, 2003. A copy of the 050 Patent is attached as Exhibit A.

14. Warner Chilcott is the sole owner of the 050 Patent.15. The 050 Patent claims, among other things, chewable, palatable oral

contraceptive tablets; methods of administering said tablets to a human female; and

methods of enhancing compliance with the oral contraception regimen.

16. Minastrin24 Fe and its use in accordance with the FDA-approved labelingare covered by the claims of the 050 Patent. The 050 Patent is listed in FDAsApproved

Drug Products with Therapeutic Equivalence Evaluations(the Orange Book) for

Minastrin24 Fe.


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17. Upon information and belief, Lupin Ltd. and Lupin Pharmaceuticals, throughtheir affiliate, agent, and alter-ego Lupin Atlantis, submitted ANDA No. 206287 to FDA

seeking approval to engage in the commercial manufacture, use, offer for sale, and sale of

a generic version of Minastrin24 Fe before the expiration of the 050 Patent. Defendants

manufacture, use, offer for sale, or sale in the United States, or importation into the

United States, of such product would infringe the claims of the 050 Patent under 35

U.S.C. 271(a), (b), and/or (c).

18. Defendants manufacture, use, offer for sale, or sale in the United States, orimportation into the United States, of the generic Minastrin24 Fe product for which

approval is sought in ANDA No. 206287 would actively induce and contribute to

infringement of the 050 Patent, and Defendants would be liable under 35 U.S.C. 271(b)

and/or (c).

19. As part of their ANDA filing, Lupin Ltd. and Lupin Pharmaceuticals, throughtheir affiliate, agent, and alter-ego Lupin Atlantis, have purportedly provided written

certification (Paragraph IV certification) to FDA that the claims of the 050 Patent are

invalid and/or will not be infringed by the manufacture, use, or sale of Defendants generic

version of Minastrin24 Fe.

20.

By letter dated April 24, 2014, Defendants counsel gave written notice of the

certification of invalidity and/or noninfringement of the 050 Patent, alleging that the

claims of the 050 Patent are invalid due to obviousness, indefiniteness, and lack of

enablement, and that claims 18, 36, and 54 are not infringed by Defendants generic


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Minastrin24 Fe product. The letter additionally informed Warner Chilcott that

Defendants seek to engage in the commercial manufacture, use, and sale of a product

bioequivalent to Minastrin24 Fe prior to the expiration of the 050 Patent.

21. Lupin Atlantis has infringed the 050 Patent under 35 U.S.C. 271(e)(2)(A)by virtue of submitting ANDA No. 206287 with a Paragraph IV certification and seeking

FDA approval of ANDA No. 206287 prior to the expiration of the 050 Patent. Moreover, if

Lupin Atlantis commercially manufactures, uses, offers for sale, or sells in the United

States, or imports into the United States, Defendants generic version of Minastrin24 Fe,

it would further infringe the 050 Patent under 35 U.S.C. 271(a), (b), and/or (c). Upon

approval of ANDA No. 206287, Lupin Atlantis will actively induce and/or contribute to

infringement of the 050 Patent under 35 U.S.C. 271(b) and/or (c).

22. Lupin Pharmaceuticals and Lupin Ltd. are jointly and severally liable for anyinfringement of the 050 Patent by virtue of submitting ANDA No. 206287 through their

agent, affiliate, and alter-ego Lupin Atlantis. Upon information and belief, Lupin

Pharmaceuticals and Lupin Ltd. contributed to, aided, abetted, and/or induced the

submission of ANDA No. 206287 and its Paragraph IV certification to FDA. Additionally,

upon information and belief, Lupin Pharmaceuticals will market and/or distribute

Defendants generic version of Minastrin

24 Fe if ANDA No. 206287 is approved by FDA.

23. Lupin Pharmaceuticals and Lupin Ltd.s participation in, contribution to,aiding, abetting, and/or inducement of the submission of ANDA No. 206287 and its

Paragraph IV certification to FDA constitute infringement of the 050 Patent under 35


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U.S.C. 271(e)(2)(A). Moreover, if Lupin Pharmaceuticals and/or Lupin Ltd. commercially

manufacture, use, offer for sale, or sell within the United States, or import into the United

States, Defendants generic version of Minastrin24 Fe, they would further infringe the

050 Patent under 35 U.S.C. 271(a), (b), and/or (c). Upon approval of ANDA No. 206287,

Lupin Pharmaceuticals and Lupin Ltd. will actively induce and/or contribute to

infringement of the 050 Patent under 271(b) and/or (c).

24. This case is an exceptional one, and Warner Chilcott is entitled to an awardof its reasonable attorneys fees under 35 U.S.C. 285.

25. Warner Chilcott will be irreparably harmed if Defendants are not enjoinedfrom infringing or actively inducing or contributing to infringement of the 050 Patent.

Warner Chilcott does not have an adequate remedy at law.

PRAYER FOR RELIEF

WHEREFORE, Warner Chilcott respectfully requests the following relief:

A. A judgment that Defendants have infringed one or more claims of the 050Patent by submitting ANDA No. 206287;

B. A permanent injunction restraining and enjoining Defendants, their officers,agents, servants, employees, parents, subsidiaries, divisions, affiliates, and those persons

in active concert or participation with any of them, from making, using, selling, offering to

sell, or importing any product that infringes the 050 Patent, including the product

described in ANDA No. 206287;


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C. A judgment declaring that making, using, selling, offering to sell, orimporting the product described in ANDA No. 206287, or inducing or contributing to such

conduct, would constitute infringement of the 050 Patent by Defendants pursuant to 35

U.S.C. 271(a), (b), and/or (c);

D. An order that the effective date of any approval of Defendants ANDA be adate that is not earlier than the expiration of the 050 Patent or any later expiration of

exclusivity to which Warner Chilcott is or becomes entitled;

E. A finding that this is an exceptional case, and an award of attorneys fees inthis action pursuant to 35 U.S.C. 285;

F. Costs and expenses in this action; andG. Such other and further relief as the Court may deem just and proper.


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Dated: June 6, 2014 Respectfully submitted,

/s/ Benjamin C. Block

George F. Pappas (D. Md. Bar No. 15339)

Jeffrey B. Elikan (D. Md. Bar No. 26179)

Benjamin C. Block (D. Md. Bar No. 15811)

Eric R. Sonnenschein

Erica N. Andersen

Sumon S. Dantiki

Jeremy D. Cobb

COVINGTON & BURLING LLP

1201 Pennsylvania Avenue, NW

Washington, DC 20004

Tel. (202) 662-6000Fax. (202) 662-6291

[email protected]


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EXHIBIT A


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u 73428 3

l Q ) N D R , " m ) " ' - Q ~ I r ' l l R E S ~ H P S E i l l ) ~ S J A f l J , ( b O M t E : ~UNITED STATES DEPARTMENT OF COMMERCE

United States Patent and Trademark OfficeFebruary 24 2012

THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROMTHE RECORDS OF THIS OFFICE OF:

U.S PATENT: 6 667 050ISSUE DATE: December 23 2003

By Authority of theUnder Secretary of Commerce for Intellectual Propertyand Director of the United States Patent and Trademark Office

~ - c Jtaw . QT. LAWRENCECertifying Officer


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12) United States PatentBoissonneault et al.54) CHEWABLE ORAL CONTRACEPTIVE75) Inventors: Roger M. Boissonneault, Long Valley,

NJ US); Tina M. deVries, LongValley, NJ US)

73) Assignee: Galen Chemicals) Limited,Dunlaoghaire IE)( * Notice: Subject to any disclaimer, the term of thispatent s extended or adjusted under 35U.S.C. 154 b) by 0 days.21) Appl. No.: 09/879,02822) Filed: Jun. 12, 2001

Related U.S. Application Data63) Continuation-in-part of application No. 09/286,908, filed onApr. 6, 1999.51) Int. Cl.7 ........... A61K 47/0052) U.S. Cl....................... 424/439; 424/400; 424/440;424/441; 424/464; 424/484; 424/489; 514/841;514/84358) Field of Search ................................. 424/400, 439,424/440, 441, 464, 484, 489; 514/841,

843

m 1 1US006667050Bl10) Patent No.: US 6,667,050 BlDec. 23, 200345) Date of Patent:

56) References CitedU.S. PAIENT DOCUMENTS

3,960,911 A4,036,983 A4,038,413 A4,136,162 A4,512,986 A4,684,534 A5,135,744 A5,569,456 A5,576,014 A5,747,480 A

6/1976 Suschitzky et al.7/1977 Rutherford et al.7/1977 Suschitzky et al.1/1979 Fuchs et al.4/1985 Reel et al.8/1987 Valentine8/1992 Alexander et al.

10/19 Gorinskyt11/19 Mizumoto et al. 5/1998 Gast ...................... .... 514/170

* cited by examinerPrimary Examiner-Thurman K. PageAssistant Examiner--Olaresse Evans74) Attorney Agent or Fir m-AkinHauer Feld, L.L.P.57) ABSTRACT

Gump, Strauss,

The present invention relates to a chewable, palatable oralcontraceptive tablet, comprising an oral contraceptive agent,a chewable carrier suitable for human consumption, and notcomprising a ferrocene compound, as well as use of thesetablets in a method of human female oral contraception, andin a method of enhancing compliance with a human femaleoral contraceptive regimen.60 Clalms, No Drawings

C ~ o p _ y _ p _ r o v ~ ~ d e d ~ b ~ y ~ U S ~ P = r ~ o ~ r r o m ~ t ~ h e = P ~ I R ~ S ~ I ~ m a g e = o ~ m ~ a ~ b a _ s e _ _ n ~ o ~ ~ ~ 2 ~ 1 ~ ~ ~ ~ 1 2 ~


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US 6,667,050 BlCHEW BLE OR L CONTR CEPTIVE

CROSS-REFERENCE TO RELATEDAPPUCMIONS

his is a continuation-in-part of U.S. patent applicationSer. No. 09/286,908, filed Apr. 6, 1999.

STATEMENT REGARDING FEDERALLYSPONSORED RESEARCH OR DEVELOPMENTNot Applicable.

REFERENCE TO MICROFICHE APPENDIXNot Applicable.

BACKGROUND OF THE INVENTIONThe present invention generally relates to an oral contraceptive delivery system, and in particular an oral contraceptive delivery system involving novel alternate dose forms toimprove compliance.The efficacy of oral contraceptives tends to be particularlypatient compliance dependent, largely due to the lack of adisease state or symptoms to remind a human female patient

(sometimes referred to simply as patient or woman ) totake a pill. The single most significant reason for failure withoral contraceptives is use, rather than method, failure. Thatis, unless the contraceptives are used according to theprescribed regimen, the contraceptives can fail to effec tivelyhelp a patien t avoid pregnancy. Further, in order to be mosteffective in preventing pregnancy and maintaining menstrual cycle control, proper compliance with an oral contraceptive dosage regimen requires that the oral contraceptivesbe taken at about the same time each day.

2to conceal, they are not necessarily easy to ingest. Access towater to facilitate contraceptive pill taking remains a problem . Most medications are typically stored in a medicinecabinet and therefore are likely to be near a water source. Onthe contrary, oral contraceptive pills are often car ried on theperson and a source of water is not always available whenit is time to take the oral contraceptive pill. Additionally, acertain segment of the patient population will have trouble

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IS

swallowing pills, irrespective of access to water.The present invention provides an improved oral contraceptive tablet. The technology encompassed in the inventioninvolves a chewable, palatable oral contraceptive tablet thathas appropriate size and hardness for blister packaging andcompliant use.

BRIEF SUMMARY OF THE INVENTIONOne 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 humanconsumption, and not comprising a ferrocene compound.Another aspect of this invention relates to a method ofhuman female oral contraception, the method comprisingproviding a chewable, palatable oral contraceptive tablet

25 comprising a contraceptively effective amount of an oralcontraceptive agent, and a chewable carrier suitable forhuman consumption, and not comprising a ferrocenecompound, and administering the tablet to a human female.

Yet another aspect of this invention relates to a method of30 enhancing compliance with a human female oral contraceptive regimen involving oral contraceptive tablets, themethod comprising providing chewable, palatable oral contraceptive tablets comprising a contraceptively effectiveamount of an oral contraceptive agent, and a chewable35 carrier suitable for human consumption, and not comprisinga ferrocene compound, and administering the tablets to thehuman female in accordance with the contraceptive regimen.

Various attempts have been made to improve patientcompliance with contraceptive regimens. For example, it hasbeen suggested that progestin rods can be inserted subdermally. This procedure has been described, for example, inU.S. Pat. No. 5,756,115. This technique has the significantdisadvantage of requiring a surgical incision, a procedure 40that is highly disfavored by a relatively large segment of thepatient population.

BRIEF DESCRIPTION OF THE SEVERALVIEWS OF THE DRAWINGSNot Applicable.

s another example, it has been suggested that DEPOPROVERA (Pharmacia, Inc.) medroxyprogesteroneacetate can be injected subcutaneously every three months. 45This technique has been described, for example, in U.S. Pat.No. 4,639,439. This procedure has the disadvantage ofrequiring an injection via hypodermic needle, which is alsoa procedure that is disfavored by many patients. 50In many cases, the patient prefers to carry the contraceptive pills on her person as a matter of lifestyle or personaldiscretion. This is especially true for younger patients, andit is not uncommon for such patients to exchange pills .Members of this population tend to view portable packagingof the pills, immediate access to the pills, and ease of pill useas significant benefits.

Prior proposed solutions to the compliance problem havetended to focus primarily or exclusively on optimizingcompliance packaging, rather than on changes to the dosage 6form. t has been suggested that instead of being packaged

DETAILED DESCRIPTION OF THEINVENTIONThe present invention relates to chewable, palatable oralcontraceptive tablets for administering an oral contraceptiveagent to human females. The tablets of this invention maysimply be chewed, and therefore are easy for a patient toingest, even in the absence of a liquid. The oral contraceptive agent formulation of this invention improves dosageregimen compliance, and thereby enhances the desired contraceptive effect of the oral contraceptive. This inventionalso includes methods for administering the oral contraceptive formulations to a woman.

DefinitionsThe articles a and an are used herein to refer to one

or more than one (i.e., to at least one) of the grammaticalobjects of the article. By way of example, an elementmeans one element or more than one element.n vials, contraceptive pills can be packaged in 21 or 28 dayblister packages. t has also been suggested that the size ofthese packages can be reduced to improve portability andconfidentiality.The term oral contraceptive agent, as used herein, refersto any compound or combination of compounds which,

65 when administered orally, prevents pregnancy.Although oral contraceptive pills provided in a smallblister package are somewhat more convenient to carry and The term estrogen, as used herein, refers to any naturalor synthetic compound which exlubits an effect on the

Copy provided by USPTO from the PIRS Image Database on 02121 2012


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US 6,667,050 Bl3

female reproductive organs in a manner simila r to the naturalfemale hormone estrogen. Examples of an estrogen include,but are not limited to, ethinyl estradiol, estradiol, estradiolvalerate, and estradiol acetate.

The term progestin, as used herein, refers any natural orsynthetic compound which exhibits a progestational effect

5

levonorgestrel ethynodiol diacetate norgestrelnorgestimate gestodene drospirenone trimegestonelevodesogestrel, gestodyne, and nesterone. Preferably, theprogestin is norethindrone.

on the female reproductive organs. Examples of a progestininclude, but are not limited to, norethindrone, norethindroneacetate, desogestrel, levonorgestrel, ethynodiol diacetate, 10norgestrel norgestimate gestodene drospirenonetrimegestone, levodesogestrel, gestodyne and nesterone.

The dosage of the oral contraceptive agent employedwould tend to be that conventionally used in the art for theparticular oral contraceptive agent selected. The proportionof the oral contraceptive agent in the tablet may be apharmaceutically effective trace amount to about 10% byweight. Thus, the quantity of oral contraceptive agent pertablet may be varied as desired, typically about 10 micro-grams to about 5 milligrams, but the lower and upperdosages 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.

The term palatable, as used herein, means tha t the tabletof this invention has a taste, mouth feel, chewability, texture,aroma, and lack of grittiness and bad aftertaste that makes 15the tablet agreeable to a woman to chew.

TABLE 1Ennmles of Dose Ranges of 011 1 Contracpt ive Ments Cmilli& 'l ms por tablet)

Description Examples Broad Intermediate PreferredProgestin

Estrogen

A tablet is chewable, as used herein, such that when thetablet is chewed, it breaks into smaller pieces that can beswallowed. This is in contrast to gum, for example, whichdoes 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 humanconsumption and not compr'.sing a ferrocene compound.The tablet of this invention expressly does not contain aferrocene compound. Ferrocene compounds are used in thetreatment of anemia and it should not be assumed that allpatients desiring an oral contraceptive agent are anemic.Administering ferrocene compounds when they are notneeded can lead to iron poisoning. Additionally, ferrocenecompounds may not be palatable whe n chewed.

In principle, virtually any oral contraceptive agent used inhuman medicine could be employed in accordance with theprinciples of the present invention. The oral contraceptiveagent may be an estrogen, a progestin, or a combination ofan estrogen and a progestin. In one embodiment, the oralcontraceptive agent is an estrogen selected from the groupconsisting of ethinyl estradiol, estradiol, estradiol valerate,and estradiol acetate. Preferably, the estrogen is ethinylestradiol.

Norethindrone 0.1 to 2.5 0.25 to 2.0 0.4 to 1.5Norethindrone acetate 0.1 to 2.5 0.25 to 2.0 0.4 to 1.5Desogestrel 0.05 to 0.5 0.1 to 0.3 0.1 to 0.2Levonorgestrel 0.025 to 1.5 0.025 to 1.0 0.05 to 0.6Ethynodiol diacetate 0 5 to 2.5 0.75 to 1.25 0.9 to 1.1Norgestrel 0 05 to 3.0 0.05 to 2.0 0.1 to 1.2Norgestimate 0.1 to 0.5 0.15 to 0.35 0.18 to 0.25Gestodene O Q3 to 0.15 0.05 to 0.10 0.06 to 0.075Drospirenone 1.0 to 5.0 2.0 to 4.0 2.5 to 3.5Trimegcstone 0.05 to 0.5 0.1 to 0.3 0.1 to 0.2Ethinyl Estradiol, 0.01 to O.Q75 O.Q15 to 0.05 0.020 to 0.050Estradiol 05 to 4.0 l to 1 5 to 2.5Estradiol valerate 0 5 to 5.0 1.5 to 3.5 1.9 to 3.0Estradiol acetate 0.5 to 5.0 1.5 to 3 5 1.8 to 3.0

In one preferred embodiment, the tablet comprises estro-gen in the form of ethinyl estradiol in an amount of about 10micrograms to about 75 microgranlS. In another preferred40 embodiment, the tablet comprises progestin in the form ofnorethindrone in an amount of about 0.1 milligram to about2.5 milligrams.

The invention also includes a tablet in which the oralcontraceptive agent is a combination of an estrogen and a45 progestin. Preferably, the estrogen is ethinyl estradiol andthe progestin is norethindrone. In a more preferredembodiment, the amount of ethinyl estradiol in the tablet isabout 10 micrograms to about 75 micrograms and theamount of norethindrone in the tablet is about 0.1 milligram50 to about 2.5 milligrams.The tablets of this invention can be used in conjunctionwith an ora l contraceptive regimen. The regimen can com-prise administering tablets on a daily basis for multipleconsecutive days. As such, throughout the duration of theregimen the amount of oral contraceptive agent in the oralcontraceptive tablets may remain constant, thereby compris-ing a uniphasic regimen. Additionally, the amount of oralcontraceptive agent in the oral contraceptive tablets may

vary throughout the duration of the regimen, thereby com-prising a multiphasic regimen. In tablets comprising an60 estrogen and a progestin, the ratio of the estrogen to theprogestin can be constant throughout the duration of theregimen. Additionally, the ratio of the estrogen to the proges-tin in the oral contraceptive tablets can vary throughout theregimen.In another embodiment, the oral contraceptive agent is a 6

progestin selected from the group consisting ofnorethindrone norethindrone acetate desogestrel

t is also possible to form placebo tablets which otherwisecorrespond in composition to the tablet of the presentinvention but are free of the oral contraceptive agent

Copy provided y USPTO from the PIRS Image Database on 02 21 2012


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US 6,667,050 BlThe oral contraceptive agent may be present in a carrier

either in a dissolved or a uniformly suspended state. Acarrier comprises all but the active oral contraceptive agentor agents and includes an inactive ingredient or a combination of one or more inactive ingredients. The carrier impartschewable and palatable characteristics to the tablet and must Ingre-dient

6TABLE 2-continued

Sweetener and Flavor Amounts Used in Chewable Omontraceptive Formulations

10

be suitable for human consumption, that is, free of harmfulamounts of any toxins or components that are adverse tohumans. All ingredients in the carrier should be generallyrecognized as safe (GRAS), as determined by the Food andDrug Administration (FDA) or the Flavor and Extract Manufacturers' Association (FEMA). The carrier selected for theinvention must be chewable and should not confer a disagreeable taste to the tablet. Thus, the carrier itse lf must be 15palatable. The primary ingredient of a carrier is one or morediluents. Non-limiting examples of diluents that can be used

Type Examples Broad Intermedia te PreferredFlavor Spearmint 0.5 to 5 1 to 3 1.5 to 2.5%Agent Winter- 0.5 to 5 1 to 3 1.5 to 2.5%green

Wild berr y 0.1 to 3 0.2 to 1 0.3 to 0.5

Optionally, a color agent may be added to aid in tabletidentification and to enhance the visual appearance of thetablet. A visually pleasing color enhances patient acceptanceand thereby compliance with an oral contraceptive regimen.The color agent may be any that are well known to those inthe tablet-making art in view of the present disclosure, andin accordance with this invention include microcrystallinecellulose, com starch, modified starch, calcium carbonate,dicalcium phosphate, and poly-alcohol sugars such as 20dextrose, maunitol, sorbitol, xylitol, lactose, sucrose, andfructose. Many other diluents or other ingredients suitable ascomponents of carriers for a chewable, palatable oral contraceptive tablet are available and would be well known to 25those skilled in the art in view of the present disclosure.

could be used in any amount to impart the desired color.The tablet can be manufactured by standard pharmaceutical techniques of solid dose formulation, such as granulation and compression. These processes are well known tothose skilled in the art of making tablets (See Lieberman,Lachman, and Schwartz, Pharmaceutical Dosage Fonns,Volume 1, NewYork, 1989). During the granulation process,other ingredients typically used in tablet formulation forhuman consumption can be included, such as binders,lubricants, anti-adherents, glidants, disintegrants and fillers

In another aspect of the invention, the tablet optionallyfurther comprises at least one of a flavor agent, a sweetener,and a color agent. A flavor agent can be use to enhance thetaste of the tablet, making the tablet more palatable than atablet without a flavor agent. Spray dried flavor agents arepreferred because they are easy to incorporate into a chewable tablet. Non-limiting examplesof preferred flavor agentsimpart the following flavors: strawberry, wild berry,spearmint, wintergreen, black cherry, orange, orange cream,and lemon. The flavoring agents are readily available frommany commercial sources. Exemplary compounds suitablyused in preparing flavors are listed in G. Burdock, Ed.,Fenaroli's Handbook of Flavor Ingredients, 3m edition,Volumesl and II, CRC Press, NewYork, 1995. Other flavorsand flavoring agents suitable for the tablet would be wellknown to those skilled in the art in view of the presentdisclosure.

A sweetener can also be used to enhance to taste of thetablet, making the tablet more palatable than a tablet withouta sweetener. Sweeteners include natural sugars and artificialsugar substitutes. Non-limiting examples of sweeteners thatcan be used in accordance with this invention includeaspartame, sucralose, xylitol, soroitol, mannitol, dextrose,sucrose, and fructose. Non-limiting examples of the amountof flavor agents or sweeteners that can be use in the tabletcomposition of the present invention are listed in Table 2.The amounts in Table 2 are given as percentage of the totaltablet weight.

Ingre-dientTypeSweet- n r

TABLE 2Sweetener and Flavor Amounts Used in Chewable Oral

Om tmceptjvs FormultiOJJs

Examples Broad Inte rmediat e l'TeferredAspartame 0.02 to 1.0 0.02% to 0.2% 0.03% to 0.05Sucralose 0.01 to 0.5 0.01% to 0.1% 0.02 to 0.04%

30 or other optional ingredients that do not adversely affectchewability or palatability of the tablet or its active oralcontraceptive agent ingredient(s).Binders aid the formation of granulated particles of active

35 oral contraceptive agents and carrier ingredients. Nonlimiting examples of binders include glucose, acacia, guargum, gelatin, simple syrup , sucrose, sorbitol, starch, alginicacid, alginate sal ts polyethylene glycol,polyvinylpyrrolidone, polymethacrylates, pregelatinized

40 starch, and celluloses such as methylcellulose, sodiumcarl>oxymethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, and ethylcellulose. A solution ofbinder is prepared (concentrations dependent on the particular binder used), and the binder solution is mixed with the

45 other excipients to form the wet granulation. A binder suchas polyvinylpyrrolidone (Povidone) is typically used in asolution of about 3 to about 15% by weight and is addedto the other tablet ingredients resulting in a final formulationconcentration of about 2% to about 5%. Similarly, cellulose5 derivatives are typically use in granulating solutions ofabout 5 to about 10% by weight and concentrations wouldbe known t one skilled in the art of making tablets using

wet granulation in view of the present disclosure.Disintegrants facilitate breakup of the tablet after admin-

55 istration during chewing. Non-linliting examples of disintegrants include crospovidone, croscarmellose sodium,starches, com starch, potato starch, modified corn starch,sodium starch glycolate, and pregelatinized starch. Disintegrants can be included in the tablet formulation in amounts

6 generally less than about 25% of the tablet weight, prefer-

65

ably less than about 20%, and more preferably about 1 toabout 20% (natural starches such as com or potato starch),about 5 to about 10% (pregelatinized starch), and about 3 to8 (modified com starch). Crospovidone and croscarmellose sodium are use at levels of about 5 or lower.

As a final step in the manufacture of the tablet, a lubricant,an anti-adherent, and a glidant can be added to the tablet

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US 6,667,050 Blgranulation. A lubricant facilitates tablet manufacture byreducing friction in the tablet die during compression andejection. An anti-adherent prevents the tablet from stickingto the tablet punch and die wall. A glidant improves ftowcharacteristics of the granulation. Non-limiting examples of sa lubricant include stearates, such as magnesium, calcium,and sodium stearates, stearic acid, hydrogenated vegetableoils, waxes, talc, boric acid, sodium benzoate, sodiumacetate, sodium chloride, DL-leucine, sodium oleate,sodium lauryl sulfate, magnesium lauryl sulfate, and CAR- 10BOWAX (Union Carbide Chemicals Plastics Technology Corp.) polyethylene glycols. Non-limiting examples ofan anti-adherent include talc, com starch, colloidal silicondioxide, DL-leucine, sodium lauryl sulfate, and metallicstearates. Non-limiting examples of a glidant include talc, 15com starch, and colloidal silicon dioxides such as CAB-0-SIL (Cabot Corp.), SYLOID W.R. Grace Co.), andAEROSIL (Degussa). Some ingredients, such as talc, cancontribute to the formulation with combined functions,acting as a lubricant, and an anti-adherent, and a glidanl 20

A lubricant is typically included in the tablet formulationin amounts less than about 10 of the tablet weight,preferably less than about 6 , and more preferably about0.25 to about 2 (stearates, stearic acid, hydrogenatedvegetable oil), about 1 to about 5 (talc, waxes, DL-leucine, 25CARBOWAX, sodium lauryl sulfate), about 1 to about 2(magnesium lauryl sulfate) and about 4 to about 6 (sodiumchloride, sodium oleate, sodium benzoate, sodium acetate).

Anti-adherents are typically included in the tablet formulation in amounts generally less than about 15 of the tablet 30weight, preferab ly less than about 12 , and more preferablyabout 3 to about 10 (cornstarch, DL-leucine), about 1 toabout 5 (talc), about 0.1 to about 0.5 (colloidal silicondioxide) and less than about 1 (sodium lauryl sulfate,metallic stearates . 35A glidant is typically included in the tablet formulation inamounts generally less than about 15 of the tablet weight,preferably less than about 12 , and more preferably lessthan about to about 10 (com starch), about 0.1 to about 400.5 (CAB-0-SIL, SYLOID), about 1 to about 3

(AEROSIL), and about 5 (talc).

8The hardness of the tablet may be any hardness thatallows for tablet formation and that is still palatable andchewable. One aspect of the invention includes a tablethaving a hardness sufficient for blister packaging while stillremaining palatable and chewable. Blister packaging iscommon in the art of oral contraceptive tablet dispensing. Ina preferred embodiment, the tablet of the invention h s a

hardness of about kilopond (kp) to about 15 kp, andpreferably about 7 kp to about 12 kp.Another aspect of this invention relates to a method ofhuman female oral contraception comprising providing achewable, palatable oral contraceptive tablet comprising acontraceptively effective amount of an oral contraceptive

agent, and a chewable carrier suitable for humanconsumption, and not comprising a ferrocene compound,and administering the tablet to a human female. The tabletis the tablet described above, and typically and preferably, anumber 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. Thetablet routinely contains a contraceptively active amount ofan oral contraceptive agent, and some tablets used in aregimen may be a placebo. The placebo tablets are admin-istered on days where the oral contraceptive agent is notrequired. As such, the woman is administered a tablet everyday to help maintain the contraceptive regimen of taking adaily tablet. For example, a dosage regimen may utilizeabout 21 to about 63 days of tablets containing the oralcontraceptive agent followed by about 3 to about 7 days oftablets comprisiog a placebo. Preferably, the regimen entailsadministering tablets for total of about 24 to about 32 days,wherein tablets containing the oral contraceptive agent areadministered for about 21 to about 25 days, followed byabout 3 to about 7 days of placebo tablets not containing thecontraceptive. In one preferred embodiment, the tablets areadministered for a total of about 28 days.As explained above, the contraceptive dosage in thetablets can be uniphasic or multiphasic.Another aspect of this invention relates to a method ofenhancing compliance with a human female oral contracep

tive regimen involving oral con traceptive tablets, themethod comprising providing chewable, palatable oral contraceptive tablets comprising a contraceptively effectiveThe chewable tablet generally is not coated with a film orsugar coating. However, thin tablet coatings of a type knownto those skilled in making coated tablets can be used. 5 amount of an oral contraceptive agent, and a chewablecarrier suitable for human consumption, and not comprisinga ferrocene compound, and administering the tablets to thehuman female in accordance with the contraceptive regimen.

In one preferred embodiment of the invention, the oralcontraceptive agent comprises norethindrone and ethinylestradiol, the carrier comprises dicalcium phosphate, lactosemonohydrate, and maltodextrin, and the tablet further comprises sucralose, a ftavor agent, sodium starch glycolate, spovidone, and magnesium stearate.The overall size of the tablet may be any tablet size thatincorporates the desired contraceptively effective amount ofthe oral contraceptive agent and the carrier and is stillchewable and palatable. In a preferred embodiment, the size 55

of the tablet is small, on the order of about 50 milligrams toabout 300 milligrams. More preferably, the tablet weight isabout 70 milligrams to about 120 milligrams, and mostpreferably, the tablet weight is about 90 milligrams to about110 milligrams. A smaller tablet is more portable than a 60larger tablet and therefore more appealing to patients preferring to carry oral contraceptive pills on their person,particularly in blister packaging. Further, smaller tablets aremore likely than larger tablets to be accepted as chewable.Therefore, smaller tablets are more likely to enhance a 65patient's compliance with an oral contraceptive regimen.The shape of the tablet of the present invention is not critical.

In connection with this aspect of the invention, each tabletof the regimen preferably comprises a daily dosage of theoral contraceptive agent. As such, daily administration ofone of the tablets would be part of the regimen. Thechewable, palatable oral contraceptive of this inventionallows the woman the convenience of ngesting the tablet ina manner that does not require taking the tablet with liquid,without chewing it. Therefore, the woman can take the tableteach day at a time and place that is suitable to her lifestyle.Ingesting the tablets at the s ame time of day on a daily basisenhances compliance with any given contraceptive regimen.

The regimen can comprise any number of days of administration of the tablets to the woman. In one preferredembodiment, the regimen comprises providing about 21 toabout 63 tablets, each tablet comprising the daily dosage ofthe oral contraceptive agent, followed by about 3 to about 7tablets, each comprising a placebo. Preferably, a total ofabout 24 to about 32 tablets are administered daily, wherein

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US 6,667,050 l9

about 21 to about 25 tablets each comprising the oralcontraceptive agent are administered, followed by about 3 toabout 7 tablets each comprising a placebo. In one preferredembodiment, a total of about 28 tablets is administered.Ingredient ~SweetenerFlavor AgentDisintegrant

1EXAMPLE 1-continued

Composition of a 90 milligram tablet

IngredientSucraloseSpearmint

Amountmilligrams/tablet)The amount of the oral contraceptive agent through theduration of the regimen can remain constant or can be variedfor tablets containing an oral contraceptive agent rather

than placebo tablets without an oral contraceptive agent). Inone embodiment, the amount of the oral contraceptive agentis present in the same amount in the oral contraceptivetablets of the regimen, thereby comprising a uniphasicregimen. n another embodiment, the amount of the oral10 Binder Sodium starch glycolatePovidone

0.021.84.11.50.41ubricant Magnesium tearate

One technique of making the tablets of the present invention is a wet granulation technique. In a wet granulationtechnique, the active ora l contraceptive agents are blended ina solution of binder which is then blended with the diluent s)to form a wet granulation. After drying, the granulation is

contraceptive agent is present in varying amounts in the oralcontraceptive tablets of the regimen, thereby comprising amultiphasic regimen. In tablets comprising an estrogen and 15a progestin, the ratio of the estrogen to the progestin can beconstant throughout the duration of the regimen .Alternatively, the ratio of the estrogen to the progestin in thetablets can vary throughout the regimen.

20 blended with the flavor ingredient s), the disintegrant, thelubricant and any other optional ingredients. The final blendis compressed into tablets. This wet granulation method isexemplified by Examples 1 and 2.

Any number of the tablets may be dispensed in any typeof packaging commonly used in the art of tablet dispensing.Blister packages are often and preferably used for dispensing oral contraceptives. Blister packages are generally smalland portable, usually and preferably containing the numberof tablets required for a month of dosing. Many patients 25desiring oral contraceptive tablets find this method of dispensing convenient. n a preferred embodiment, the tabletsfor the oral contraceptive regimen of this invention aredispensed in a blister package. The packaging is preferablyin the form of a 28-daily dosage units blister package 30comprising about 21 to about 25 tablets comprising the oralcontraceptive agent and the remaining respective about 7 toabout 3 tablets comprising a placebo.

Alternatively, a dry granulation technique can be used. Ina dry granulation technique, the active oral contraceptiveagents are blended with the diluent s) to form a dry granulation. This is then blended with the flavor ingredient s), thelubricant and any other optional ingredients, and finallycompressed into tablets. This dry granulation method isexemplified by Examples 3, 4 and 5

Alternatively, the active pharmaceutical ingredients arewet granulated as described previously, then blended with

35 additional diluent s) to form a dry granulation. This is thenblended with the flavor ingredients, the lubricant and anyother optional ingredients, and finally compressed into tablets. This method is exemplified by Example 6.

A tablet made in accordance with the present inventionmay simply be chewed. This substantially reduces the existing barriers to compliance. The use of a chewable, palatabletablet in accordance with the present invention eliminatesthe need to incorporate liquid to facilitate swallowing andmakes oral contraceptives more agreeable for patients who 40have difficulty or reluctance to swallowing tablets. Thechewable, palatable tablets of this invention have a tabletsize aod hardness suitable for use in blister packaging and

EXAMPLE2Composition of a 90 milligram tablet

are synergistic with the existing design and intent of oral Amountcontraceptive package portability and convenience. 45 lngredie n t ~ e _ _ sr e 10 _t mil. _Hgramsfm_b_e.;._Therefore, the oral contraceptive formulations of this Oral Contraceptive Agent Norethindrone 0.40invention, administered according to this invention, provide Oral Contraceptive Agent Ethinyl Estradiol 0.035a method of enhancing compliance with a human female Diluent Dicalcium Phosphate 40.8oral contraceptive regun en. Diluent Lactose Monohydrate 40.8Diluent Maltodextrin 0.36The invention will now be described in more detail with so Sweetener Aspartame 0.04reference to the following specific, non-limiting examples. Flavor Agent Spearmint 1.8Disintegrnnt Sodium starch glycolate 4.11Compositions that have been prepared in accordance with Binder Povidone 1.54this invention are given in Examples 1 2. Additional Lubricant Magoesium stearnte 0.41examples of compositions that can be formulated in accordance with this invention are given in Examples 3-6.

EXAMPLE 1Composition of a 90 milligram tablet

Amountn g r e d i e n t ~ Ingredient milligrams/tablet)

Oral Contraceptive Agent Norethindrone 0.40Oral Contraceptive Agent Ethinyl Estradiol 0.035Diluent Dicalcium Phosphste 40.8Diluent lactose Monohydrate 40.8Diluent Maltodextrin 0.16

55

60

65


Amountn g r e d i e n t ~ Ingredient milligrams/tablet)

Oral Contraceptive Agent Norethindrone 0.40Oral ContraceptiveAgent Ethinyl Estradiol 0.035Diluent Dextrose 97Flavor Agent SpearmintLuhricant Magnesium stearate o.s

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US 6,667,050 Bl11


Ingredient TypeOral Contraceptive AgentOral Contraceptive AgentDiluentFlavor AgentLubricant

IngredientNorethindroneEthinyl EstradiolMannitolStrawberryMagnesium stearate

EXAMPLE6

Amount(milligrams/tablet)0.400.0359720 5

Composition of a 100 milligram tabletAmount

Ingredient TYPe Ingredient (milligrams/tablet)Oral Contraceptive Agent Norethindrone 0.40Oral Contraceptive Agent Ethinyl Estradiol 0.035Diluent Dextrose 60Diluent Lactose 37Flavor Agent Strawberry 2Lubricant Magnesium stearate 0 5


Ingredient TYPe IngredientOral Contraceptive Agent NorethindroneOral Contraceptive Agent Ethinyl EstradiolDiluent Dicalcium PhosphateDiluent lActose MonohydrateDiluent DextroseDiluent MaltodexuinSweetener SucraloseFlavor Agent SpearrointDisintegrant Sodium starch glycolateBinder PovidoneLubricant Magnesium stearate

Amouot(milligrams/tablet)

0.400.03520.820.8700.16

0.021.84 11.50.41

125. The tablet of claim 1 wherein the oral contraceptiveagent comprises an estrogen.6. The tablet of claim 5, wherein the estrogen is selectedfrom the group consisting of ethinyl estradiol, estradiol,

5 estradiol valerate, and estradiol acetate.7. The tablet of claim 6, wherein the carrier is selectedfrom the group consisting of dicalcium phosphate, lactose,corn starch, microcrystalline cellulose, maltodextrin,dextrose, mannitol, sorbitol, xylitol, fructose, sucrose, and

10 calcium carbonate.8. The tablet of claim 1 wherein the oral contraceptiveagent comprises a progestin.9. The tablet of claim 8, wherein the progestin is selectedfrom the group consisting of norethindrone, norethindrone15 acetate, desogestrel, levonorgestrel, ethynodiol diacetate,

norgestrel norgestimate gestodene drospirenonetrimegestone, levodesogestrel, gestodyne, and nesterone.

20

25

10. The tablet of claim 9, wherein the carrier is selectedfrom the group consisting of dicalcium phosphate, lactose,corn starch, microcrystalline cellulose, maltodextrin,dextrose, mannitol, sorbitol, xylitol, fructose, sucrose, andcalcium carbonate.11. The tablet of claim 1, wherein the oral contraceptiveagent comprises an estrogen and a progestin.

12. The tablet of claim 11, wherein the estrogen is selectedfrom the group consisting of ethinyl estradiol, estradiol,estradiol valerate, and estradiol acetate, and the progestin i sselected from the group consisting of norethindrone, nore-thindrone acetate, desogestrel, levonorgestrel, ethynodiol30 diacetate, norgestrel, oorgestimate, gestodene, drospirenooe,trimegestone, levodesogestrel, gestodyne, and nesterone.13. The tablet of claim 12, wherein the carrier is selectedfrom the group consisting of dicalcium phosphate, lactose,

corn starch, microcrystalline cellulose, maltodextrin,35 dextrose, mannitol, sorbitol, xylitol, fructose, sucrose, andcalcium carbonate.14. The tablet of claim 13, further comprising at least one

of a flavor agent, a sweetener, and a color agent.15. The tablet of claim 1 wherein the tablet weighs about40 50 mi ligranlS to about 300 milligrams.16. The tablet of claim 1 wherein the tablet has a hardnesssufficient for blister packaging.

It will be appreciated by those skilled in the art thatchanges could be made to the embodiments described abovewithout departing from the broad inventive concept thereof. 45It is understood, therefore, that this invention is not limited

17. The tablet of claim 1 wherein the tablet has a hardnessof about 5 kiloponds to about 15 kiloponds.18. The tablet of claim 1 wherein the oral contraceptiveagent comprises norethindrone and ethinyl estradiol, thecarrier comprises dicalcium phosphate lactosemonohydrate, and maltodextrin, and the tablet further com-prises sucralose, a flavor agent, sodium starch glycolate,

to the particular embodiments disclosed, but it is intended tocover modifications within the spirit and scope of the presentinvention as defined by the appended clainls.We claim:1. A chewable, palatable oral contraceptive tablet, com-prising an oral contraceptive agent, a chewable carriersuitable for human consumption, wherein the contraceptivetablet is chewable and palatable and does not contain aferrocene compound.2. The tablet of claim 1 wherein the oral contraceptiveagent is selected from the group consisting of an estrogen,a progestin, and a combination thereof.3. The tablet of claim 2, wherein the carrier is selectedfrom the group consisting of dicalcium phosphate, lactose,

corn starch, microcrystalline cellulose, maltodextrin,dextrose, mannitol, sorbitol, xylitol, fructose, sucrose, andcalcium carbonate.4 The tablet of claim 1, wherein the carrier is selectedfrom the group consisting of dicalcium phosphate, lactose,

corn starch, microcrystalline cellulose, maltodextrin,dextrose, mannitol, sorbitol, xylitol, fructose, sucrose, andcalcium carbonate.

so povidone, and magnesium stearate.19. A method of human female oral contraception, themethod comprising providing a chewable, palatable oralcontraceptive tablet comprising a contraceptively effectiveamount of an oral contraceptive agent, and a chewablecarrier suitable for human consumption, and does not con-tain a ferrocene compound, and administering the tablet toa human female.20. The method of claim 19, wherein the oral contracep-tive agent is selected from the group consisting of an

60 estrogen, a progestin, and a combination thereof.21. The method of claim 20, wherein the carrier isselected from the group consisting of dicalcium phosphate,lactose corn starch microcrystalline cellulosemaltodextrin, dextrose, mannitol, sorbitol, xylitol, fructose,

65 sucrose, and calcium carbonate.22. The method of claim 19, wherein the carrier isselected from the group consisting of dicalcium phosphate,

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lactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol smbitol xylitol fructosesucrose and calcium carbonate.

439. The method of claim 38 wherein the carrier is

selected from the group consisting of dicalcium phosphatelactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol sorbitol xylitol fructose3. 1be method of claim 19 wherein the oral contraceptive agent comprises an estrogen. 5 sucrose and calcium carbonate.24. The method of claim 23 wherein the estrogen isselected from the group consisting of ethinyl estradiol

estradiol estradiol valerate and estradiol acetate.40 . The method of claim 37 wherein the carrier is

selected from the group consisting of dicalcium phosphatelactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol sorbitol xylitol fructosesucrose and calcium carbonate.41. The method of claim 37 wherein the oral contraceptive agent comprises an estrogen.

25. The method of claim 24 wherein the carrier isselected from the group consisting of dicalcium phosphate 10lactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol sorbitol xylitol fructosesucrose and calcium carbonate. 42. The method of claim 41 wherein the estrogen is

5 selected from the group consisting of ethinyl estradiolestradiol estradiol valerate and estradiol acetate.26. The method of claim 19 wherein the oral contraceptive agent comprises a progestin.27. The method of claim 26 wherein the progestin isselected from the group consisting of norethindrone norethindrone acetate desogestrel levonorgestrel ethynodioldiacetate norgestrel norgestimate gestodene drospirenonetrimegestone levodesogestrel gestodyne and nesterone.28. The method of claim 27 wherein the carrier isselected from the group consisting of dicalcium phosphate

lactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol sorbitol xylitol fructosesucrose and calcium carbonate .

43. The method of claim 42 wherein the carrier isselected from the group consisting of dicalcium phosphatelactose corn starch microcrystalline cellulose

20 maltodextrin dextrose mannitol sorbitol xylitol fructosesucrose and calcium carbonate.44. The method of claim 37 wherein the oral contraceptive agent comprises a progestin.45. The method of claim 44 wherein the progestin is

29. The method of claim 19 wherein the oral contraceptive agent comprises an estrogen and a progestin.25 selected from the group consisting of norethindrone norethindrone acetate desogestrel levonorgestrel ethynodiol

diacetate norgestrel norgestimate gestodene drospirenonetrimegestone levodesogestrel gestodyne and nesterone.0. The method of claim 29 wherein the estrogen isselected from the group consisting of ethinyl estradiolestradiol estradiol valerate and estradiol acetate and the 30

progestin is selected from the group consisting ofnorethindrone norethindrone acetate desogestrellevonorgestrel ethynodiol diacetate norgestrelnorgestimate gestodene drospirenone trimegestonelevodesogestrel gestodyne and nesterone.

46. The method of claim 45 wherein the carrier isselected from the group consisting of dicalcium phosphatelactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol sorbitol xylitol fructosesucrose and calcium carbonate.

35 47. The method of claim 37 wherein the oral contracep-tive agent comprises an estrogen and a progestin.48. The method of claim 47 wherein the estrogen isselected from the group consisting of ethinyl estradiolestradiol estradiol valerate and estradiol acetate and the

31. The method of claim 30 wherein the carrier isselected from the group consisting of dicalcium phosphatelactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol sorbitol xylitol fructosesucrose and calcium carbonate.32. The method of claim 31 wherein the tablet furthercomprises at least one of a flavor agent a sweetener and acolor agent.

40 progestin is selected from the group consisting ofnorethindrone nore thindrone acetate desogestrellevonorgestrel e thynodiol diacetate norgestrelnorgestimate gestodene drospirenone trimegestone33. The method of claim 19 wherein the tablet weighsabout 50 milligrams to about 300 milligrams.34. The method of claim 19 wherein the tablet has ahardness sufficient for blister packaging.35. The method of claim 19 wherein the tablet has ahardness of about 5 kiloponds to about 15 kiloponds.

45levodesogestrel gestodyne and nesterone.

49. The method of claim 48 wherein the carrier isselected from the group consisting of dicalcium phosphatelactose corn starch microcrystalline cellulosemaltodextrin dextrose mannitol sorbitol xylitol fructosesucrose and calcium carbonate.

50. The method of claim 49 wherein the tablets furthercomprise at least one of a flavor agent a sweetener and acolor agent.36. The method of claim 19 wherein the oral contracep- 50tive agent comprises norethindrone and ethinyl estradiol the

carrier comprises dicalcium phosphate lactosemonohydrate and maltodextrin and the tablet further comprises sucralose a flavor agent sodium starch glycolatepovidone and magnesium stearate.51. The method of claim 37 wherein each tablet weighs

55 about 50 milligrams to about 300 milligrams.52. The method of claim 37 wherein the tablets have ahardness sufficient for blister packaging.37. A method of enhancing compliance with a humanfemale oral contraceptive regimen involving oral contraceptive tablets the method comprising providing chewablepalatable oral contraceptive tablets comprising a contraceptively effective amount of an oral contraceptive agent and a 60chewable carrier suitable for human consumption and notcomprising a ferrocene compound and administering thetablets to the human female in accordance with the contraceptive regimen.

53. The method of claim 37 wherein the tablet has ahardness of about 5 kiloponds to about 15 kiloponds.54. The method of claim 37 wherein the oral contracep-tive agent comprises norethindrone and ethinyl estradiol thecarrier comprises dicalcium phosphate lactosemonohydrate and maltodextrin and the tablet further comprises sucralose a flavor agent sodium starch glycolate38. The method of claim 37 wherein the oral contraceptive agent is selected from the group consisting of anestrogen a progestin and a combination thereof.

65 povidone and magnesium stearate.55 . The method of claim 37 wherein each tablet comprises a daily dosage of the oral contraceptive agent.

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56. The method of claim 55 wherein the regimen com-prises providing about 2 to about 25 tablets comprising theoral contraceptive agent.57. The method of claim 56 wherein the regimen furthercomprises about 3 to about 7 tablets comprising a placebo.58. The method of claim 56 wherein the regimen is auniphasic regimen wherein the oral contraceptive agent ispresent in the same amount in the tablets .

659. The method of claim 56 wherein the regimen is a

multiphasic regimen wherein the oral contraceptive agent ispresent in differing amounts in the tablets.

60. The method of claim 37 wherein the tablets areprovided in a blister package.

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Warner Chilcott Company v. Lupin Atlantis Holdings et. al.

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Transcript of Warner Chilcott Company v. Lupin Atlantis Holdings et. al.