Horizon Pharma Et. Al. v. Watson Laboratories, Inc. - Florida Et. Al.

7/30/2019 Horizon Pharma Et. Al. v. Watson Laboratories, Inc. - Florida Et. Al.

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Karen A. Confoy

FOX ROTHSCHILD, LLPFormed in the Commonwealth of Pennsylvania

Princeton Pike Corporate Center997 Lenox Drive, Building 3

Lawrenceville, New Jersey 08648

(609) 896-3600

Attorneys for Plaintiffs Horizon Pharma

AG and Jagotec AG

Dennis A. Bennett

GLOBAL PATENT GROUP, LLC

1005 North Warson RoadSuite 201

St. Louis, Missouri 63132

(314) 812-8018

Attorneys for Plaintiff Horizon Pharma AG

Robert F. Green

Caryn C. Borg-BreenJessica M. Tyrus

Ann K. Kotze

LEYDIG, VOIT & MAYER, LTD.

Two Prudential Plaza, Suite 4900180 North Stetson

Chicago, Illinois 60601

(312) 616-5600


John A. Bauer

MINTZ, LEVIN, COHN, FERRIS,GLOVSKY AND POPEO, P.C.

666 Third Avenue

New York, New York 10017

(212) 692-6795

Attorneys for Plaintiff Jagotec AG

UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF NEW JERSEY

HORIZON PHARMA AG andJAGOTEC AG

Plaintiffs,

v.

WATSON LABORATORIES, INC.

FLORIDA, ACTAVIS PHARMA, INC.,ANDRX CORPORATION., and ACTAVIS,

INC.

Defendants.

CIVIL ACTION No.

Document Filed Electronically

COMPLAINT FOR

PATENT INFRINGEMENT

Plaintiffs Horizon Pharma AG and Jagotec AG (collectively Plaintiffs) by their

attorneys, for their complaint against Watson Laboratories, Inc. Florida, Actavis


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Pharma, Inc., Andrx Corporation, and Actavis, Inc. (collectively, Defendants) allege as

follows:

NATURE OF THE ACTION

1. This is an action for patent infringement arising under the patent laws of

the United States, Title 35, United States Code, arising from Watsons filing of an

Abbreviated New Drug Application (ANDA) with the United States Food and Drug

Administration (FDA) seeking approval to market a generic version of Horizons

pharmaceutical product RAYOS prior to the expiration of United States Patent Nos.

6,488,960 (the 960 patent), 6,677,326 (the 326 patent), 8,309,124 (the 124

patent), 8,168,218 (the 218 patent), and 8,394,407 (the 407 patent) which cover

RAYOS and its use.

THE PARTIES

2. Plaintiff Horizon Pharma AG is a company organized and existing under

the laws of Switzerland, with a principal place of business at Kagenstrasse 17, CH-4153

Reinach, Switzerland.

3. Plaintiff Jagotec AG is a company organized and existing under the laws

of Switzerland, with a principal place of business at Eptingerstrasse 61, CH-4132

Muttenz, Switzerland.

4. On information and belief, Defendant Watson Laboratories, Inc. Florida

(WLF) was formerly known as Andrx Pharmaceuticals, Inc. On information and

belief, WLF is a corporation organized and existing under the laws of the State of

Florida, with a principal place of business at 4955 Orange Drive, Davie, Florida 33314.

On information and belief, WLF is in the business of, inter alia, developing,


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manufacturing, and obtaining regulatory approval of generic copies of branded

pharmaceutical products throughout the United States, including within this district.

5. On information and belief, Defendant Actavis Pharma, Inc. (Actavis

Pharma) was formerly known as Watson Pharma, Inc. On information and belief,

Actavis Pharma is a corporation organized and existing under the laws of the State of

Delaware, having a principal place of business at Morris Corporate Center III, 400

Interpace Parkway, Parsippany, New Jersey, 07054. On information and belief, Actavis

Pharma is in the business of, inter alia, selling and distributing generic copies of branded

pharmaceutical products in New Jersey and throughout the United States, including some

that are manufactured by WLF and/or for which WLF is the named applicant of the

approved ANDAs.

6. On information and belief, Defendant Actavis, Inc. (Actavis) was

formerly known as Watson Pharmaceuticals, Inc. (WPI) until on or around January 24,

2013. On information and belief, Actavis is a corporation organized and existing under

the laws of the State of Nevada, having a principal place of business at Morris Corporate

Center III, 400 Interpace Parkway, Parsippany, New Jersey, 07054. On information and

belief, Actavis is in the business of, inter alia, developing, manufacturing, obtaining

regulatory approval, marketing, selling, and distributing generic copies of branded

pharmaceutical products throughout the United States, including within this district,

through its own actions and through the actions of its agents and subsidiaries, including at

least WLF, Actavis Pharma and Andrx Corporation.

7. On information and belief, Defendant Andrx Corporation (Andrx) is a

corporation organized and existing under the laws of the State of Delaware, having a


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principal place of business at 4955 Orange Drive, Davie, Florida 33314. On information

and belief, Andrx is in the business of, inter alia, marketing, selling, and distributing

generic copies of branded pharmaceutical products throughout the United States,

including within this district, through its own actions and through the actions of its agents

and subsidiaries, including at least WLF.

8. On information and belief, WPI acquired Andrx Pharmaceuticals on or

around November 3, 2006. On information and belief, WPI renamed Andrx

Pharmaceutials as WLF.

9. On information and belief, WLF is a wholly-owned subsidiary of Andrx,

which is a wholly owned subsidiary of Actavis.

10. On information and belief, Actavis Pharma is another wholly-owned

subsidiary of Actavis.

11. On information and belief, Actavis organizes its operations by divisions

including at least Generics, Brands, and Distributionand, before the name change, WPI

reported its financial results in its Securities and Exchange Commission (SEC) filings

by reference to these divisions. On information and belief, WPI consolidated its financial

results with subsidiaries in its SEC filings at least since 2007 and did not file separate

reports to the SEC for each subsidiary.

12. On information and belief, Actavis Generics division is involved in the

development, manufacture, marketing, sale, and distribution of generic pharmaceuticals.

On information and belief, each Defendant acts as an agent of the other and/or works in

concert with each other as integrated parts of the Generics Division. On information and

belief, the Generics Division develops and submits Abbreviated New Drug Applications


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(ANDAs) to the FDA, relying on contributions from at least WLF, Actavis Pharma and

Andrx.

13. On information and belief, the head of the Generics Division is an

employee of Actavis, the Generic Divisions products are developed and manufactured

by at least WLF, and the Generic Divisions products are marketed, sold, and distributed

throughout the United States, including in New Jersey, by at least Actavis Pharma. On

information and belief, WLF, Actavis Pharma, and Andrx are parties to one or more

contractual agreements regarding the distribution of generic pharmaceutical products.

14. On information and belief, each Defendant shares with the others at least

some common employees, officers, and directors.

15. On information and belief, WLF, Andrx, and Actavis Pharma are within

the control of Actavis for purposes of responding to discovery in this action.

16. On information and belief, Defendants collaborated in the research and

development of WLFs ANDA No. 204867 (Watsons ANDA) for prednisone delayed-

release tablets (the Watson Products), continue to collaborate in seeking approval of

that application by the FDA, and intend to collaborate in the commercial manufacture,

marketing, offer for sale and sale of the Watson Products throughout the United States,

including in the State of New Jersey, in the event the FDA approves Watsons ANDA.

17. On information and belief, WLF has submitted to the jurisdiction of this

Court in at least six prior New Jersey actions (Astrazeneca AB, et al. v. Watson Labs.,

Inc. Florida, et al., Civil Action No. 13-3038; Astrazeneca AB, et al. v. Watson Labs.,

Inc. Florida, Civil Action No. 13-1669; Depomed, Inc. v. Actavis Elizabeth LLC, et al.,

Civil Action No. 12-1358; Warner Chilcott Co., et al. v. Watson Labs., Inc. Florida ,


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Civil Action No. 11-5989; Abbott Labs., et al. v. Watson Labs., Inc. Florida, et al. ,

Civil Action No. 10-3241; Mallinckrodt Inc. v. Watson Labs., Inc. Florida, et al., Civil

Action No. 10-6424). On information and belief, WLF has availed itself of the rights,

benefits, and privileges of this Court by asserting counterclaims in at least one prior New

Jersey action (Astrazeneca AB, et al. v. Watson Labs., Inc. Florida, et al., Civil Action

No. 13-1669).

18. On information and belief, Actavis has submitted to the jurisdiction of this

Court in at least nine prior New Jersey actions (Astrazeneca AB, et al. v. Watson Labs.,

Inc. Florida, et al., Civil Action No. 13-3038; Auxilium Pharms., Inc., et al. v. Watson

Labs., Inc. et al., Civil Action No. 12-3084;1

Depomed, Inc. v. Actavis Elizabeth LLC, et

al., Civil Action No. 12-1358; Noven Pharms. v. Watson Labs., Inc., et al., Civil Action

No. 11-5997;2

Shire LLC, et al. v. Amneal Pharms. LLC, et al., Civil Action No. 11-3781;

King Pharms. Inc., et al. v. Actavis, Inc., et al., Civil Action No. 09-6585; Shire LLC v.

Actavis South Atlantic, LLC, et al., Civil Action No. 09-479; King Pharms. Inc., et al. v.

Actavis, Inc., et al., Civil Action No. 07-5041; Sanofi-Aventis U.S. LLC, et al. v. Actavis

Totowa LLC, et al., Civil Action No. 07-3142). On information and belief, Actavis has

availed itself of the rights, benefits, and privileges of this Court by asserting

counterclaims in at least one prior New Jersey action (Auxilium Pharms., Inc., et al. v.

Watson Labs., Inc. et al., Civil Action No. 12-3084).

19. On information and belief, Actavis Pharma has submitted to the

jurisdiction of this Court in at least six prior New Jersey actions (Astrazeneca AB, et al. v.

1Watson Pharmaceuticals, Inc. submitted to the jurisdiction of this Court on July 6, 2012.

Watson Pharmaceuticals, Inc. thereafter changed its name to Actavis Inc.2

Watson Pharmaceuticals, Inc. submitted to the jurisdiction of this Court on November 4,

2011. Watson Pharmaceuticals, Inc. thereafter changed its name to Actavis Inc.


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Watson Labs., Inc. Florida, et al., Civil Action No. 13-3038; Auxilium Pharms., Inc., et

al. v. Watson Labs., Inc. et al., Civil Action No. 12-3084;3

Abbott Labs., et al. v. Watson

Labs., Inc. Florida, et al., Civil Action No. 10-3241;4

Teva Neuroscience, Inc., et al. v.

Watson Pharma, Inc., et al., Civil Action No. 10-5078;5

Duramed Pharms. v. Watson

Pharma, Inc., Civil Action No. 07-5941;6

Hoffman La-Roche Inc., et al. v. Cobalt

Pharms. Inc., et al., Civil Action No. 07-4539).7

On information and belief, Actavis

Pharma has availed itself of the rights, benefits, and privileges of this Court by asserting

counterclaims in at least one prior New Jersey action (Auxilium Pharms., Inc., et al. v.

Watson Labs., Inc. et al., Civil Action No. 12-3084). On information and belief, Actavis

Pharma is registered as a manufacturer and wholesale drug distributor in the State of New

Jersey under the registration number 5003854.

JURISDICTION AND VENUE

20. This Court has subject matter jurisdiction over this action pursuant to 28

U.S.C. 1331 and 1338(a).

21. This Court has personal jurisdiction over Defendants by virtue of, inter

alia, their presence in New Jersey, having conducted business in New Jersey, having

availed themselves of the rights and benefits of New Jersey law such that they should

reasonably anticipate being haled into court in this judicial district, previously consenting

3Watson Pharma, Inc. submitted to the jurisdiction of this Court on July 6, 2012. Watson

Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc.4 Watson Pharma, Inc. submitted to the jurisdiction of this Court on May 3, 2010.

Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc.5

Watson Pharma, Inc. submitted to the jurisdiction of this Court on December 23, 2010.

Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc.6

Watson Pharma, Inc. submitted to the jurisdiction of this Court on March 3, 2008.Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc.7

Watson Pharma, Inc. submitted to the jurisdiction of this Court on September 1, 2011.

Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc.


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to personal jurisdiction in this Court, availing themselves of the jurisdiction of this Court,

and having engaged in systematic and continuous contacts with the State of New Jersey

through the marketing and sales of generic drugs throughout the United States, and in

particular within this judicial district, through the receipt of revenue from the sales and

marketing of generic drug products, including WLF products, within this judicial district,

and through their intent to market and sell the Watson Products, if approved, to residents

of this judicial district.

22. Venue is proper in this judicial district under 28 U.S.C. 1391(b) and (c)

and 1400(b).

PATENTS-IN-SUIT

23. On December 3, 2002, the U.S. Patent and Trademark Office (PTO)

duly and legally issued the 960 patent titled Corticosteroid Formulation. At the time

of its issue, the 960 patent was assigned to Arakis, Ltd., Babraham Hall, Babraham,

Cambridge, United Kingdom (now known as Sosei R&D Ltd., Chesterford Research

Park, Little Chesterford, Saffron Walden, Essex, United Kingdom), which later assigned

the 960 patent to Nitec Pharma AG (now known as Horizon Pharma AG), Kagen-Strasse

17, Reinach Switzerland CH-4153. Horizon Pharma AG is the sole current assignee of

the 960 patent, which discloses and claims, inter alia, a pharmaceutical composition

containing prednisone. A true and correct copy of the 960 patent is attached hereto as

Exhibit A.

24. On January 13, 2004, the PTO duly and legally issued the 326 patent

titled Corticosteroid Formulation Comprising Less Than 2.5 mg Prednisolone for Once

Daily Administration. At the time of its issue, the 326 patent was assigned to Arakis,


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Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, Essex, United

Kingdom (now known as Sosei R&D Ltd., Chesterford Research Park, Little Chesterford,

Saffron Walden, Essex, United Kingdom), which later assigned the 960 patent to Nitec

Pharma AG (now known as Horizon Pharma AG), Kagen-Strasse 17, Reinach

Switzerland CH-4153. Horizon Pharma AG is the sole current assignee of the 326

patent, which discloses and claims, inter alia, a pharmaceutical composition containing

prednisone. A true and correct copy of the 326 patent is attached hereto as Exhibit B.

25. On November 13, 2012, the PTO duly and legally issued the 124 patent

titled Delayed Release Tablet with Defined Core Geometry. Jagotec AG is the sole

current assignee of the 124 patent, which discloses and claims, inter alia, a

pharmaceutical composition containing prednisone. A true and correct copy of the 124

patent is attached hereto as Exhibit C.

26. On May 1, 2012, the PTO duly and legally issued the 218 patent titled

Delayed Release Tablet with Defined Core Geometry. Jagotec AG is the sole current

assignee of the 218 patent, which discloses and claims, inter alia, a pharmaceutical

composition containing prednisone. A true and correct copy of the 218 patent is

attached hereto as Exhibit D.

27. On March 12, 2013, the PTO duly and legally issued the 407 patent titled

Delayed Release Tablet with Defined Core Geometry. Jagotec AG is the owner of the

407 patent, which discloses and claims, inter alia, a pharmaceutical composition

containing prednisone. A true and correct copy of the 407 patent is attached hereto as

Exhibit E.


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RAYOS

28. Horizon Pharma, Inc. is the owner of the approved New Drug Application

No. 202020 (the RAYOS NDA) for prednisone delayed-release tablets in 1 mg, 2

mg, and 5 mg dosage strengths, which are sold by Horizon Pharma USA, Inc. under the

trade name RAYOS. The RAYOS tablets are currently approved for use as an anti-

inflammatory or immunosuppressive agent for certain allergic, dermatologic,

gastrointestinal, hematologic, ophthalmologic, nervous system, renal respiratory,

rheumatologic, specific infectious diseases or conditions and organ transplantation; for

the treatment of certain endocrine conditions; and for palliation of certain neoplastic

conditions.

29. Pursuant to 21 U.S.C. 355(b)(1), and attendant FDA regulations, the

960, 326, 124, 218 and 407 patents are listed in the FDA publication entitled

Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book)

for the RAYOS NDA.

30. The 960 and 326 patents are listed in the Orange Book for the 1 mg and

2 mg strength RAYOS tablets. The 124 and 407 patents are listed in the Orange

Book for the 1 mg, 2 mg, and 5 mg strength RAYOS tablets. The 218 patent is listed

in the Orange Book for the 5 mg strength RAYOS tablets.

31. The 960, 326, 124, 218 and 407 patents cover the RAYOS product.

WATSONS ANDA

32. On information and belief, WLF submitted ANDA No. 204867 (the

Watson ANDA) to the FDA, pursuant to 21 U.S.C. 355(j), seeking approval to market

prednisone delayed-release tablets in 1 mg, 2 mg, and 5 mg dosage strengths. On


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information and belief, the Watson ANDA is seeking approval to market the Watson

Products as an anti-inflammatory or immunosuppressive agent for certain allergic,

dermatologic, gastrointestinal, hematologic, ophthalmologic, nervous system, renal

respiratory, rheumatologic, specific infectious diseases or conditions and organ

transplantation; for the treatment of certain endocrine conditions; and for palliation of

certain neoplastic conditions.

33. The Watson ANDA refers to and relies upon the RAYOS NDA and

contains data that, according to Watson, demonstrate the bioequivalence of the Watson

Products and RAYOS.

34. Plaintiffs have received from WLF a letter, dated July 15, 2013 (the

Watson Notification), stating that WLF had included a certification in the Watson

ANDA pursuant to 21 U.S.C. 355(j)(2)(A)(vii)(IV), that the 960, 326, 124, 218 and

407 patents are invalid or will not be infringed by the commercial manufacture, use or

sale of the Watson Products (the Paragraph IV Certification).

COUNT I FOR INFRINGEMENT OF U.S. PATENT 6,488,960

35. Plaintiffs reallege and incorporate by reference the allegations of

paragraphs 1-34 of this Complaint.

36. Defendants have infringed the 960 patent, pursuant to 35 U.S.C.

271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval

from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or

importation of the Watson Products in 1 mg and 2 mg strengths prior to the expiration of

the 960 patent.


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37. Defendants commercial manufacture, use, offer to sell, or sale of the

Watson Products within the United States, or importation of the Watson Products in 1 mg

and 2 mg strengths into the United States during the term of the 960 patent would further

infringe the 960 patent under 35 U.S.C. 271(a), (b) and/or (c).

38. This action is being filed within 45 days of receipt by Plaintiffs of the

Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of

Watsons Paragraph IV Certification with respect to the 960 patent.

39. Upon information and belief, Defendants had actual and constructive

notice of the 960 patent prior to filing Watsons ANDA, and Defendants infringement

of the 960 patent has been, and continues to be, willful.

40. Plaintiffs are entitled to the relief provided by 35 U.S.C. 271(e)(4),

including an order of this Court that the effective date of the approval of Watsons

ANDA be a date that is not earlier than the expiration of the 960 patent, or any later

expiration of exclusivity for the 960 patent to which they become entitled.

41. Plaintiffs will be substantially and irreparably harmed if Defendants are

not enjoined from infringing or actively inducing or contributing to infringement of the

960 patent.

42. Plaintiffs have no adequate remedy at law.

43. This case is an exceptional one, and Plaintiffs are entitled to an award of

attorneys fees under 35 U.S.C. 285.

COUNT II FOR INFRINGEMENT OF U.S. PATENT 6,677,326




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importation of the Watson Products in 1 mg and 2 mg strengths prior to the expiration of

the 326 patent.



and 2 mg strengths into the United States during the term of the 326 patent would further














326 patent.



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COUNT III FOR INFRINGEMENT OF U.S. PATENT 8,309,124






importation of the Watson Products in 1 mg, 2 mg and 5 mg strengths prior to the

expiration of the 124 patent.


Watson Products within the United States, or importation of the Watson Products in 1

mg, 2 mg and 5 mg into the United States during the term of the 124 patent would

further infringe the 124 patent under 35 U.S.C. 271(a), (b) and/or (c).










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124 patent.




COUNT IV FOR INFRINGEMENT OF U.S. PATENT 8,168,218






importation of the Watson Products in 5 mg dosage strength prior to the expiration of the

218 patent.



dosage strength into the United States during the term of the 218 patent would further






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218 patent.




COUNT V FOR INFRINGEMENT OF U.S. PATENT 8,394,407






importation of the Watson Products in 1 mg, 2 mg and 5 mg prior to the expiration of the

407 patent.

73. Watsons commercial manufacture, use, offer to sell, or sale of the Watson

Products within the United States, or importation of the Watson Products in 1 mg, 2 mg


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and 5 mg into the United States during the term of the 407 patent would further infringe

the 407 patent under 35 U.S.C. 271(a), (b) and/or (c).





notice of the 407 patent prior to filing Watsons ANDA, and Watsons infringement of

the 407 patent has been, and continues to be, willful.







407 patent.




PRAYER FOR RELIEF

WHEREFORE, Horizon Pharma AG and Jagotec AG pray for a judgment in their

favor against Defendants Watson Laboratories, Inc. Florida, Actavis Pharma, Inc.,

Andrx Corporation, and Actavis, Inc., and respectfully request the following relief:


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A. A judgment declaring that Defendants have infringed one or more claims

of U.S. Patent 6,488,960;

B. A judgment declaring that Defendants have infringed one or more claims


C. A judgment declaring that Defendants have infringed one or more claims


D. A judgment declaring that Defendants have infringed one or more claims


E. A judgment declaring that Defendants have infringed one or more claims


F. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and

permanently enjoining Defendants, their officers, agents, servants, and employees, and

those persons in active concert or participation with any of them, and their successors and

assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1

mg and 2 mg dosage strengths within the United States, or importing the Watson

Products into the United States, prior to the expiration date of the 960 patent;

G. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and




mg and 2 mg dosage strengths within the United States, or importing the Watson



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H. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and




mg, 2 mg and 5 mg dosage strengths within the United States, or importing the Watson


I. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and




mg dosage strength within the United States, or importing the Watson Products into the

United States, prior to the expiration date of the 218 patent;

J. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and




mg, 2 mg and 5 mg dosage strengths within the United States, or importing the Watson


K. If Defendants commercially manufacture, use, offer to sell, or sell the

Watson Products within the United States, or import the Watson Products in 1 mg and 2

mg dosage strengths into the United States, prior to the expiration of the 960 patent,

including any extensions, a judgment awarding Plaintiffs monetary relief together with

interest;


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L. If Defendants commercially manufacture, use, offer to sell, or sell the

Watson Products within the United States, or import the Watson Products in 1 mg and 2

mg dosage strengths into the United States, prior to the expiration of the 326 patent,

including any extensions, a judgment awarding Plaintiffs monetary relief together with

interest;

M. If Defendants commercially manufacture, use, offer to sell, or sell the

Watson Products within the United States, or import the Watson Products in 1 mg, 2 mg

and 5 mg dosage strengths into the United States, prior to the expiration of the 124

patent, including any extensions, a judgment awarding Plaintiffs monetary relief together

with interest;

N. If Defendants commercially manufacture, use, offer to sell, or sell the

Watson Products within the United States, or import the Watson Products in 5 mg dosage

strength into the United States, prior to the expiration of the 218 patent, including any

extensions, a judgment awarding Plaintiffs monetary relief together with interest;

O. If Defendants commercially manufacture, use, offer to sell, or sell the

Watson Products within the United States, or import the Watson Products in 1 mg, 2 mg

and 5 mg dosage strengths into the United States, prior to the expiration of the 407

patent, including any extensions, a judgment awarding Plaintiffs monetary relief together

with interest;

P. Attorneys fees in this action as an exceptional case pursuant to 35 U.S.C.

285;

Q. Costs and expenses in this action; and


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R. Such other and further relief as the Court deems just and proper.

Date: August 26, 2013 /s/ Karen A. ConfoyKaren A. Confoy

FOX ROTHSCHILD, LLP

997 Lenox Drive, Building 3Lawrenceville, New Jersey 08648

(609) 896-3600Attorneys for Plaintiffs Horizon Pharma

AG and Jagotec AG

Robert F. Green

Caryn C. Borg-BreenJessica M. Tyrus

Ann K. Kotze

LEYDIG, VOIT & MAYER, LTD.Two Prudential Plaza, Suite 4900

180 North Stetson

Chicago, Illinois 60601

(312) 616-5600


John A. Bauer

MINTZ, LEVIN, COHN, FERRIS,GLOVSKY AND POPEO, P.C

666 Third Avenue

New York, New York 10017(212) 692-6795

Of Counsel for Plaintiff Jagotec AG

Dennis A. Bennett

GLOBAL PATENT GROUP, LLC

1005 North Warson Road, Suite 201St. Louis, Missouri 63132

(314) 812-8018

Of Counsel for Plaintiff Horizon PharmaAG


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EXHIBIT A


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|1|1111111111||||II||I|I1|||||||||||||||l|IHI11l1lIIIIIIIIIIHIIHIIIIIIIUS006488960B1

(12) United States Patent Us 6,488,960 B1(10) Patent NoDec. 3, 2002(45) Date of PatentBardsley

(54) CORTICOSTEROID FORMULATION (58) Field of Search 514/179, 180;424/465, 489

(75) Inventor: Hazel Judith Bardsley, Cambridge

(56) Relbrencw Cited

U.S. PATENT DOCUMENTS(73) Assignee: Amkis Ltd. (GB)

5,792,47 6 A * 8/1998 Hal lgren 424/465( * ) Notice: Subject lo any disclaimer, the term of this

patent is extended or adjusted under 35U.S.C. l54(b) by 0 days.

FOREIGN PATENT DOCUMENTS

WO 95/08323 =|< 3/ 1995 A6 1 K/9/54

(21) App1. No 09/936,586 OTHER PUBLICATIONS

(22) PCT Fi led Rote Liste 1998, 31 037 Decortin H 1mg.*Mar. 14, 2000

cited by examiner(86) PCT No PCT/GB00/00924

PrimaryExaminer ames H. Reamer(74) Attorney Ageng or Firm-Saliwanchik, Lloyd &Saliwanchik

371 ()(1),(2), (4) Date: Sep. 13, 2001

(sv) PC' l Pub. No.: WO00/54780

7) ABSTRACTPCT Pub. Date: Sep. 21, 2000The present invention pertains to a unit dose formulationcomprising 0.25 to 2 mg of a corticosteroid. This small dosecan be used to treat rheumatoid arthritis, especially ifadapted to release at least 90% by weight of thecorticosteroid, 2 to 8 hours after administration.

30) Foreign Application Priority Data

Mar. 15, 1999 (GB) 9905898

(51) In t. C17

(52) U.s . Cl.

A61K 31/09

424/465; 424/485; 514/179514/180 8 Claims, 1 Drawing Sheet


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U.S. Patent Us 6,488,960 B1Dec. 3, 2002

Concentration(ng/ml)

50

I

5L40

30

20

10

0

6 12 180 24

Time

Fig. 1


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Us 6,488,960 B1

1 2Arvidson et al (and in U.S. Pat. No. 5792496), a much lowerdosage of the glucocorticoid was also effective. Given thestate of the art and the known side-eifects of conicosteroids.

CORTICOSTEROII) FORMULATION

FIELD OF THE INVENTION this increase in their therapeutic index is surprising

This invention relates to a controlled-release formulation. 5 According lo the present invention, a unit dosage com~prises 0.25 to 2 mg of a corticosteroid. Preferably, such a

dosage is in the form of a controlled-release formulation ofthe type generally or specifically described in U.S. Pat. No.5,792,476.

and in particular to a formulation of a corticosteroid, suitable

for use in the treatment of rheumatoid arthritis.

BACKGROUND OF THE INVENTION

Glucocor t icoids, and in particular prednisone and 10prednisolone, are widely used for the treatment of rheuma-toid arthritis. The use of glucocorticoids may be ellicaciousbut has disadvantages, particularly in terms of side~elfectssuch as bone loss.

Thus, in accordance with the present invent ion, acontrolled-close formulation of the drug is adapted lo releasethe drug at a predetermined period of time afteradministration, or at a predetermined time. Advantages ofthe invention may include enhanced ellicaey, reduced side-effects, reduced Cmax and/or a reduced level of activematerial.

It appears to be generally recognised that it would bedesirable to use low doses of, say, prednisolone, in thetreatment of rheumatoid arthritis. While it is clear that low

l

dose oral prednisolone can be eiiieacious, there is somecontroversy over what is actually meant by a low dose.

Kirwan, New England J. Med. 333: 142-5 (1995), indi-cates that a daily dosage of 7.5 mg prednisolone is elfective.This is supported by Boers et al, The Lancet 3502309-318

(1997). Boers et al also reports that a typical treatment ofrheumatoid arthritis following initial treatment with a non-steroidal anti-inliamrnatory dnug (NSAID) involves a highini tial dose and, when the condit ion is under cont rol,reduced doses, down to a "low maintenance" of 7.5 mg/day.

Gotzsche and Johansen, B. M. J. 316811-818 (1998),reviews a number of studies of low dose prednisolone in thetreatment of rheumatoid arthritis. Most of these studies

20

25

30

DESCRIPTION OF THE INVENTION

The intention behind the invention is that the activeingredient should be released at a predetermined time, e.g.between midnight and 6 a.m., e.g. 2 a.m. and 4 a.m., or apredetermined time after administration. Thus, the user can

take the formulation before going to sleep, but have the fullvalue of an effective dosage of the drug during the night, orduring sleep, at a dosage that has minimal sideeffects.Accordingly, a predominant amount of the active ingredient,e.g. at least 90% by weight, is released at least 2 or 3 hoursafter administration, and preferably no more than 6, 7 or 8hours after administration.

Formulations of the invention are intended for the treat-report doses of at least 7.5 mg. There is one report, but fromas long ago as 1967, of a 2.5 mg dose.

It is evident that, in c linical practice, rheumatologiststaper the dose of glucocorticoid to as a low a level as theycan, before symptoms return. There may be patients who arestable on less than 5 mg prednisolone per day, but there islittle or no clinical data to support that such a low dose isactually providing any benefit. This is important, because in

many of these patients, prednisolone may be contributingonly side-effects. There is no evidence that any dose ofprednisolone, lower than those generally used, is effectivewhen given chronically for the treatment of rheumatoidarthritis.

Arvidson et al, Annals of th e Rheumatic Diseases56:27_31 (1997), reports that the timing of glucocorticoidadministration in rheumatoid arthritis may be important, incontrolling the acute inflammatory aspects of the disease. Inthe reponed study, patients were woken at 2.00 a.m. andgiven 7.5 mg or 5 mg prednisolone.

35

40

45

50

ment of disorders associated with the release of cytokines. lnparticular, the invention is sui table for the treatment ofinflammatory diseases, and most especially rheumatoidarthritis, asthma, inflammatory bowel disease and atopicdermatitis. The dwg that is used in the formulation may bechosen accordingly. Examples are glucocortocoids and othercor ticosteroids, e.g. budesonide, methylprednisolone,deflazacort, prednisone and prednisolone. lf desir ed, the

active ingredient may be formulated as a pro-dnug, so thatthe active component is released in vivo.

The preferred route of administration of a formulation ofthis invention is oral. However, it will be readily apparent tothose skilled in the art that other routes of administrationmay be used, e.g. having regard to the nature of the conditionbeing treated and the most effective means of achievingdelayed release.

The dwg may be administered in any conventional for-mulation that provides delayed release, via any suitableroute of administration. Conventional dosing parameters

U.S. Pat. No. 5,792,476 claims a sustained-release for-mulation of a glucocorticoid such as prednisone or pred-nisolonhe. The formulation comprises 2.5-7 mg of theglucocorticoid and releases at least 90% of the drug during40~80 minutes, starting about 1-3 hours after the entry of

the drug into the small intestine. The intention is that theformulation should be taken immediately before the patientgoes to sleep, that the drug should be released during sleep,and that the greatest symptoms of rheumatoid arthritis(which occur shortly before waking) should thus be treatedmost effectively. This is based on the same data as inArvidson et al, supra, i.e. us ing doses of 5 or 7.5 mgprednisolone given at 2 a.m.

55

60

may be adopted, i.e. those which are known to or adapted tothe practice of those sldlled in the art. The daily dosage isusually at least 0.25 or 0.5 mg, eg. l to 2 mg, but will bechosen according to the age, weight and health of theSubject, and other factors that are routinely considered by the

man skilled in the art.A formulation of the invention may be a unit dosage such

as a tablet, capsule, ampoule, vial or suspens ion. Acontrolled-release formulation may be in matrix, coating,reservoir, osmotic, ion-exchange or density exchange form.It may comprise a soluble polymer coating which is dis-solved or eroded, after administration. Alternatively, theremay be an insoluble coating, e.g. of a polymer, throughwhich the active ingredient permeates, as from a reservoir,

65 diifuses, e.g. through u porous matrix, or undergoes osmoticexchange. A further option for a controlled-release formu-lation involves density exchange, e.g. in the case where the

SUMMARY OF THE INVENTION

This invention is based on the discovery that, in a studydesigned to test the reproducibility of the results reported by


26/78

Us 6,488,960 B1

3 4formulation alters on administration, e.g. from micropar-ticles to a gel so that the active ingredient dilfuses orpermeates out. Ion-based resins may also be used, the activecomponent being released by ionic exchange, and whereinthe rate of release can be controlled by using cationic oranionic forms of the drug. Another type of controlled-release

formulation involves pulsed dosing. Further examples aregiven in U.S. Pat. No. 5,792,476.

An example of a controlled dose of acti ve ingredient isdosing with a tablet containing 1.25 mg prednisolone. In thisexample, a patient taking a controlled dose of 1 .25 mgprednisolone takes the tablet a number of hours before it isdue to be released. Time Zero on the plot (FIG. 1) denotes theearliest time at which active ingredient is released, probablymidnight. The plasma levels achieved by release of theactive agent at di5erent times (2, 4 and 6 a.m.) are shown.

It can be seen that the range for Clnuxobtained from the

125 mg prednisolone dose is from approximately 20 to 50ng/ml (total prednisolone which includes protein bound andunbound active) depending on how quickly a patient absorbsthe active ingredient. The time to Cmax or Tm is usuallybetween 1 and 3 hours, Where absorption is particularly fast,

theCnmxmay be 100 ng/ml total prednisolone or higher (thisis not shown on the plot).

The following Study provides the basis of the presentinvention.Study Design

The study was an assessor blind comparison of the eiectsof two doses of prednisolone (1 mg and 5 mg) given at02.00. Patients stayed the night in hospital but were free tobe up and about and to leave the hospital during the day. At2 a.m. on the appropriate days patients were woken gently,administered the prednisolone, and settled back to sleep.Blood samples and clinical assessments were made at 08.30and further clinical assessments related to symptoms on theday of drug administration at 12.00 and 08.30 the followingday (except the final day when this last assessment was madebefore departure from the hospital). Patients were admittedon Monday and had a "control" night that evening with no

prednisolone but full assessment the following day. On eachof the following three nights prednisolone was administered.Patients went home on Friday afternoon but returned thefollowing Monday to repeat the procedure. Allocation to 1mg or 5 mg prednisolone in the first or second week was byrandomisation in sealed envelopes. The patient and assessorwere not aware of which dose was given.Outcome

Clinical: Outcome was measured at 08.30 each day for:swollen joint count (n=28); tender joint count (n=28); pain(0.100 mm, VAS). Outcome was measured at 12.00 each dayfor. morning stihness (minutes); patient opinion of condition(0-100 mm, VAS); clinician opinion of condition (0-100mm, VAS). Outcome was measured the following day for:whether the arthritis worse in the morning or afternoon onthe previous day? (-1 morning, 0 equal, +1 afternoon).

Serological: Seam samples were obtained at 08.30, kepton ice for up to 1 hour, separated and stored at -70 C. tomeasure: C-reactive protein (CRP); IL6 concentration; 6soluble receptor (IL-6sR) concentration; byaluronate (HA)concentration.Procedure

5

10

15

20

25

30

35

40

45

50

55

60

(and probably remained blind), but no placebo tablets were

used and it was possible for a patient to be un-blind.

Patients invited to take part in the study had the following

characteristics:

Over 18 years old

Had rheumatoid arthritis by the criteria of the AmericanCollege of Rheumatology; see Arnett et al, Arthritis

Rheum. 31:315-324 (1988)

Had active disease as evidenced by 3 or more swollen and

tender joints

Were not taking glucocorticoid medication

Had not had intra-anicular glucocorticoid injections in the

previous 3 weeks

Had no medical conditions which, in the opinion of the

investigator, would contraindicate low dose predniso-

lone therapy

Informed consent was obtained and the patient prescr ip-

tion written by a doctor not associated with trial evaluation.

Medication was dispensed at 2 a.m. on each treatment day

after gently waking the patient. The patient was encouragedto settle back to sleep immediately.

On the morning before medication and on each morning

on the day of medication, blood samples were taken at 8.30

a.m. and outcome assessments recorded then, and at noon, as

indicated above,

Evaluation

Symptoms, signs and laboratory results were compared

within and between patients, but the main assessment wasvisual inspection of the overall pattern of response. Means

and standard deviations were used to define variation rates

and for calculating trial size for future studies. An overall

assessment of practicality and the potential for more fre-

quent (but smaller volume) blood taking was made by

discussion arnongst the staff and patients involved.Results

Three patients were able to take part in the study in the

time available. One patient (3) was inadvertently given the

Hrst dose of treatment in the second week on the hrst night

in hospital. Patient 3 took prednisolone for the next two

nights and remained in hospital for a fourth night without

prednisolone treatment. This patient's assessments have

been included normally in the first week, but in the second

week they have been used diierently. Here, this patient's

results have been included with those of the other patients in

accordance with the dose of prednisolone received. This

patient's final assessment (no prednisolone the night before)

therefore appears as an extra day after the other patients inthe study.

The results for 5 mg prednisolone place the patients in thispilot study well within the range of findings published byArvidson et al and reinforce the conclusions which can be

drawn from that paper.

The results from 1 mg prednisolone raise the possibilitythat even at this dose there may be an appreciable effect onPatients acted as their own control and took each dose of

prednisolone for three consecutive nights. They were ran-domly. allocated by cards kept in sealed envelopes to either1 mg prednisolone on three consecutive nights followed by 655 mg on three consecutive nights, or the opposite sequence.The assessor was not aware of the treatment order allocation

symptoms. Pain, EMS, pat1ent's opinion and clin1cian'sopinion were statistically significantly reduced, even withonly three patients in the study. CRP and IL-6 were reduced

significantly on 5 mg prednisolone and there was a tendencyfor reduction on 1 mg prednisolone.


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Us 6,488,960 B1

65

TABLE 1

Mean and 95% confidence intervals for each variable

More

L ClnSwollen Painful OT

Less EMS Opn Opn CRP HA m e IL-6sRDav Dose Joinis Joints Pain

Mean Results

345.1 44 .1 31557.820.3 21.0 37.7 -1.0 70.0 31.3 34.3 4051

2

3

101 1

18.718718.3

12.3

18.0

20.0

20.3

20.3

15.319.0

26.0

20.3

16.7

25.0

19.7

-0.7-0.7

0.0

0.3

0.3

55.0

51.7

40.0

40.0

30.0

23,7

26.7

12.7

24.3

19.3

28.7

29.3

16.323.3

27.7

35.5

31.2

25.815.0

36.6

241 .9

320.3

372.5

396.3

322.5

28.1

31.1

22.8

19.3

30.3

31959.9

31468.0

30898.9

22937.2

423%.2

0 11.7 15.7 31.1 339.5 18.5 353312 5 17.313 5 14,0 19.7 16.0 ~0.7 33.3 13.3 11.7 19.1 193.9 13.8 361727

8.0 19.5 363.5 107 .1 32180.514 0 12.0 9.0

95% CI Resulls

213.0 18.1 8838.90.7 5.7 24.9 0.0 19.6 20.3

1.3 7,4 25.2 0.7 9.8 15.4 10.3 23.0 152.3 18.1 102251 1

3.5 7.7 20.3 0.7 8.6 5.7 10.5 27.5 321.8 32.7 1022094.6 25.3 96.7 28,4 11329.4

29.6 22.8 718.7 23.3 27617.3

3.6 9.1 16.9 1.1 9.8 1

10 0 15.2 19.2 31.8 0.8 48.0 3148.6 2 4 1 23485.311 5 3.9 9.1 21.1 1.3 29.4 20.1 13.6 291

12 5 6.5 9.6 15.4 0.7 19.6 11.6 1.7 26.0 221.4 23.6 8919.1113.3 13,3 7069513 5 6.9 10.3

14

What is claimed is effective amount of a controlled-release formulation com1. A controlled-release formulation comprising f rom 0.25

mg to 2 mg of a corticosteroid selected from the groupconsisting of prednisone, methylprednisolone, andprednisolone, wherein said formulation is adapted to releaseat least 90% by weight of the corticosteroid 2 hours to 8hours after administration.

2. The formulation according to claim 1, which comprisesfrom 05 mg to 2 mg of the corticosteroid.

3. The formulation according to claim 1, which comprisesfrom l mg to 1.25 mg of the corticosteroid.

4. The formulation according to claim 1, Wherein thecorticosteroid is prednisolone.5. A method for the treatment of rheumatoid arthritis,

Wherein said method comprises administering to a patient an

30

35

40

prising from 0.25 mg to 2 mg of a corticosteroid selected

from the group consisting of prednisone,methylprednisolone, and prednisolone, wherein said formu-

lation is adapted to release at least 90% by weight of thecorticosteroid 2 hours to 8 hours after administration.

6. The method according to claim 5, wherein the formu-lation comprises from 0.5 mg to 2 mg of the corticosteroid.

7. The method according to claim 5, W herein the formu-lation comprises from 1 mg to 1.25 mg of the corticosteroid.

8. The method according to c laim 5, wherein the corti-costeroid is prednisolone.

=t< =l< >l * *


28/78

EXHIBIT B


29/78

||||||||||1||||||1111||||1|||||IIIIIII III|11|1II111|1|I|||H||||||||I|||||US006677326B2

(12) United States Patent (10) Patent No.: US 6,677,326B 2(45) Date of Patent: *Jan. 13, 2004Bardsley et al

(58) Field of Search 514/179, 180(54) CORTICOSTEROID FORMULATIONCOMPRISING LESS THAN 2.5 MGPREDNISOLONE FOR ONCE DAILYADMINISTRATION

References Cited(56)

U.S. PATENT DOCUMENTS

(75) Inventors: Hazel Judith Bardsley, Cambridge 5,792,476 A 8/1998 Hi il lgren

(GB); Robin Mark Bannister, Essex(GB); Julian Clive Gilbert, Essex (GB)


WO WO 95/08323 A1 3/1 995

(73) As Fi led Oct. 1, 2002

Prior Publication Daw(65) PrimarvExaminer-James H. Reamer(74) Attorney Agent, or Firm-Saliwanchik, Lloyd &Saliwanchik

US 2003/0149009 A1 Aug. 7, 2003

Related U.S. Application Data7) ABSTRACT

63) Continuation of application No. PCT/GB01/04181, filed onSep. 19, 2001, and a continuation-in-part of application No.09/9361586, filed on Sep. 13, 2001, now Pat. No. 6,488,960.

The subject invention concerns a unit dose formulationcompr is ing less than 2.5 mg of prednisolone or anequivalent, equipotent amount of another cortioosteroid.One embodiment of a method of the invention concernsonce daily administration of the unit dose formulationbetween midnight and 6 a.m. for the treatment of rheumatoidarthritis.

Foreign Application Priority Data0)

Mar. 15, 1999 (GB)

Sep. 21, 2000 (GB)

9905898

0023220

(51) Int. Ci7

(sz) U.s. Cl.

A61K 31/56

514/179; 514/1 80 17 Claims, 1 Drawing Sheet


30/78

U.S. Patent Us 6,677,326 B2Jan. 13, 2004

Concentration(nglml)

50

wr

\\

x

r'

40l\

`\;\3 0 4

\\/

32 iV~

U

0 +12 18 2460

Time

FIG. l


31/78

Us 6,677,326 B2

21the dmg into the small intestine. The intention is that theformulation should be taken immediately before the patientgoes to sleep, that the dwg should be released during sleep,and that the greatest secretion of cytokines (which occurshortly before waking) should thus be treated most eff ec-tively. This is based on the same data as in Arvidson et al.,

supra, i.e. using doses of 5 or 7.5 mg prednisolone given at2 am.

C()R'1`IC()S'l`ER()ID FORMULATIONCOMPRISING LESS THAN 2.5 MG

PREDNISOLONE FOR ONCE DAILYADMINISTRATION

CROSS-REFERENCE TO RELATED

APPLICATIONSThis application is a continuation of International Appli-

cation PCT/GB01/04181, with an international filing date ofSep. 19, 2001, published in English under PCTArticlc 21(2),and is a continuation-in-part of U.S. application Scr. No.09/936,S86, filed Sep. 13, 2001 now U.S. Pat. No. 6,488,960.

10 BRIEF SUMMARY OF T HE INVENTION

15

This invention is based on the discovery that, in a studydesigned to test the reproducibility of the results reported byArvidson et al . (and in U.S. Pat. No. 5,792,496), a muchlower dosage of the glucocorticoid was also effective. Giventhe state of the art and the kn own side-effects of corticosteroids, this increase in their therapeutic index is

FIELD OF THE INVENTION

This invention relates to a controlled-release formulation,and in particular to a formulation of a corticosteroid, suitablefor use in the treatment of rheumatoid arthritis.

surpnsmg

20

According to the present invention, a uni t dosage com-prises less than 2.5 mg of prednisolone or an equivalentamount of a conicosteroid. Equivalence is in terms ofpotency. It will be understood that drugs vary in potency, andthat doses can therefore vary, in order to obtain equivalenteffects.

BACKGROUND OF THE INVENTION

Glucocorticoids, and in particular prednisone and

prednisolone, are widely used for the treatment of rheuma-toid arthritis. The use of glucocorticoids may be eficacious

but has disadvantages, particularly in terms of side-effects 25 Thus, in accordance with the present invention, asuch as bone loss. controlled-dose formulation of the drug is adapted to release

It appears to be generally recognized that it would bedesirable to use low doses of, say, prednisolone, in thetreatment of rheumatoid arthritis. W hile it is c lear that lowdose oral prednisolone can be elficacious, there is somecontroversy over what is actually meant by a low dose.

Kirwan, New England J. Med. 3331142-5 (1995), indi-cates that a daily dosage of 7.5 mg prednisolone is effective.This is supported by Boers et al., The Lancet 3501309-318(1997). Boers et al. also reports that a typical treatment ofrheumatoid arthritis following initial treatment with a non-steroidal anti-iniiammatory dmg (NSAID) involves a highini tial dose and, when the Condition is under control ,

reduced doses, down to a "low maintenance" of 7.5 mg/day.Gotzsche and Johansen, B. M. J . 3162811-818 (1998),

reviews a number of studies of low dose prednisolone in thetreatment of rheumatoid arthritis. Most of these studiesreport doses of at least 7.5 mg. There is one report, but fromas long ago as 1967, of a 2.5 mg dose.

It is evident that, in clinical practice, rheumatologiststaper the dose of glucoconicoid to as a low a level as theycan, before symptoms return. There may he patients who arestable on less than 5 mg prednisolone per day, but there islittle or no clinical data to support that such a low dose isactually providing any beneiit. This is important, because inmany of these patients, prednisolone may he contributingonly side-effects. There is no evidence that any dose ofprednisolone, lower than those generally used, is effectivewhen given chronically for the tr eatment of rheumatoid

arthritis.

30

35

40

45

50

55

the drug at a predetermined per iod of time after administration, or at a predetermined time. Advantages ofthe invention may include enhanced eliicacy, reduced side-elfects and/or reducedCmax'Further or in addition, chrono-therapeutic administration allows the use of a reduced levelof active material.

DESCRIPTION OF THE INVENTION

The intention behind the invention is that the activeingredient should be released at a predetermined time, e.g.between midnight and 6 a.m., e.g. 2 a.m. and 4 a.m., or apredetermined time after administration. Thus, the user can

take the formulation before going to sleep, but have the fullvalue of an eilective dosage of the dnig during the night, orduring sleep, at a dosage that has minimal side~elfects.

Accordingly, a predominant amount of the active ingredient,e.g. at least 90% by weight, is released at least 2 or 3 hoursafter administration, and preferably no more than 6, 7 or 8hours after administration.

Formulations of the invention are intended for the treat-ment of disorders associated with the release of cytokines,e.g. TNF ot, IL-1, IL-2, IL-6 and IL-8. In particular, theinvention is suitable for the treatment of inflammatorydiseases, including polyarthropathies, and more especiallyrheumatoid arthritis, asthma, inflammatory bowel disease,chronic obstnuctive pulmonary disease, psoriasis, psoriaticarthritis, polymyalgia rheumatica and atopic dermatitis. Thedrug that is used in the formulation may be chosen accord-

ingly. If desired, the active ingredient may be formulated asArvidson et al., Annals of the Rheumatic Diseases

56:27-31 (1997), reports that the timing of glucocorticoidadministration in rheumatoid arthritis may be important, incontrolling thc acute inflammatory aspects of the disease. Inthe reported study, patients were woken at 2.00 a.m. andgiven 7.5 mg or 5 mg prednisolone.

a pro-drug, so that the active component is released in vivo.

Among active agents that can he used in the invention,examples are glucocorticoids and other conieosteroids, e.g.

60 budesonide, methylprednisolone, deflazacorl, fluticasone,prednisone and prednisolone. The appropriate dosage ofeach such drug depends on its potency,

U.S. Pat. No. 5,792,496 claims a sustained-release for- Equivalent potency in clinical dosing is well known.mulation of a glucocorticoid such as prednisone or pred- Information relating to equivalent steroid dosing (in a non-nisolone. The formulation comprises 2.5-7 mg of the glu- 65 chronotherapeutic manner) may be found in the Britishcocorticoid and releases at least 90% of the drug during Nadonal Formulary (BNF), 37 March 1999, the content of40-80 minutes, starting about 1-3 hours after the entry of which is incorporated herein by reference.


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Us 6,677,326 B2

3 4The BNF guidelines are included in the table below. In

addition, the proposed clinical dose equivalent to 1 Ing ofprednisolone when administered in a chronotherapeuticmanner is included in the table. More specifically, thefollowing Table is of doses of steroids equivalent to mg ofprednisolone and equivalence to 1 mg of prednisolone When

administered in a chronotherapeutic manner according tothis invention and 1 mg of prednisolone.

5

An example of a controlled dose of active ingredient isdosing With a tablet containing 1,25 mg prednisolone. In thisexample, a patient taldng a controlled dose of 1.25 mgprednisolone takes the tablet a number of hours before it isdue to be released. Time zero on the plot (FIG. 1) denotes theearliest time at which active ingredient is released, probably

midnight. The plasma levels achieved by release of theactive agent at dilferent times (2, 4 and 6 a.m.) are shown,

10

15

It can be seen that the range for Cmax obtained from the1.25 mg prednisolone dose is from approximately 20 to 50ng/ml (total prednisolone which includes protein bound andunbound active) depending on how quickly a patient absorbsthe active ingredient. The time to Cm or Tm" is usuallybetween 1 and 3 hours. Where absorption is particularly fast,the Cmax may be 100 ng/ml total prednisolone or higher (thisis not shown on the plot).

The following Study provides the basis of the presentinvention.

Euuivalent dose in chronotheraneutic administration

Equal to 5 mg

prednisoloneNormal dosing)*

Equal lo1 mg prednisoloneSteroid

bctamelhasonc 750 #S

25 mg

6 m e

150

5

1.2

150

4

0.8

1

0.8

/lgmg

me#8

memg

me

me

corlisone acetate

dcfiazacoxt

750 N8

20 mg

dexamethasoneStudy Design

The study was an assessor blind comparison of the effectsof two doses of prednisolone (1 mg and 5 mg) given at02.00. Patients stayed the night in hospital but were free tobe up and about and to leave the hospital during the day. At

hydrocorlisone

methyl prednisone 204 me

Smspredmsonetriamcinolone 4m;z

It is also known (BNF 37 March 1999) from clinicaldosing equivalence that doses of triamcinolone, fluticasoneand budesonide are broadly similar in nasal administration(110 pg, 100 ,ug and 200 pg). Achronotherapeutic advantagemay be expected upon dosing these drugs.

Corticosteroids such as cortisone acetate and hydrocorti-sone are less preferred for use in the invention, owing tothei r sys temic side-ef fec ts on long- term use. Suchcompounds, having ef fect on glucose and mineralmetabolism, will be known to those skilled in the art.

The preferred route of administration of a formulation of

25

30

z a.m. on me appropriate days patients were woken gently,administered the prednisolone, and settled back to sleep.Blood samples and clinical assessments were made at 08.30and further clinical assessments related to symptoms on theday of drug administration at 12.00 and 08.30 the followingday (except the final day when this last assessment was madebefore departure from the hospital). Patients were admittedon Monday and had a "control" night that evening with noprednisolone but full assessment the following day. On eachof the following three nights prednisolone was administered.Patients went home on Friday afternoon but returned the

this invention is oral. However, it will be readily apparent to 35 following Monday to repeat the procedure. Allocation to 1those skilled in the art that other routes of administrationmay be used, e.g. having regard to the nature of the conditionbeing treated and the most effective means of achievingdelayed release.

The drug may be administered in any conventional for-mulation that provides delayed release, via any suitableroute of administration. Conventional dosing parametersmay be adopted, i.c. those which are known to or adapted tothe practice of those sldlled in the art. The daily dosage(relative to prednisolone) is usually at least 0.25 or 0,5 mg,e.g. 1 to 2 mg, but will be chosen according to the age,weight and health of the subject, and other factors that areroutinely considered by the man sldlled in the art.

A formulation of the invention may be a unit dosage suchas a tablet , capsule, ampoule, vial or suspension. Acontrolled-release formulation may be in matrix, coating,reservoir, osmotic, ion-exchange or density exchange form.It may comprise a soluble polymer coating which is dis-solved or eroded, after administration. Alternatively, theremay be an insoluble coating, eg. of a polymer, through

which the active ingredient permeates, as f rom a reservoir,dilfuses, e.g. through a porous matrix, or undergoes osmoticexchange. A further option for a controlled-release formu-lation involves density exchange, e.g. in the case where theformulation alters on administration, e.g. from micropar-ticles to a gel, so that the active ingredient diflitses orpermeates out. Ion-based resins may also be used, the activecomponent being released by ionic exchange, and Whereinthe rate of release can be controlled by using cationic oranionic forms of the dnig. Another type of controlled-releaseformulation involves pulsed dosing. Further examples aregiven in U.S. Pat. No. 5,792,496.

40

45

50

55

60

65

mg or 5 mg prednisolone in the Hrst or second week was byrandomization in sealed envelopes. The patient and assessorwere not aware of which dose was given.Outcome

Clinical: Outcome was measured at 08.30 each day for:swollen joint count (n=28); tender joint count (n=28); pain(0.l()0 mm, VAS). Outcome was measured at 12.00 each dayfor: morning stiiness (minutes); patient opinion of condition(0_100 mm, VAS); clinician opinion of condition (0-100mm, VAS). Outcome was measured the following day for:whether the arthritis was worse in the morning or afternoonon the previous day (-1 morning, 0 equal, +1 afternoon).

Serological: Semm samples were obtained at 08.30, kepton ice for up to 1 hour, separated and stored at -70 C. tomeasure: C-reactive protein (CRP); IL-6 concentration; IL-6soluble receptor (IL-6sR) concentration; hyaluronate (HA)concentration.Procedure

Patients acted as their own control and took each dose ofprednisolone for three consecutive nights. They were ran-

domly allocated by cards kept in sealed envelopes to either1 mg prednisolone on three consecutive nights followed by5 mg on three consecutive nights, or the opposite sequence.The assessor was not aware of the treatment order allocation(and probably remained blind), but no placebo tablets wereused and it was pomible for a patient to be un-blind.

Patients invited to take part in the study had the followingcharacteristics:

Over 18 years old

Had rheumatoid arthritis by the criteria of the AmericanCollege of Rheumatology; see Arnett et al., ArthritisRheum. 312315_324 (1988)


33/78

US 6,677,326 B2

65Had active disease as evidenced by 3 or more swollen and

tender joints

Were not taking glucocorticoid medication

Had not had intra-articular glucocorticoid injections in theprevious 3 weeks

Had no medical conditions which, in the opinion of the

investigator, would contraindicate low dose predniso-lone therapy

Informed consent was obtained and the patient prescrip-tion written by a doctor not associated with trial evaluation.Medication was dispensed at 2 a.m. on each treatment dayafter gently waking the patient. The patient was encouragedto settle back to sleep immediately.

On the morning before medication and on each morningon the day of medication, blood samples were taken at 8.30a.m. and outcome assessments recorded then, and at noon, as

indicated above.

5

10

is

The results for 5 mg prednisolone place the patients in thispilot study Well Within the range of findings published by

Arvidson et al. and reinforce the conclusions which can be

drawn from that paper.

The results from 1 mg prednisolone raise the possibility

that even at this dose there may be an appreciable elfect onsymptoms. Pain, EMS, patient's opinion and clinician's

opinion were statistically signilicantly reduced, even withonly three patients in the study. CRP and IL-6 were reduced

significantly on 5 mg prednisolone and there was a tendencyfor reduction on l mg prednisolone.

All patents, patent applications, provisional applications,and publications referred to or cited herein are incorporated

bv reference in their entirety to the extent thev are not

iriconsistcnt with the explicit ieachings of this spci:ificationEvaluation

TABLE 1

Mean and 95% confidence intervals for each variable

MoreSwollen Painful L Clnor

Day Dose Joints Joints Pain Less EMS Opn Opn CRP H A IL-6 IL-6sR

Mean Results

0

1

23

10

11

12

13

14

20.3

18.7

18.718.3

12.3

18.0

17.3

14.012.0

21.0

20.0

20.320.3

15.3

19.0

19.7

19.79.0

37.7

26.0

20.316.7

25.0

19.7

15.7

16.00.0

1.0-0.7-0.7

0.0

-0.3-0.3-0.3-0.7

0.0

70.0

55.0

51.7

40.0

40.0

30.0

20.033.3

0.0

31.3

23.7

26.7

12.7

24.3

19.311.7

13.3

0.0

34.3

28.7

29.3

16.3

23.3

27.715.7

11,7

8 0

40.5

35.5

31.2

25.8

15.0

36.631.1

19.1

19.5

345.1

241.9

320.3

372.5

396.3

322.5339.5

193.9

363.5

44.128.1

31.1

22.8

19.3

30.3

18.5

13.8

1 07.1

315578

31959.9

31468.0

30898.9

22937.2

423282

353316

36172.7

321805

95% CI Resuhs

01

2

3

10

11

1213

0.71.3

3.5

3.615.2

3.9

6.5

6.9

5.77.4

7.7

9.119.2

9.1

9.6

10.3

24.925.2

20.3

16.931.8

21.1

15.47.8

0.0

0.7

0.71. 1

0.8

1.3

0.7

0.7

19.6

9.8

8.6

9.848.0

29.4

19.6

6.5

20.3

15.4

5.7

12.930.2

20.1

11.6

6.2

14.1

10.3

10.5

4.629.6

13.6

1.7

4.6

17.1

23.0

27.525.3

22.8

29.1

26.018.2

213.015233

321.8

96 7

718.7

148.6

221.4113.3

18.1

18.1

32.728.4

23.3

24.1

23.613.3

8838.9

10225.5

10220.9

11329.427617.3

234853

8919.1

7069,514

Symptoms, signs and laboratory results were comparedWithin and between patients, but the main assessment wasvisual inspection of the overall pattern of response. Meansand standard deviations were used to define variation ratesand for calculating trial size for future studies. An overallassessment of practicality and the potential for more fre-quent (but smaller volume) blood taking was made bydiscussion amongst the stall and patients involved.T\.,...1._

What is claimed is1. Aunit dose formulation comprising less than 2.5 mg of

prednisolone or an equivalent, equipotent amount of another50 corticosteroid.

2. The formulation according to claim 1, which comprisesat least 0.25 mg of prednisolone or said equivalent.

3. The formulation according to claim 2, which comprises0.5 to 2 mg of prednisolone or said equivalent.

I\ChLl1lb

Three patients were able to take part in the study in thetime available. One patient (3) was inadvertently given thefirst dose of treatment in the second week on the first nightin hospital. Patient 3 took prednisolone for the next twonights and remained in hospital for a fourth night withoutprednisolone treatment. This patient's assessments havebeen included normally in the first week, but in the secondWeek they have been used differently. Here, this patient'sresults have been included With those of the other patients inaccordance with the dose of prednisolone received. Thispatient's final assessment (no prednisolone the night before)therefore appears as an extra day after the other patients inthe study.

55

60

65

4. The formulation according to claim 3, which comprises

l to 1.25 mg of prednisolone or said equivalent.5. The formulation according to claim 1, adapted to

release at least 90% by weight of p rednisolone or saidequivalent 2 to 8 hours after administration.

6. The formulation according to claim 1, Wherein saidcorticosteroid is a glucocorticoid.

7. The formulation according to claim 1, wherein saidcorticosteroid is selected from the group consisting ofprednisone, budesonide, methylprednisolone, Iluticasone,betamethasone, and dellazacort.

8. The formulation according to claim 7, wherein saidcorticosteroid is prednisone.


34/78

Us 6,677,326 B2

879. A method for the treatment of a patient sulfering from

a condition selected from the group consisting of asthma,inflammatory bowel disease, psoriasis, psoriatic arthr itis,polymyalgia rheumatica, chronic obstructive pulmonary_|' . , . , .__ .1 _.|_ ..__ / ; : 1 -_ L _. Z4 J- - . . J - 4 L ..

13. The method according to claim 9, Wherein the for-

mulation is adapted to release at least 90% by weight of the

prednisolone or said equivalent 2 to 8 hours after adminis-

tration

polyarthropathies, which comprises administering to the

patient a unit dosage formulation comprising less than 2.5mg of prednisolone or an equivalent, equipotcnt amount ofanother corticosteroid.

10. The method according to claim 9, Wherein the for-mulation comprises at least 0.25 mg of prednisolone or saidequivalent.

11. The method according to claim 10, Wherein theformulation comprises 0.5 to 2 mg of the prednisolone orsaid equivalent.

12. ' l he method according to claim 11, wherein theformulation comprises 1 to 1.25 mg of the prednisolone orsaid equivalent.

>

10

:15

14. The method according to claim 9, wherein said

corticosteroid is a glucocorticoid.


corticosteroid is selected from the group consisting of

prednisone, budesonide, methylprednisolone, ilutacasone,

betamethasone, and deflazacort.

16. The method according to claim 15, Wherein said

corticosteroid is prednisone.


corticosteroid is administered between midnight and 6 a.m.

>| < >| = > l< =i < ' | =


35/78

EXHIBIT C


36/78

nlm|||||m1|I|IImIIIIIIIIIImuIII|ImluII|I|1|u|||1|u|IlulnlmUS008309124B2

(12> United States Patent (10) Patent No.: US 8,309,124 B2(45) Date of Patent: Nov . 13, 2012Vergnault et al

0 939 623 A1 9/1999106 79 10 A1 1/20011275 381 A1 1/2003

EP

EP

EP

(54) DELAYED RELEASE TABLET WITH

DEFINED CORE GEOMETRYJP 200 1 -0 10950

WO-92/00064WO-92/ 1 1845WO-93/ 19741WO-96/40078WO-0 1/08421WO-0 1/528 19WO-0 1/68056WO-0 1/80 824WO-02/00204Wo.0200204

W0_02/072033WO~02/072034W0.02072034

AA1A1A1A1A2A1A1A2A1A1

A2A2

1/2001

1/ 1 992

7/ 1 992

10/ 1 993

12/ 1996

2/20017/20019/2001

11/200 1

1/2002

1/2002

9/20029/20029/2002

(75) Inventors: Guy Vergnault, Kcmbs (FR); Pascal WOWOWOWOWOWOWOWOWOWOWOWOWOWOWO

Grenier, Kappelen (FR); Christophe

Dragan, Geispitzen (FR)

(73) Assignee: Jagotec AG,Mut'renz (CH)

*' ) Notice: Subject to any disclaimer, the term of thispatent is extended or adjusted under 35U.S.C. 154(b) by 0 days.

App1.No.: 13/424,069

WO-03/026626 4/2003WO-03 /075919 A1 9/2003O-2004/0285 10 4/2004

F il ed Mar. 19, 2012WO WWO

WOWOWO

WO-2004/093 843

WO-2004/093 850WO-2004/ 103349WO-200 5/027843

A1

A1A2A2

11/2004

11/200412/20043/2005

(65) Prior Publication Data

US 201 2/0177734 A1 Jul. 12, 2012

Related U.S. Application Data OTHER PUBLICATIONS

(63) Continuation of application No. 10/554,538, Hled asapplication No. PCT/1132004/001 693 on Apr. 23,

Conte et al. "Press-coated Tablets for Time-programmed Release of

Drugs," Biomaterials. 14.l3(1993): 1017-1023.Fukui et al. "Studies on Applicability of Press-Coated Tablets UsingHydroxypropylcellulose (HPC) in the Outer Shell for Time-ReleasePreparation." J. Controlled Release. 68.2(2000):215-223.GB Search Report dated Aug. 22, 2003 corresponding to GB0309342.4.

GB Search Report dated Oct. 23, 2003 corresponding to GB0309342.4.

2004, now Pat. No. 8,168,21 8

0) Foreign Application Priority Data

Apr. 24, 2003 (GB) 0309342.4

(51) I nt. Cl

424/464

International Search Report mailed Oct. 21, 2004 corresponding toPCT/152004/001693.

A61K 9/20 (2006.01)

(52) U .s .C1.

(58) Field of Classification SearchLin et al. "Compression Forces and Amount ofOuter Coating LayerAffecting the Time~Conf1ol1ed Disintegration of the Compression-

Coated Tablets Prepared by Direct Compression With MicronizedEthylcellulose." .Z Pharmaceutical Sciences.90.121 2005-2009.Zlaikina, A.P., "The Modern Therapeutic Tactics of InilaxmnaloryBowel Disease, Consilium Medicum." Gastroenterology. 6.1: 2004.

None

See application file for complete Search histoly.

(56) References Cited

U.S. PATENT DOCUMENTS>z< cited by examiner

5,279,8325,464,6335,567,6965,792,4766,183,7806,365,1856,488,9606,599,2846,620,439

2004/0018327

AAAAB 1

B1B 1

B2B1A1

1/199411/199510/1996

|< 8 /1 99 8

2/20014/2002

12/20027/20039/20031/2004

Greissinger et alConte et al.McGuire et al.HallgrenVan Ba1ken et al

Ritschel et al.BardsleyFaourMehtaWvnn et al.

Primary Examiner- Paul Dicldnson(74) Attorney, Agent,or Hrm - Muriel Liberto, Esq.; MintzLevin Cohn Ferris Glovsky and Popeo PC

424/465

(57) ABSTRACT

A tablet comprising a core containing an active agent, and acoating, the core being disposed within the coating such thatthe coating has a thickness about a longitudinal axis (X-Y) ofabout 4.85 to 4.95 nun. The position of the core within thecoating dictating that the active agent is released rapidly after

a lag time during which time no active agent is released.

2005/0008702 Al 1/2005 Fzfour et al2006/0057200 A1 3/2006 Schaefl ier


EP

EP

EP

0 463 877 A1 1/19920 673 645 A2 9/19950 776 660 A2 6/1997 14 Claims, 2 Drawing Sheets


37/78

U.S. Patent US 8,309,124 B2Sheet 1 of 2Nov. 13, 2012

BI

I

YX

II

A

FIG. 1


38/78

U.S. Patent US 8,309,124 B2Nov. 13, 2012 Sheet 2 of 2

% Release - Prednisone

f

. g

..1

/100.0

80.0

Ea> 60.0mcvGJ

'63nc

40.0

20.0

0.0iz '-fa d ~fz =fa Q ~rz


39/78

Us 8,309,124 B2

21peak plasma drug concentrations at a pre-detemiined time,irrespective of whether a patient is in a fed or fasted state.

Time controlled release formulations are known in the art

DELAYED RELEASE TABLET WITHDEFINED CORE GEOMETRY

that are able to deliver drug substances with a defined release5 :ale aller a lag time during which no drug substance is

RELATED APPLICATIONS

This application is a continuation ofU.S. Ser. No. 10/554,

538, filed on Jan. 16, 2007, which is a 35 U.S.C. 371 ofPCT/IB2004/001693, filed on Apr. 23, 2004, which claims

priority to GB Application No. 0309342.4, hled on Apr. 24,2003, all of which are incorporated herein by reference in 10

their entireties.

released. Such a dosage form is disclosed in WO 02/072033.

This dosage form is characterized by a coating containing anatural or synthetic gum that gels in the presence of aqueous

media, The coating acts as a bather to the ingress of aqueous

media into an active-agent-containing core and thereby cre-ating a lag time during which no drug substance is released.

This invention is concerned with a tablet comprising a core

containing a drug substance and a coating that is applied tosaid core by means of compression-coating techniques. The

tablet can contain all manner of drug substances, but is par-ticularly suitable for administering those that are advanta-geously released only after a predetermined lag time after

administration. The tablets are particularly suitable for

administering lucocorticosteroids selected from prednisone,prednisolone or methylprednisolone.

Research into the chronopharmacological field has dem-onstrated the importance of biological rhythms in drugtherapy. Very often, optimal clinical outcomes cannot beachieved if a drug is released constantly after ingestion. Thisis particularly die case if symptoms of a disease displaycircadian variations. ln such cas

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