Bristol-Myers Squibb Company v. Aurobindo Pharma Et. Al

8/12/2019 Bristol-Myers Squibb Company v. Aurobindo Pharma Et. Al.

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Liza M. WalshChristine I. Gannon

CONNELL FOLEY LLP85 Livingston Avenue

Roseland, New Jersey 07068-1765

(973) [email protected]@connellfoley.com

Attorneys for Plaintiff

Bristol-Myers Squibb Company

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF NEW JERSEY

BRISTOL-MYERS SQUIBB COMPANY,

Plaintiff,

v.

AUROBINDO PHARMA U.S.A., INC. and

AUROBINDO PHARMA LTD.,

Defendants.

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CA. No. __________

Electronically Filed

COMPLAINT FOR PATENT INFRINGEMENT

Plaintiff Bristol-Myers Squibb Company (BMS), through its attorneys, hereby alleges as

follows:

Nature of the Action

1. This is an action for patent infringement of United States Patent No. 6,087,383(the 383 patent) against defendants Aurobindo Pharma Ltd. and Aurobindo Pharma U.S.A.,

Inc. (collectively Aurobindo). This action relates to Abbreviated New Drug Application

(ANDA) No. 204806 filed by Aurobindo Pharma Ltd. with the United States Food and Drug

Administration (FDA) for approval to market a generic version of BMSs Reyataz drug

product. This action arises under the patent laws of the United States, 35 U.S.C. 100, et seq.


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Parties

2. BMS is a Delaware corporation having its corporate headquarters at 345 ParkAvenue, New York, New York.

3. BMS is engaged in the business of creating, developing, and bringing to marketrevolutionary biopharmaceutical products to help patients prevail in their fight against serious

diseases.

4. Upon information and belief, Aurobindo Pharma Ltd. is a company organized andexisting under the laws of India, having a place of business at Maitri Vihar, Plot #2, Ameerpet,

Hyderabad - 500038, Andhra Pradesh, India.

5. On information and belief, Aurobindo Pharma U.S.A., Inc. is a corporationorganized and existing under the laws of the State of Delaware, having its principal place of

business at 6 Wheeling Road, Dayton, New Jersey 08810 (Middlesex County). On information

and belief, Aurobindo Pharma U.S.A. is a wholly-owned subsidiary of Aurobindo Pharma Ltd.

Jurisdiction and Venue

6. This Court has jurisdiction over the subject matter of this action pursuant to 28U.S.C. 1331, 1338(a), 2201, and 2202.

7. Venue is proper in this judicial district pursuant to, inter alia, 28 U.S.C. 1391(b)and 1400(b).

8. This Court has jurisdiction over the defendants because, upon information andbelief, Aurobindo Pharma U.S.A., Inc. has a principal place of business in New Jersey and is the

subsidiary and agent of Aurobindo Pharma Ltd. Upon information and belief, Aurobindo Pharma

U.S.A., Inc. is acting as the agent of Aurobindo Pharma Ltd. with respect to ANDA No. 204806.


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9. This Court has jurisdiction over Aurobindo Pharma Ltd. because it has corporateoffices in Dayton, New Jersey, and Dayton, New Jersey is also the center of its U.S. operations.

Aurobindo Pharma Ltd. has at least three significant subsidiaries based in Dayton, New Jersey.

10. In the alternative, this Court has jurisdiction over Aurobindo Pharma Ltd. becausethe requirements of Federal Rule of Civil Procedure 4(k)(2)(A) are met.

11. This Court also has jurisdiction over the defendants because, inter alia, this actionarises from actions of the defendants directed toward New Jersey, and because the defendants have

purposefully availed themselves of the rights and benefits of New Jersey law by engaging in

systematic and continuous contacts with New Jersey. Upon information and belief, the defendants

regularly and continuously transact business within the state of New Jersey, including by selling

pharmaceutical products in New Jersey, either on their own or through affiliates. Upon

information and belief, the defendants derive substantial revenue from the sale of those products in

New Jersey and have availed themselves of the privilege of conducting business within the State of

New Jersey.

12. The defendants have previously been sued in this judicial district without objectingon the basis of lack of personal jurisdiction and have availed themselves of New Jersey courts

through the assertion of counterclaims.

13. For these reasons, and for other reasons that will be presented to the Court ifjurisdiction is challenged, the Court has personal jurisdiction over the defendants.

BMSs ReyatazProduct and the 383 Patent

14. On July 11, 2000, the U.S. Patent and Trademark Office duly and legally issued the383 patent, titled Bisulfide Salt of HIV Protease Inhibitor. A true and correct copy of the 383

patent is attached as Exhibit A. The claims of the 383 patent are valid and enforceable.

15. BMS is the owner of the 383 patent.


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16. The expiration date of the 383 patent is December 21, 2018.17. BMS is the holder of New Drug Application (NDA) No. 21-567, by which the

FDA granted approval for atazanavir sulfate capsules (Eq. 100 mg base, Eq., 150 mg base, Eq. 200

mg base, and Eq. 300 mg base). BMS markets and sells atazanavir sulfate capsules in the United

States under the trade name Reyataz.

18. The Food and Drug Administration Center for Drug Equivalence Evaluations (theOrange Book) lists the 383 patent for each of the strengths of Reyataz

approved by the FDA

under NDA No. 21-567.

Aurobindos ANDA Filing and Notice Letter

19. Upon information and belief, Aurobindo filed with the FDA ANDA No. 204806(the Aurobindo ANDA) under Section 505(j) of the Federal Food, Drug and Cosmetic Act (21

U.S.C. 355(j)), seeking approval to engage in the commercial manufacture, use, or sale of

Atazanavir Sulfate Capsules (Eq. 100 mg, 150 mg, 200 mg, and 300mg base) (the Aurobindo

ANDA Products) generic versions of the FDA-approved Reyataz

capsules, Eq. 100 mg, 150

mg, 200 mg, and 300 mg base before the expiration date of the 383 patent.

20. Upon information and belief, the Aurobindo ANDA Products contain atazanavirbisulfate.

21. Upon information and belief, the Aurobindo ANDA Products will be manufacturedby, or at the direction of, Aurobindo.

22. Upon information and belief, Aurobindo intends to directly or indirectly manufacture, use, market, sell, offer for sale, and distribute the Aurobindo ANDA products,

including within this District, upon regulatory approval.

23. By letter dated April 24, 2014 (Aurobindo Notice Letter), Aurobindo notifiedBMS that it had filed an ANDA for the Aurobindo ANDA Products, including a Paragraph IV


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certification asserting that the 383 patent is invalid, unenforceable, and/or will not be infringed

by the commercial manufacture, use, and sale of the Aurobindo ANDA products, and that it sought

approval of its ANDA prior to the expiration date of the 383 patent.

24. BMS received the Aurobindo Notice Letter on or about April 25, 2014.25. This action is being commenced before the expiration of forty-five days from the

date BMS received the Aurobindo Notice Letter.

Count 1

(Infringement of United States Patent No. 6,087,383)

26. BMS incorporates the preceding paragraphs as if fully set forth herein.27. Aurobindos submission of the Aurobindo ANDA to obtain approval to engage in

the commercial manufacture, use, offer to sell, or sale of the Aurobindo ANDA Products prior to

the expiration of the 383 patent constitutes infringement of claims 1 and 2 of the 383 patent under

35 U.S.C. 271(e)(2)(A).

28. Aurobindos commercial manufacture, use, offer to sell, sale, or importation of theAurobindo ANDA Products prior to the expiration of the 383 patent, and its inducement of and/or

contribution to such conduct, would further infringe claims 1 and 2 of the 383 patent under 35

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

29. Upon FDA approval of the Aurobindo ANDA, Aurobindo will infringe claims 1and 2 of the 383 patent by making, using, offering to sell, selling, or importing the Aurobindo

ANDA Products in the United States, and by actively inducing and/or contributing to infringement

by others, unless enjoined by this Court.

30. BMS will be irreparably harmed if Aurobindos infringement is not enjoined. BMSdoes not have an adequate remedy at law.


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PRAYER FOR RELIEF

WHEREFORE, Plaintiffs pray that this Court grant the following relief:

A. A declaration that the 383 patent is valid and enforceable;B. A declaration that Aurobindo has infringed a claim or claims of the 383

patent by submitting the aforesaid ANDA and certification, and that

Aurobindos making, using, offering to sell, selling, or importing theAurobindo ANDA Products and its inducement of and/or contribution to

such conduct by others, will infringe the 383 patent;

C. An Order providing that the effective date of any approval of the AurobindoANDA shall be a date which is not earlier than the expiration of the 383patent and all exclusivities to which Plaintiff is or becomes entitled;

D. An Order permanently enjoining Aurobindo and its affiliates andsubsidiaries, and each of its officers, agents, servants, and employees, frommaking, using, offering to sell, selling, or importing the Aurobindo ANDAProducts and from inducing or contributing to such conduct by others, until

after expiration of the 383 patent and all exclusivities to which Plaintiff isor becomes entitled;

E. Damages or other monetary relief to BMS if Aurobindo engages in thecommercial manufacture, use, offer to sell, sale, or importation of the

Aurobindo ANDA Products, or inducing or contributing to such conduct byothers, prior to expiration of the 383 patent and all exclusivities to which

Plaintiff is or becomes entitled, and that any such damages or monetary

relief be awarded to BMS with prejudgment interest; and,

F. Such further and other relief as this Court deems proper and just, includingany appropriate relief under 35 U.S.C. 285.


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Dated: June 4, 2014 CONNELL FOLEY LLP

/s/ Liza M. Walsh

OF COUNSEL:

Amy K. WigmoreAmanda Major

Tracey C. AllenWilmer Cutler Pickering Hale

and Dorr LLP1875 Pennsylvania Avenue, N.W

Washington, DC 20006(202) 663-6000

Liza M. Walsh

Christine I. Gannon

85 Livingston AvenueRoseland, New Jersey 07068973-535-0500

[email protected]




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RULE 11.2 CERTIFICATION

I hereby certify that, to the best of my knowledge, the matter in controversy is not the

subject of any other pending or anticipated litigation in any court or arbitration proceeding, nor are

there any non-parties known to Plaintiff that should be joined to this action. In addition, I

recognize a continuing obligation during the course of this litigation to file and to serve on all other

parties and with the Court an amended certification if there is a change in the facts stated in this

original certification.


/s/ Liza M. Walsh

OF COUNSEL:




Washington, DC 20006(202) 663-6000

Liza M. Walsh

Christine I. Gannon85 Livingston Avenue

Roseland, New Jersey 07068973-535-0500

[email protected]@connellfoley.com




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RULE 201.1 CERTIFICATION

I hereby certify that the above-captioned matter is not subject to compulsory arbitration in

that the Plaintiff seeks, inter alia, injunctive relief.


/s/ Liza M. Walsh

OF COUNSEL:




Washington, DC 20006(202) 663-6000

Liza M. Walsh

Christine I. Gannon85 Livingston Avenue

Roseland, New Jersey 07068973-535-0500

[email protected]@connellfoley.com




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EXHIBIT A


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United S t a t e s Patent [ 1 9 ]S i n g h e t a l .

US006087383A6 0 8 7 3 8 3

J u l . 1 1 , 2 0 0 0[ 1 1 ] P a t e n t Number:[ 4 5 ] Date o f P a t e n t :

[ 5 4 ] BISULFATE SALT OF HIV PROTEASEINHIBITOR[ 7 5 ] I n v e n t o r s : J a n a k S i n g h , L a W r e n c e v i l l e ;Madhusudhan P u d i p e d d i , P l a i n s b o r o ;Mark D . L i n d r u d , B a s k i n g R i d g e , a l l

o f NJ.[ 7 3 ] A s s i g n e e : B r i s t o l - M y e r s S q u i b b C o m p a n y ,

P r i n c e t o n , NJ.[ 2 1 ] A p p l . N o . : 0 9 / 2 1 7 , 5 3 8[ 2 2 ] F i l e d : D e c . 2 1 , 1 9 9 8

R e l a t e d US. A p p l i c a t i o n Data[ 6 0 ] P r o v i s i o n a l a p p l i c a t i o n N o . 6 0 / 0 7 1 , 9 6 8 , J a n . 2 0 1 9 9 8 .[ 5 1 ] I n t . C l . 7 A61K 1/44; C07D 213/56[ 5 2 ] US l . 51 4 /357; 546/332[ 5 8 ] Field of Search 546/332; 5 1 4 / 3 57[ 5 6 ] R e f e r e n c e s C i t e d

U . S . PATENT DOCUMENTS5 849 911 1 2 / 1 999 Fassler e t a l . . . . . . . . . . . . . . . . . . . . . . . . . 5 4 4 / 3 3 5

FOREIGN PATENT DOCUMENTSWO97/40029 1 0 / 1 997 W PO

P r i m a r y ExaminerBernard D e n t ZA t t o r n e y , A g e n t , o r FirmDavid M. Morse[ 5 7 ] ABSTRACTT h e p r e s e n t i n v e n t i o n p r o v i d e s t h e c r y s t a l l i n e b i s u l f a t e s a l to f t h e f o r m u l a

0 O

oH

/ \ N T O C H 3 H 2 S O 40

W h i c h i s f o u n d t o h a v e u n e x p e c t e d l y h i g h s o l u b i l i t y /d i s s o l u t i o n r a t e and o r a l b i o a v a i l a b i l i t y r e l a t i v e t o t h e f r e eb a s e form o f t h i s a Z a p e p t i d e HIV p r o t e a s e i n h i b i t o r comp o u n d .

2 C l a i m s , 5 Drawing S h e e t s


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U.S. Patent J u l . 1 1 2 0 0 0 S h e e t 1 0 f 5 6,087,383

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U.S. Patent J u l 1 1 2 0 0 0 S h e e t 2 0 f 5 6 087 383

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BISULFATE SALT OF HIV PROTEASEINHIBITORT h i s a p p l i c a t i o n c l a i m s p r i o r i t y f r o m P r o v i s i o n a l A p p l i

c a t i o n 6 0 / 0 7 1 , 9 6 8 ? l e d J a n . 2 0 , 1 9 9 8 .BACKGROUND OF THE INVENTION

1 . F i e l d o f t h e I n v e n t i o nT h e p r e s e n t i n v e n t i o n p r o v i d e s t h e n o v e l c r y s t a l l i n e b i s u lf a t e s a l t o f t h e a Z a p e p t i d e HIV p r o t e a s e i n h i b i t o r o f t h e

f o r m u l a

ocH3\NHH3CO NH

W h i c h e x h i b i t s u n e x p e c t e d l y s u p e r i o r a q u e o u s s o l u b i l i t y /d i s s o l u t i o n b e h a v i o r c o m p a r e d t o o t h e r s a l t s , a n d s i g n i ?c a n t l y i m p r o v e d o r a l b i o a v a i l a b i l i t y i n a n i m a l s c o m p a r e d t ot h e f r e e b a s e . The b i s u l f a t e s a l t i s t h u s u s e f u l f o r pharmac e u t i c a l d o s a g e f o r m s o f t h e a b o v e - i n d i c a t e d p r o t e a s ei n h i b i t o r , p a r t i c u l a r l y o r a l d o s a g e f o r m s .2 . B a c k g r o u n d A r t

P u b l i s h e d PCT a t e n t a p p l i c a t i o n WO 7 / 4 0 0 2 9 d i s c l o s e sa s e r i e s o f a Z a p e p t i d e HIV p r o t e a s e i n h i b i t o r s r e p o r t e d t oh a v e a h i g h d e g r e e o f i n h i b i t o r y a c t i v i t y a g a i n s t t h e HIVv i r u s . One o f t h e a g e n t s i n c l u d e d W i t h i n t h e s c o p e o f W9 7 / 4 0 0 2 9 i s t h e compound h a v i n g t h e s t r u c t u r a l f o r m u l a

a n d t h e c h e m i c a l name [ 3 S - ( 3 R * , 8 R * , 9 R * , 1 2 R * ) ] - 3 , 1 2b i s ( 1 , 1 - d i m e t h y l e t h y l ) - 8 - h y d r o x y - 4 , 1 1 - d i o x o - 9p h e n y l m e t h y l ) - 6 - [ [ 4 - 2 - p y r i d i n y l ) p h e n y l m e t h y l ] - 2 , 5 , 6 , 1 0 ,1 3 - p e n t a a Z a t e t r a d e c a n e d i o i c ] a c i d , d i m e t h y l e s t e r a n d i su n d e r e v a l u a t i o n a s a p o s s i b l e s e c o n d g e n e r a t i o n HIV r ot e a s e i n h i b i t o r .W 7 / 4 0 0 2 9 d i s c l o s e s t h e f r e e b a s e f o r m o f a Z a p e p t i d e

d e r i v a t i v e s s u c h a s compound a n d a l s o v a r i o u s pharmac e u t i c a l l y a c c e p t a b l e a c i d a d d i t i on s a l t s . W h i l e s e v e r a lo r g a n i c a n d i n o r g a n i c a c i d s a r e m e n t i o n e d a s p o s s i b l e s a l t

10

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2f o r m i n g a g e n t s , i n c l u d i n g s u l f u r i c a c i d , t h e r e i s n o m e n t i o no f t h e p a r t i c u l a r b i s u l f a t e s a l t W h i c h i s t h e s u b j e c t o f t h ep r e s e n t a p p l i c a t i o n .

SUMMARY OF THE INVENTIONThe p r e s e n t i n v e n t i o n p r o v i d e s t h e b i s u l f a t e s a l t o f c o mp o u n d a b o v e h a v i n g t h e s t r u c t u r a l f o r m u l a

OHHN

H3CO NHo

oH\ N O C H 3 H 2 S O 4H T

DETAILED DESCRIPTION OF THEINVENTION

Com p ound a s d i s c l o s e d a b o v e i s a Weak o r g a n i c b a s eW i t h a n a q u e o u s s o l u b i l i t y o f l e s s t h a n 1 pg mL t 2413 C .The r y s t a l l i n e f r e e b a s e form a s a s u s p e n s i o n i n W a t e r o r o i lh a s p o o r o r a l b i o a v a i l a b i l i t y i n a n i m a l s , p r o b a b l y b e c a u s e o fi t s e x t r e m e l y l o W s o l u b i l i t y i n t h e s e v e h i c l e s .

F o r d e v e l o p m e n t o f p h a r m a c e u t i c a l f o r m u l a t i o n s , p a r t i c ul a r l y o r a l d o s a g e f o r m s , t h e a c t i v e i n g r e d i e n t m u s t h a v es u f f i c i e n t o r a l b i o a v a i l a b i l i t y . S i n c e t h e f r e e b a s e f o r m o fcompound d i d n o t p o s s e s s s u c h b i o a v a i l a b i l i t y , a c i d a d d it i o n s a l t s W e r e e x p l o r e d by t h e p r e s e n t i n v e n t o r s . A umbero f c o m m o nl y used a c i d a d d i t i o n s a l t s such a s t h eh y d r o c h l o r i d e , b e n Z e n e s u l f o n a t e , m e t h a n e s u l f o n a t e ,p - t o l u e n e s u l f o n a t e , p h o s p h a t e , n i t r a t e , 1 , 2e t h a n e d i s u l f o n a t e , i s e t h i o n a t e a n d s u l f a t e Were e v a l u a t e d , i na d d i t i o n t o t h e b i s u l f a t e s a l t o f t h e p r e s e n t i n v e n t i o n . A l l o ft h e s e s a l t s i n t h e i r c r y s t a l l i n e f o r m e x h i b i t e d l o W e r a q u e o u ss o l u b i l i t y ( 1 3 mg mL r l e s s a t 2 4 1 3 C . ) t h a n t h e b i s u l f a t eWhich had a s o l u b i l i t y u n d e r t h e same c o n d i t i o n s o f a p p r o x im a t e l y 4 5 m g / m L .

S o l i d s t a t e t r a n s f o r m a t i o n W a s observed When t h e o t h e ra c i d a d d i t i o n s a l t s mentioned a b o v e Were s u s p e n d e d i nW a t e r , p r o b a b l y d u e t o t h e i r d i s s o c i a t i o n t o form t h e f r e eb a s e . I n t h e m a j o r i t y o f c a s e s , t h i s t r a n s f o r m a t i o n Wasa c c o m p a n i e d by g e l f o r m a t i o n . U n l i k e t h e o t h e r s a l t s ment i o n e d a b o v e , t h e e x t r a p r o t o n o f t h e b i s u l f a t e s a l t p r e v e n t st h e c o n v e r s i o n t o t h e f r e e b a s e W h i c h , a s mentioned a b o v e ,i s v e r y i n s o l u b l e i n W a t e r a n d h a s p o o r o r a l b i o a v a i l a b i l i t y .The u n u s u a l s o l u b i l i t y b e h a v i o r o f t h e b i s u l f a t e s a l t i n W a t e ri s f u r t h e r e l a b o r a t e d i n t h e f o l l o W i n g .


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6 , 0 8 7 , 3 8 33

I n g e n e r a l , c o n v e r s i o n o f s a l t s t o t h e u n i o n i z e d form o rv i c e v e r s a can be e x p l a i n e d on t h e b a s i s o f p H - s o l u b i l i t yt h e o r y . The s o l u b i l i t y o f t h e f r e e b a s e i n W a t e r Was d e t e rmined a s a f u n c t i o n o f pH t 2413 C . and i s shoWn b e l o W .The pH a t W h i c h t h e compound e x h i b i t s t h e h i g h e s t s o l ub i l i t y i s r e f e r r e d t o a s pHmwc a n d Was f o u n d t o b e a p p r o x im a t e l y 1 . 2 . I t h a s b e e n r e p o r t e d i n t h e l i t e r a t u r e t h a t a tpH>pHmax o f a W e a k l y b a s i c o r g a n i c c o m p o u n d , t h e e q u il i b r i u m s o l i d p h a s e i n a n aqueous s u s p e n s i o n o f t h e c o mp o u n d i s t h e f r e e b a s e . A t pH


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6 , 0 8 7 , 3 8 35

( 0 . 0 2 1 3 m o l e ) o f f r e e b a s e compound a n d 1 1 3 mL f 2 0 0p r o o f e t h a n o l W e r e a d d e d W i t h s t i r r i n g . T o t h i s s u s p e n s i o n ,1 . 2 8 mL o n c e n t r a t e d s u l f u r i c a c i d Was added dropWise o v e r90 s e c o n d s . A f t e r t h e a d d i t i o n o f s u l f u r i c a c i d , a c l e a ramber-colored s o l u t i o n Was o b t a i n e d . The s o l u t i o n Wasp o l i s h ? l t e r e d u s i n g 1 Whatman ? l t e r p a p e r a n d WashedW i t h 5 mL f 200 p r o o f e t h a n o l . To t h i s s o l u t i o n Was added5 8 mL f h e p t a n e a n d 3 7 . 5 m g ( 0 . 2 5 W t ) o f s e e d c r y s t a l so f t h e compound o f f o r m u l a I I f o l l o W e d by 5 5 mL o fa d d i t i o n a l h e p t a n e . The r e s u l t i n g m i x t u r e Was s t i r r e d f o r 6h o u r s a t 300 r p m . The r e s u l t i n g c r y s t a l s l u r r y Was ? l t e r e da n d W a s h e d W i t h 5 0 mL t h a n o l / h e p t a n e ( 1 : 1 ) s o l u t i o n a n dd r i e d under vacuum a t 6 0 C . o v e r n i g h t t o a f f o r d 1 5 . 1 1 g o ft h e d e s i r e d c r y s t a l l i n e b i s u l f a t e s a l t ( 8 8 . 4 m o l e i e l d )h a v i n g f o r m u l a I I a b o v e .

C h a r a c t e r i z i n g P r o p e r t i e s o f B i s u l f a t e S a l tA n a l . C a l c d . f o r C 3 8 H 5 2 N 6 O . 1 . 0 H 2 S O 4 : C , 5 6 . 8 4 ; H ,

6 . 7 8 ; N , 1 0 . 3 7 ; S , 3 . 9 9 . F o u n d : C , 5 6 . 7 2 ; H , 6 . 6 5 ; N , 1 0 . 4 1 ;S , 3 . 8 3 . m . p . 1 9 5 . 0 , H2O=0.28E x a m p l e 2

P r e p a r a t i o n o f B i s u l f a t e S a l t f r o m A c e t o n e5M HZSO4 ( 8 . 5 2 mL, 4 2 . 6 mM) Was a d d e d d r o p W i s e t oa s u s p e n s i o n o f t h e f r e e b a s e compound o f f o r m u l a I ( 3 0 . 0g . , 4 2 . 6 mM) n a c e t o n e ( 2 1 3 mL) t i r r e d m e c h a n i c a l l y i n a

50 C . o i l - b a t h . Aclear s o l u t i o n Was o b t a i n e d a l m o s t i m m ed i a t e l y . The s o l u t i o n Was s e e d e d W i t h c r y s t a l s o f t h e f r e eb a s e compound o f f o r m u l a I I . A f t e r tWo m i n u t e s , a p r e c i p it a t e formed Which be came a p a s t e . The mixture Was s t i r r e da t 5 0 C . f o r one h o u r , a t 2 5 C . f o r 3 0 minutes and a t 0 C .f o r 2 h o u r s . The s o l i d Was ? l t e r e d and t h e ? r s t ? l t r a t e Wasu s e d t o t r a n s f e r t h e r e m a i n i n g m a t e r i a l i n t h e ?ask t o t h e? l t r a t i o n f u n n e l . The p r o d u c t Was Washed W i t h a c e t o n e , t h e nh e p t a n e , a n d d r i e d u n d e r vacuum o v e r n i g h t t o g i v e 3 1 . 4 8 g( c o r r e c t e d y i e l d 92 ) o f t h e b i s u l f a t e s a l t o f f o r m u l a I I m . p .198199 C . d e c .

A n a l . C a l c d . C 3 8 H 5 2 N 6 O 7 1 0 H 2 S O 4 . 0 . 2 H 2 O : c , 5 6 . 5 9 ;H , 6 . 8 0 ; N , 1 0 . 4 2 , s , 3 . 9 8 ; H 2 O , 0 . 4 5 . F o u n d : c , 5 6 . 6 6 ; H ,6 . 7 8 ; N , 1 0 . 5 0 , s , 4 . 2 0 , H 2 O , 0 . 4 5 ( K F ) .E x a m p l e 3

P r e p a r a t i o n o f B i s u l f a t e S a l t f r o m I s o p r o p a n o lA q u e o u s s u l f u r i c a c i d ( 5 . 0 M, 0 . 2 0 mL, 1 mM) Was a d d e dt o a s u s p e n s i o n o f t h e f r e e b a s e c o m p o u n d o f f o r m u l a I

( 0 . 7 0 4 g , 1 . 0 0 mM) i n i s o p r o p a n o l ( 4 . 0 mL) c h i l l e d i n a ni c e - b a t h . The i c e - b a t h Was removed and t h e m i x t u r e s t i r r e da t r o o m t e m p e r a t u r e . The s u s p e n s i o n had d i s s o l v e d a f t e r 1 5m i n u t e s . The s o l u t i o n Was s e e d e d W i t h c r y s t a l s p r e p a r e d a si n Examples 1 o r 2 above a n d s t i r r e d f o r 5 h o u r s . The s o l i dWas ? l t e r e d and t h e ? l t r a t e Was used t o t r a n s f e r t h e s o l i dfrom t h e ?ask t o t h e f u n n e l . The p r o d u c t Was Washed W i t hh e p t a n e a n d d r i e d u n d e r vacuum t o g i v e 0 . 7 5 2 g o f c r y s t a ll i n e b i s u l f a t e s a l t o f f o r m u l a I I y i e l d 90 , m p . 1 6 0 1 9 0 C . , d e c .

A n a l . C a l c d . f o r C38H52N6O710 H 2 S O 4 . 2 . 0 H 2 O ; C ,5 4 . 4 0 ; H , 6 . 9 7 ; N , 1 0 . 0 2 ; S , 3 . 8 2 ; H 2 O , 4 . 2 9 . F o u n d : C ,5 4 . 2 5 ; H , 6 . 7 3 ; N , 1 0 . 0 2 ; S , 3 . 6 7 ; H 2 O , 4 . 5 3T h e c r y s t a l s o b t a i n e d f r o m i s o p r o p a n o l shoWed a poWderx - r a y d i f f r a c t i o n p a t t e r n d i f f e r e n t f r o m t h e c r y s t a l s o b t a i n e d

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6from a c e t o n i t r i l e , e t h a n o l - h e p t a n e o r a c e t o n e . They a r e n o Wr e f e r r e d t o a s T y p e - I I c r y s t a l s . The T y p e - I c r y s t a l s a p p e a r t ob e a n a n h y d r o u s / d e s o l v a t e d c r y s t a l l i n e m a t e r i a l W h i l e t h eT y p e - I I c r y s t a l s a r e a h y d r a t e d , h y g r o s c o p i c c r y s t a l l i n ef o r m .

E x a m p l e 4P r e p a r a t i o n o f C a p s u l e F o r m u l a t i on s o f B i s u l f a t e

S a l tA . C a p s u l e s ( 5 0 a n d 2 0 0 mg f r e e b a s e e q u i v a l e n t )C a p s u l e s a r e p r o v i d e d f o r o r a l a d m i n i s t r a t i o n i n Which t h e

c a p s u l e i s a s i Z e 0 , g r a y , o p a q u e , h a r d g e l a t i n c a p s u l ec o n t a i n i n g t h e b i s u l f a t e s a l t o f formula I I f o r m u l a t e d a s aW e t g r a n u l a t i o n W i t h l a c t o s e , c r o s p o v i d o n e a n d m a g n e s i u ms t e a r a t e .

B . C a p s u l es ( 1 0 0 m g f r e e b a s e e q u i v a l e n t )C a p s u l e s a r e p r o v i d e d f o r o r a l a d m i n i s t r a t i o n i n Which t h e

c a p s u l e i s a s i Z e 0 , g r a y , o p a q u e , h a r d g e l a t i n c a p s u l ec o n t a i n i n g t h e b i s u l f a t e s a l t o f f o r m u l a I I s u s p e n d e d i nG e l u c i r e 4 4 / 1 4 . G e l u c i r e 4 4 / 1 4 i s a s a t u r a t e d p o l y g l y c o l i Z e dg l y c e r i d e c o n s i s t i n g o f m o n o - , d i - a n d t r i g l y c e r i d e s a n dmono- a n d d i - f a t t y a c i d e s t e r s o f p o l y e t h y l e n e g l y c o l . Caps u l e s a r e p r e p a r e d by m e l t i n g G e l u c i r e 4 4 / 1 4 a t 4 5 7 0 C .f o l l o W e d b y a d d i t i o n o f t h e b i s u l f a t e s a l t W i t h s t i r r i n g . Them o l t e n m i x t u r e i s ? l l e d i n t o h a r d g e l t i n c a p s u l e s a n da l l o W e d t o c o o l a n d s o l i d i f y .We l a i m :1 . The b i s u l f a t e s a l t h a v i n g t h e f o r m u l a

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