Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 1 of 155 PageID: 398 UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY

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1 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 1 of 155 PageID: 398 Charles M. Lizza William C. Baton Sarah A. Sullivan Saul Ewing LLP One Riverfront Plaza, Suite 1520 Newark, NJ (973) clizza@saul.com Attorneys for Plaintiff Supernus Pharmaceuticals, Inc. UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY SUPERNUS PHARMACEUTICALS, INC., Plaintiff, Civil Action No (SDW) (SCM) v. ACTAVIS INC., et al., Defendants. SUPERNUS PHARMACEUTICALS, INC., v. Plaintiff, Civil Action No (SDW) (SCM) (Filed Electronically) ZYDUS PHARMACEUTICALS (USA) INC., et al., Defendants. SUPERNUS PHARMACEUTICALS, INC., Plaintiff, Civil Action No (SDW) (SCM) v. PAR PHARMACEUTICAL COMPANIES, INC., et al., Defendants.

2 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 2 of 155 PageID: 399 SECOND AMENDED COMPLAINT AGAINST ZYDUS PHARMACEUTICALS (USA) INC. AND CADILA HEALTHCARE LIMITED Plaintiff Supernus Pharmaceuticals, Inc. ( Supernus ) by its undersigned attorneys, for its Second Amended Complaint against defendants Zydus Pharmaceuticals (USA) Inc. ( Zydus USA ) and Cadila Healthcare Limited ( Zydus Cadila ) (collectively, Defendants ), 1 herein alleges as follows: NATURE OF THE ACTION 1. This is a civil action for patent infringement arising under the patent laws of the United States, Title 35, United States Code, involving United States Patent Nos. 8,298,576 ( the 576 patent ), 8,298,580 ( the 580 patent ), 8,663,683 ( the 683 patent ), 8,877,248 ( the 248 patent ), 8,889,191 ( the 191 patent ), and 8,992,989 ( the 989 patent ) attached hereto as Exhibits A, B, C, D, E, and F respectively. THE PARTIES 2. Plaintiff Supernus is a corporation organized and existing under the laws of Delaware, having its principal place of business at 1550 East Gude Drive, Rockville, Maryland Upon information and belief, Zydus Cadila is a public limited liability company organized and existing under the laws of India, having its principal place of business at Zydus Tower, Satellite Cross Roads, Ahmedabad Gujarat, India. 4. Upon information and belief, Zydus Cadila is in the business of, inter alia: (i) the development and manufacture of generic pharmaceutical products for sale throughout the United States, including throughout the State of New Jersey; (ii) through its various subsidiaries, including defendant Zydus USA, the preparation, submission, and filing of Abbreviated New 1 Defendants have consented to Supernus s amendment of its Complaint pursuant to Fed. R. Civ. P. 15(a)(2). (ECF No. 24 at 14.) 2

3 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 3 of 155 PageID: 400 Drug Applications ( ANDAs ) seeking U.S. Food and Drug Administration ( FDA ) approval to market generic drugs throughout the United States; and (iii) through its various subsidiaries, including defendant Zydus USA, the distribution of generic pharmaceutical products for sale throughout the United States, including throughout the State of New Jersey. 5. Zydus Cadila s Annual Report states that [t]he Company s operations in the US are spearheaded by its wholly-owned subsidiary Zydus Pharmaceuticals (USA) Inc and that [t]he Company filed a record 50 ANDAs with the USFDA during the year, taking the cumulative ANDA filings to 227. Cadila Healthcare Limited Annual Report , at 9. Zydus Cadila s Annual Report further states, [o]ur US business was the key driver in growth. We are currently the 8th largest generic company in the US in terms of prescriptions. Id. at Upon information and belief, Zydus USA is a corporation organized and existing under the laws of New Jersey, having its principal place of business at 73 Route 31 North, Pennington, New Jersey Upon information and belief, Zydus USA is registered as a wholesale drug distributor in the State of New Jersey under the registration number Upon information and belief, Zydus USA is wholly owned by defendant Zydus Cadila. Upon information and belief, Zydus USA acts at the direction of, under the control of, and for the direct benefit of Zydus Cadila and is controlled and/or dominated by Zydus Cadila. Upon information and belief, Zydus USA and Zydus Cadila have at least one officer and/or director in common. 8. Upon information and belief, Zydus USA is in the business of: (i) developing generic pharmaceutical products for sale throughout the United States, including throughout the State of New Jersey; (ii) preparing, submitting, and filing Abbreviated New Drug Applications ( ANDAs ) seeking U.S. Food and Drug Administration ( FDA ) approval to market generic 3

4 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 4 of 155 PageID: 401 drugs throughout the United States; and (iii) distributing generic pharmaceutical products for sale throughout the United States, including throughout the State of New Jersey. 9. Upon information and belief, Zydus USA prepared and then submitted and filed ANDA No ( the Zydus ANDA ) with the FDA seeking approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of generic topiramate extended-release capsules, 25 mg, 50 mg, and 100 mg ( the Zydus Products ). 10. Upon information and belief, Zydus Cadila manufactures and Zydus USA distributes generic pharmaceutical products for which Zydus USA is the named ANDA applicant, including Donepezil Hydrochloride Tablets (5 mg and 10 mg); Divalproex Sodium Capsules (125 mg); and Gabapentin Tablets (600 mg and 800 mg). Upon information and belief, Defendants derive substantial revenue from the sale of such generic pharmaceutical products. JURISDICTION AND VENUE 11. This Court has jurisdiction over the subject matter of this action pursuant to 28 U.S.C and 1338(a). 12. This Court has personal jurisdiction over Zydus Cadila because, inter alia: (i) Zydus Cadila, together with its subsidiary Zydus USA, has committed, induced, or contributed to acts of patent infringement in New Jersey; (ii) Zydus Cadila regularly does or solicits business in New Jersey and/or derives substantial revenue from services or things used or consumed in New Jersey; (iii) Zydus Cadila is doing business in New Jersey and maintains continuous and systemic contacts with this Judicial District; and (iv) Zydus Cadila has availed itself of the rights, benefits, and privileges of this Court by asserting claims in at least five prior New Jersey actions (Zydus Pharms. (USA) Inc., et al. v. Gilead Sciences, Inc., Civil Action No ; Otsuka Pharm. Co., Ltd. v. Zydus Pharms. USA Inc., et al., Civil Action No ; Actelion Pharms. Ltd., et al. v. Apotex Inc., et al., Civil Action No ; Depomed, Inc. v. 4

5 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 5 of 155 PageID: 402 Zydus Pharms. USA Inc., et al., Civil Action No ; and Takeda Pharm. Co. Ltd., et al. v. Zydus Pharms. (USA) Inc., et al., Civil Action No ). 13. This Court has personal jurisdiction over Zydus USA because, inter alia: (i) Zydus USA s principal place of business is located in New Jersey; (ii) Zydus USA, together with Zydus Cadila, has committed, induced, or contributed to acts of patent infringement in New Jersey; (iii) Zydus USA regularly does or solicits business in New Jersey and/or derives substantial revenue from services or things used or consumed in New Jersey; (iv) Zydus USA is doing business in New Jersey and maintains continuous and systematic contacts with this Judicial District; and (v) Zydus USA has availed itself of the rights, benefits, and privileges of this Court by asserting claims in at least five prior New Jersey actions (Zydus Pharms. (USA) Inc., et al. v. Gilead Sciences, Inc., Civil Action No ; Otsuka Pharm. Co., Ltd. v. Zydus Pharms. USA Inc., et al., Civil Action No ; Actelion Pharms. Ltd., et al. v. Apotex Inc., et al., Civil Action No ; Depomed, Inc. v. Zydus Pharms. USA Inc., et al., Civil Action No ; and Takeda Pharm. Co. Ltd., et al. v. Zydus Pharms. (USA) Inc., et al., Civil Action No ). 14. Venue is proper in this Judicial District under 28 U.S.C. 1391(b) and (c), and 1400(b). FACTS AS TO ALL COUNTS 15. Supernus owns New Drug Application ( NDA ) No , which was approved by the FDA for the manufacture and sale of topiramate extended-release capsules, 25 mg, 50 mg, 100 mg, and 200 mg, which Supernus markets under the name Trokendi XR. 16. Trokendi XR is an antiepileptic drug indicated for: (i) initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures; (ii) adjunctive therapy in patients 6 years of age and older with partial onset or primary 5

6 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 6 of 155 PageID: 403 generalized tonic-clonic seizures; and (iii) adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome. 17. The 576 patent, entitled Sustained-Release Formulations of Topiramate was duly and legally issued by the United States Patent and Trademark Office on October 30, 2012, to Supernus upon assignment from inventors Likan Liang, Hua Wang, Padmanabh P. Bhatt, and Michael L. Vieira. Supernus owns all rights, title, and interest in the 576 patent. 18. The 580 patent, entitled Sustained-Release Formulations of Topiramate was duly and legally issued by the United States Patent and Trademark Office on October 30, 2012, to Supernus upon assignment from inventors Likan Liang, Hua Wang, Padmanabh P. Bhatt, and Michael L. Vieira. Supernus owns all rights, title, and interest in the 580 patent. 19. The 683 patent, entitled Sustained-Release Formulations of Topiramate was duly and legally issued by the United States Patent and Trademark Office on March 4, 2014, to Supernus upon assignment from inventors Likan Liang, Hua Wang, Padmanabh P. Bhatt, and Michael L. Vieira. Supernus owns all rights, title, and interest in the 683 patent. 20. The 248 patent, entitled Sustained-Release Formulations of Topiramate was duly and legally issued by the United States Patent and Trademark Office on November 4, 2014, to Supernus upon assignment from inventors Likan Liang, Hua Wang, Padmanabh P. Bhatt, and Michael L. Vieira. Supernus owns all rights, title, and interest in the 248 patent. 21. The 191 patent, entitled Sustained-Release Formulations of Topiramate was duly and legally issued by the United States Patent and Trademark Office on November 18, 2014, to Supernus upon assignment from inventors Likan Liang, Hua Wang, Padmanabh P. Bhatt, and Michael L. Vieira. Supernus owns all rights, title, and interest in the 191 patent. 22. The 989 patent, entitled Sustained-Release Formulations of Topiramate was duly and legally issued by the United States Patent and Trademark Office on March 31, 2015, to 6

7 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 7 of 155 PageID: 404 Supernus upon assignment from inventors Likan Liang, Hua Wang, Padmanabh P. Bhatt, and Michael L. Vieira. Supernus owns all rights, title, and interest in the 989 patent. 23. Pursuant to 21 U.S.C. 355(b)(1), the 576, 580, 683, 248, 191, and 989 patents are listed in the FDA s publication titled Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book ) as covering Trokendi XR. Supernus submitted the 576, 580, 683, 248, 191, and 989 patents to the FDA to be listed in the Orange Book for NDA No Upon information and belief, Defendants worked in concert to prepare, and then submit and file the Zydus ANDA with the FDA under 505(j) of the Federal Food, Drug, and Cosmetic Act ( FDCA ) (codified at 21 U.S.C. 355(j)), seeking approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of the Zydus Products and included a paragraph IV certification seeking approval before the expiration of the 576, 580, 683, 248, 191, and 989 patents U.S.C. 355(j)(2)(B)(iv)(II) requires that a letter notifying a patent holder of the filing of an ANDA containing a paragraph IV certification include a detailed statement of the factual and legal basis of the opinion of the applicant that the patent is invalid or will not be infringed. Likewise, 21 C.F.R (c)(6) requires that such a letter include [a] detailed statement of the factual and legal basis of the applicant s opinion that the patent is not valid, unenforceable, or will not be infringed. The detailed statement must include (i) [f]or each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is not infringed and (ii) [f]or each claim of a patent alleged to be invalid or unenforceable, a full and detailed explanation of the grounds supporting the allegation. 21 C.F.R (c)(6)(i)-(ii). 7

8 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 8 of 155 PageID: Supernus received a letter dated October 9, 2014, which was purportedly sent pursuant to 505(j)(2)(B)(iv) of the FDCA, regarding the Zydus Products and the 576, 580, and 683 patents (the October 9 Notice Letter ). 27. The October 9 Notice Letter was signed by Brij Khera, Ph.D., Executive Vice President and Chief Legal Officer, Zydus Pharmaceuticals (USA) Inc. 28. The October 9 Notice Letter does not include any non-infringement contentions unique to claims 2-14, 16-18, 20-26, or of the 576 patent, claims 2-12, 14-16, 18-27, or of the 580 patent, or claims 2-17, 19, or of the 683 patent. 29. The October 9 Notice Letter does not include any invalidity contentions to any claim of the 576, 580, or 683 patent. 30. Supernus received a letter dated February 19, 2015, which was purportedly sent pursuant to 505(j)(2)(B)(iv) of the FDCA, regarding the Zydus Products and the 248 and 191 patents (the February 19 Notice Letter ). 31. The February 19 Notice Letter was signed by Brij Khera, Ph.D., Executive Vice President and Chief Legal Officer, Zydus Pharmaceuticals (USA) Inc. 32. The February 19 Notice Letter does not include any non-infringement contentions to claims 1-2, 4-12, and of the 248 patent. 33. The February 19 Notice Letter does not include any non-infringement contentions unique to claims 2-24 of the 191 patent. 34. The February 19 Notice Letter does not include any invalidity contentions to any claim of the 191 patent. 35. Supernus received a letter dated April 21, 2015, which was purportedly sent pursuant to 505(j)(2)(B)(iv) of the FDCA, regarding the Zydus Products and the 989 patent (the April 21 Notice Letter ). 8

9 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 9 of 155 PageID: The April 21 Notice Letter was signed by Brij Khera, Ph.D., Executive Vice President and Chief Legal Officer, Zydus Pharmaceuticals (USA) Inc. 37. The April 21 Notice Letter does not include any non-infringement contentions to claims 14 and of the 989 patent. forth herein. FIRST COUNT (Defendants Infringement of the 576 Patent) 38. Plaintiff repeats and re-alleges each of the foregoing Paragraphs as if fully set 39. Upon information and belief, Defendants seek FDA approval for the manufacture, use, marketing, sale, and/or distribution of the Zydus Products. 40. Upon information and belief, Defendants included in ANDA No a paragraph IV certification to the 576 patent to obtain approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of the Zydus Products before the expiration of the 576 patent. 41. Upon information and belief, Defendants will commercially manufacture, use, sell, offer for sale, and/or import the Zydus Products upon, or in anticipation of, FDA approval. 42. The submission and filing of ANDA No with a paragraph IV certification to the 576 patent for the purpose of obtaining approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products before the expiration of the 576 patent is an act of infringement by Defendants of one or more claims of the 576 patent under 35 U.S.C. 271(e)(2)(A). 43. Upon information and belief, Defendants commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products that are the subject of ANDA No will infringe, directly and/or indirectly (including by inducement and/or 9

10 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 10 of 155 PageID: 407 contributory infringement), one or more claims of the 576 patent under 35 U.S.C. 271(a), 35 U.S.C. 271(b), and/or 35 U.S.C. 271(c). 44. Upon information and belief, the sale or offer for sale of the Zydus Products by Defendants would induce and/or contribute to third party infringement of one or more claims of the 576 patent under 35 U.S.C Upon information and belief, Zydus Cadila is jointly and severally liable for Zydus USA s infringement of one or more claims of the 576 patent. 46. Upon information and belief, Zydus Cadila knowingly induced Zydus USA to infringe and/or contributed to Zydus USA s infringement of one or more claims of the 576 patent. 47. Upon information and belief, Zydus Cadila actively induced, encouraged, aided, or abetted Zydus USA s preparation, submission and filing of ANDA No with a paragraph IV certification to the 576 patent. 48. Zydus Cadila s inducement, encouragement, aiding, or abetting of Zydus USA s preparation, submission, and filing of ANDA No with a paragraph IV certification constitutes infringement of the 576 patent under 35 U.S.C. 271(e)(2)(A). Further, Zydus Cadila s commercial use, sale, offer for sale, and/or importation of the Zydus Products would induce and/or contribute to Zydus USA s infringement of the 576 patent under 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c). 49. Upon information and belief, Zydus Cadila s inducement, encouragement, aiding, and/or abetting of the sale or offer for sale of the Zydus Products by Zydus USA would induce and/or contribute to third party infringement of one or more claims of the 576 patent under 35 U.S.C

11 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 11 of 155 PageID: Upon information and belief, Zydus Cadila has, continues to, and will actively induce, encourage, aid, or abet Zydus USA s infringement of the 576 patent with knowledge of infringement in contravention of the rights of Supernus. 51. Defendants infringement of the 576 patent has caused and will cause Supernus to suffer irreparable harm. Defendants infringement will continue unless enjoined by the Court. Supernus has no adequate remedy at law and thus preliminary and permanent injunctions are appropriate to prohibit Defendants from infringing the 576 patent. 52. As of the date of the October 9 Notice Letter, Defendants were aware of the existence of the 576 patent as well as the statutory provisions and regulations set forth in 21 U.S.C. 355 and 21 C.F.R and acted without a reasonable basis for believing that they would not be liable for infringement of the 576 patent, thus rendering this case exceptional under 35 U.S.C forth herein. SECOND COUNT (Defendants Infringement of the 580 Patent) 53. Plaintiff repeats and re-alleges each of the foregoing Paragraphs as if fully set 54. Upon information and belief, Defendants seek FDA approval for the manufacture, use, marketing, sale, and/or distribution of the Zydus Products. 55. Upon information and belief, Defendants included in ANDA No a paragraph IV certification to the 580 patent to obtain approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of the Zydus Products before the expiration of the 580 patent. 56. Upon information and belief, Defendants will commercially manufacture, use, sell, offer for sale, and/or import the Zydus Products upon, or in anticipation of, FDA approval. 11

12 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 12 of 155 PageID: The submission and filing of ANDA No with a paragraph IV certification to the 580 patent for the purpose of obtaining approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products before the expiration of the 580 patent is an act of infringement by Defendants of one or more claims of the 580 patent under 35 U.S.C. 271(e)(2)(A). 58. Upon information and belief, Defendants commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products that are the subject of ANDA No will infringe, directly and/or indirectly (including by inducement and/or contributory infringement), one or more claims of the 580 patent under 35 U.S.C. 271(a), 35 U.S.C. 271(b), and/or 35 U.S.C. 271(c). 59. Upon information and belief, the sale or offer for sale of the Zydus Products by Defendants would induce and/or contribute to third party infringement of one or more claims of the 580 patent under 35 U.S.C Upon information and belief, Zydus Cadila is jointly and severally liable for Zydus USA s infringement of one or more claims of the 580 patent. 61. Upon information and belief, Zydus Cadila knowingly induced Zydus USA to infringe and/or contributed to Zydus USA s infringement of one or more claims of the 580 patent. 62. Upon information and belief, Zydus Cadila actively induced, encouraged, aided, or abetted Zydus USA s preparation, submission and filing of ANDA No with a paragraph IV certification to the 580 patent. 63. Zydus Cadila s inducement, encouragement, aiding, or abetting of Zydus USA s preparation, submission, and filing of ANDA No with a paragraph IV certification constitutes infringement of the 580 patent under 35 U.S.C. 271(e)(2)(A). Further, Zydus Cadila s commercial use, sale, offer for sale, and/or importation of the Zydus Products would 12

13 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 13 of 155 PageID: 410 induce and/or contribute to Zydus USA s infringement of the 580 patent under 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c). 64. Upon information and belief, Zydus Cadila s inducement, encouragement, aiding, and/or abetting of the sale or offer for sale of the Zydus Products by Zydus USA would induce and/or contribute to third party infringement of one or more claims of the 580 patent under 35 U.S.C Upon information and belief, Zydus Cadila has, continues to, and will actively induce, encourage, aid, or abet Zydus USA s infringement of the 580 patent with knowledge of infringement in contravention of the rights of Supernus. 66. Defendants infringement of the 580 patent has caused and will cause Supernus to suffer irreparable harm. Defendants infringement will continue unless enjoined by the Court. Supernus has no adequate remedy at law and thus preliminary and permanent injunctions are appropriate to prohibit Defendants from infringing the 580 patent. 67. As of the date of the October 9 Notice Letter, Defendants were aware of the existence of the 580 patent as well as the statutory provisions and regulations set forth in 21 U.S.C. 355 and 21 C.F.R and acted without a reasonable basis for believing that they would not be liable for infringement of the 580 patent, thus rendering this case exceptional under 35 U.S.C forth herein. THIRD COUNT (Defendants Infringement of the 683 Patent) 68. Plaintiff repeats and re-alleges each of the foregoing Paragraphs as if fully set 69. Upon information and belief, Defendants seek FDA approval for the manufacture, use, marketing, sale, and/or distribution of the Zydus Products. 13

14 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 14 of 155 PageID: Upon information and belief, Defendants included in ANDA No a paragraph IV certification to the 683 patent to obtain approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of the Zydus Products before the expiration of the 683 patent. 71. Upon information and belief, Defendants will commercially manufacture, use, sell, offer for sale, and/or import the Zydus Products upon, or in anticipation of, FDA approval. 72. The submission and filing of ANDA No with a paragraph IV certification to the 683 patent for the purpose of obtaining approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products before the expiration of the 683 patent is an act of infringement by Defendants of one or more claims of the 683 patent under 35 U.S.C. 271(e)(2)(A). 73. Upon information and belief, Defendants commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products that are the subject of ANDA No will infringe, directly and/or indirectly (including by inducement and/or contributory infringement), one or more claims of the 683 patent under 35 U.S.C. 271(a), 35 U.S.C. 271(b), and/or 35 U.S.C. 271(c). 74. Upon information and belief, the sale or offer for sale of the Zydus Products by Defendants would induce and/or contribute to third party infringement of one or more claims of the 683 patent under 35 U.S.C Upon information and belief, Zydus Cadila is jointly and severally liable for Zydus USA s infringement of one or more claims of the 683 patent. 76. Upon information and belief, Zydus Cadila knowingly induced Zydus USA to infringe and/or contributed to Zydus USA s infringement of one or more claims of the 683 patent. 14

15 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 15 of 155 PageID: Upon information and belief, Zydus Cadila actively induced, encouraged, aided, or abetted Zydus USA s preparation, submission and filing of ANDA No with a paragraph IV certification to the 683 patent. 78. Zydus Cadila s inducement, encouragement, aiding, or abetting of Zydus USA s preparation, submission, and filing of ANDA No with a paragraph IV certification constitutes infringement of the 683 patent under 35 U.S.C. 271(e)(2)(A). Further, Zydus Cadila s commercial use, sale, offer for sale, and/or importation of the Zydus Products would induce and/or contribute to Zydus USA s infringement of the 683 patent under 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c). 79. Upon information and belief, Zydus Cadila s inducement, encouragement, aiding, and/or abetting of the sale or offer for sale of the Zydus Products by Zydus USA would induce and/or contribute to third party infringement of one or more claims of the 683 patent under 35 U.S.C Upon information and belief, Zydus Cadila has, continues to, and will actively induce, encourage, aid, or abet Zydus USA s infringement of the 683 patent with knowledge of infringement in contravention of the rights of Supernus. 81. Defendants infringement of the 683 patent has caused and will cause Supernus to suffer irreparable harm. Defendants infringement will continue unless enjoined by the Court. Supernus has no adequate remedy at law and thus preliminary and permanent injunctions are appropriate to prohibit Defendants from infringing the 683 patent. 82. As of the date of the October 9 Notice Letter, Defendants were aware of the existence of the 683 patent as well as the statutory provisions and regulations set forth in 21 U.S.C. 355 and 21 C.F.R and acted without a reasonable basis for believing that they would not be liable for infringement of the 683 patent, thus rendering this case exceptional under 35 U.S.C

16 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 16 of 155 PageID: 413 forth herein. FOURTH COUNT (Defendants Infringement of the 248 Patent) 83. Plaintiff repeats and re-alleges each of the foregoing Paragraphs as if fully set 84. Upon information and belief, Defendants seek FDA approval for the manufacture, use, marketing, sale, and/or distribution of the Zydus Products. 85. Upon information and belief, Defendants included in ANDA No a paragraph IV certification to the 248 patent to obtain approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of the Zydus Products before the expiration of the 248 patent. 86. Upon information and belief, Defendants will commercially manufacture, use, sell, offer for sale, and/or import the Zydus Products upon, or in anticipation of, FDA approval. 87. The submission and filing of ANDA No with a paragraph IV certification to the 248 patent for the purpose of obtaining approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products before the expiration of the 248 patent is an act of infringement by Defendants of one or more claims of the 248 patent under 35 U.S.C. 271(e)(2)(A). 88. Upon information and belief, Defendants commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products that are the subject of ANDA No will infringe, directly and/or indirectly (including by inducement and/or contributory infringement), one or more claims of the 248 patent under 35 U.S.C. 271(a), 35 U.S.C. 271(b), and/or 35 U.S.C. 271(c). 89. Upon information and belief, the sale or offer for sale of the Zydus Products by Defendants would induce and/or contribute to third party infringement of one or more claims of the 248 patent under 35 U.S.C

17 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 17 of 155 PageID: Upon information and belief, Zydus Cadila is jointly and severally liable for Zydus USA s infringement of one or more claims of the 248 patent. 91. Upon information and belief, Zydus Cadila knowingly induced Zydus USA to infringe and/or contributed to Zydus USA s infringement of one or more claims of the 248 patent. 92. Upon information and belief, Zydus Cadila actively induced, encouraged, aided, or abetted Zydus USA s preparation, submission and filing of ANDA No with a paragraph IV certification to the 248 patent. 93. Zydus Cadila s inducement, encouragement, aiding, or abetting of Zydus USA s preparation, submission, and filing of ANDA No with a paragraph IV certification constitutes infringement of the 248 patent under 35 U.S.C. 271(e)(2)(A). Further, Zydus Cadila s commercial use, sale, offer for sale, and/or importation of the Zydus Products would induce and/or contribute to Zydus USA s infringement of the 248 patent under 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c). 94. Upon information and belief, Zydus Cadila s inducement, encouragement, aiding, and/or abetting of the sale or offer for sale of the Zydus Products by Zydus USA would induce and/or contribute to third party infringement of one or more claims of the 248 patent under 35 U.S.C Upon information and belief, Zydus Cadila has, continues to, and will actively induce, encourage, aid, or abet Zydus USA s infringement of the 248 patent with knowledge of infringement in contravention of the rights of Supernus. 96. Defendants infringement of the 248 patent has caused and will cause Supernus to suffer irreparable harm. Defendants infringement will continue unless enjoined by the Court. Supernus has no adequate remedy at law and thus preliminary and permanent injunctions are appropriate to prohibit Defendants from infringing the 248 patent. 17

18 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 18 of 155 PageID: As of the date of the February 19 Notice Letter, Defendants were aware of the existence of the 248 patent as well as the statutory provisions and regulations set forth in 21 U.S.C. 355 and 21 C.F.R and acted without a reasonable basis for believing that they would not be liable for infringement of the 248 patent, thus rendering this case exceptional under 35 U.S.C forth herein. FIFTH COUNT (Defendants Infringement of the 191 Patent) 98. Plaintiff repeats and re-alleges each of the foregoing Paragraphs as if fully set 99. Upon information and belief, Defendants seek FDA approval for the manufacture, use, marketing, sale, and/or distribution of the Zydus Products Upon information and belief, Defendants included in ANDA No a paragraph IV certification to the 191 patent to obtain approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of the Zydus Products before the expiration of the 191 patent Upon information and belief, Defendants will commercially manufacture, use, sell, offer for sale, and/or import the Zydus Products upon, or in anticipation of, FDA approval The submission and filing of ANDA No with a paragraph IV certification to the 191 patent for the purpose of obtaining approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products before the expiration of the 191 patent is an act of infringement by Defendants of one or more claims of the 191 patent under 35 U.S.C. 271(e)(2)(A) Upon information and belief, Defendants commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products that are the subject of ANDA No will infringe indirectly (including by inducement and/or contributory 18

19 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 19 of 155 PageID: 416 infringement) one or more claims of the 191 patent under 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c) Upon information and belief, the sale or offer for sale of the Zydus Products by Defendants would induce and/or contribute to third party infringement of one or more claims of the 191 patent under 35 U.S.C Upon information and belief, Zydus Cadila is jointly and severally liable for Zydus USA s infringement of one or more claims of the 191 patent Upon information and belief, Zydus Cadila knowingly induced Zydus USA to infringe and/or contributed to Zydus USA s infringement of one or more claims of the 191 patent Upon information and belief, Zydus Cadila actively induced, encouraged, aided, or abetted Zydus USA s preparation, submission and filing of ANDA No with a paragraph IV certification to the 191 patent Zydus Cadila s inducement, encouragement, aiding, or abetting of Zydus USA s preparation, submission, and filing of ANDA No with a paragraph IV certification constitutes infringement of the 191 patent under 35 U.S.C. 271(e)(2)(A). Further, Zydus Cadila s commercial use, sale, offer for sale, and/or importation of the Zydus Products would induce and/or contribute to Zydus USA s infringement of the 191 patent under 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c) Upon information and belief, Zydus Cadila s inducement, encouragement, aiding, and/or abetting of the sale or offer for sale of the Zydus Products by Zydus USA would induce and/or contribute to third party infringement of one or more claims of the 191 patent under 35 U.S.C

20 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 20 of 155 PageID: Upon information and belief, Zydus Cadila has, continues to, and will actively induce, encourage, aid, or abet Zydus USA s infringement of the 191 patent with knowledge of infringement in contravention of the rights of Supernus Defendants infringement of the 191 patent has caused and will cause Supernus to suffer irreparable harm. Defendants infringement will continue unless enjoined by the Court. Supernus has no adequate remedy at law and thus preliminary and permanent injunctions are appropriate to prohibit Defendants from infringing the 191 patent As of the date of the February 19 Notice Letter, Defendants were aware of the existence of the 191 patent as well as the statutory provisions and regulations set forth in 21 U.S.C. 355 and 21 C.F.R and acted without a reasonable basis for believing that they would not be liable for infringement of the 191 patent, thus rendering this case exceptional under 35 U.S.C forth herein. SIXTH COUNT (Defendants Infringement of the 989 Patent) 113. Plaintiff repeats and re-alleges each of the foregoing Paragraphs as if fully set 114. Upon information and belief, Defendants seek FDA approval for the manufacture, use, marketing, sale, and/or distribution of the Zydus Products Upon information and belief, Defendants included in ANDA No a paragraph IV certification to the 989 patent to obtain approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of the Zydus Products before the expiration of the 989 patent Upon information and belief, Defendants will commercially manufacture, use, sell, offer for sale, and/or import the Zydus Products upon, or in anticipation of, FDA approval. 20

21 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 21 of 155 PageID: The submission and filing of ANDA No with a paragraph IV certification to the 989 patent for the purpose of obtaining approval to engage in the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products before the expiration of the 989 patent is an act of infringement by Defendants of one or more claims of the 989 patent under 35 U.S.C. 271(e)(2)(A) Upon information and belief, Defendants commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products that are the subject of ANDA No will infringe, directly and/or indirectly (including by inducement and/or contributory infringement), one or more claims of the 989 patent under 35 U.S.C. 271(a), 35 U.S.C. 271(b), and/or 35 U.S.C. 271(c) Upon information and belief, the sale or offer for sale of the Zydus Products by Defendants would induce and/or contribute to third party infringement of one or more claims of the 989 patent under 35 U.S.C Upon information and belief, Zydus Cadila is jointly and severally liable for Zydus USA s infringement of one or more claims of the 989 patent Upon information and belief, Zydus Cadila knowingly induced Zydus USA to infringe and/or contributed to Zydus USA s infringement of one or more claims of the 989 patent Upon information and belief, Zydus Cadila actively induced, encouraged, aided, or abetted Zydus USA s preparation, submission and filing of ANDA No with a paragraph IV certification to the 989 patent Zydus Cadila s inducement, encouragement, aiding, or abetting of Zydus USA s preparation, submission, and filing of ANDA No with a paragraph IV certification constitutes infringement of the 989 patent under 35 U.S.C. 271(e)(2)(A). Further, Zydus Cadila s commercial use, sale, offer for sale, and/or importation of the Zydus Products would 21

22 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 22 of 155 PageID: 419 induce and/or contribute to Zydus USA s infringement of the 248 patent under 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c) Upon information and belief, Zydus Cadila s inducement, encouragement, aiding, and/or abetting of the sale or offer for sale of the Zydus Products by Zydus USA would induce and/or contribute to third party infringement of one or more claims of the 989 patent under 35 U.S.C Upon information and belief, Zydus Cadila has, continues to, and will actively induce, encourage, aid, or abet Zydus USA s infringement of the 989 patent with knowledge of infringement in contravention of the rights of Supernus Defendants infringement of the 989 patent has caused and will cause Supernus to suffer irreparable harm. Defendants infringement will continue unless enjoined by the Court. Supernus has no adequate remedy at law and thus preliminary and permanent injunctions are appropriate to prohibit Defendants from infringing the 989 patent As of the date of the April 21 Notice Letter, Defendants were aware of the existence of the 989 patent as well as the statutory provisions and regulations set forth in 21 U.S.C. 355 and 21 C.F.R and acted without a reasonable basis for believing that they would not be liable for infringement of the 989 patent, thus rendering this case exceptional under 35 U.S.C PRAYER FOR RELIEF WHEREFORE, Plaintiff respectfully requests the following relief: i. A Judgment declaring that, pursuant to 35 U.S.C. 271(e)(2)(A), the submission to the FDA and filing of ANDA No with a paragraph IV certification to obtain approval for the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products was an act of infringement of the 576, 580, 683, 248, 191, and 989 patents by Defendants; 22

23 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 23 of 155 PageID: 420 ii. A Judgment declaring that, pursuant to 35 U.S.C. 271(e)(2)(A), the submission to the FDA and filing of ANDA No with a paragraph IV certification to obtain approval for the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the Zydus Products was an act of infringement of the 576, 580, 683, 248, 191, and 989 patents by Defendants indirectly, including by inducement and/or contributory infringement; iii. A Judgment declaring that, pursuant to 35 U.S.C. 271(b) and/or 35 U.S.C. 271(c), the commercial manufacture, use, sale, offer for sale, and/or importation in the United States of the products that are the subject of ANDA No by Defendants would induce and/or contribute to third party infringement of the 576, 580, 683, 248, 191, and 989 patents; iv. A Judgment declaring that, pursuant to 35 U.S.C. 271(e)(2)(A), 35 U.S.C. 271(a), 35 U.S.C. 271(b), and/or 35 U.S.C. 271(c), the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the products that are the subject of ANDA No prior to the expiration of the 576, 580, 683, 248, 191, and 989 patents, including any regulatory extensions, will constitute an act of infringement by Defendants; v. A Judgment declaring that, pursuant to 35 U.S.C. 271(e)(2)(A), 35 U.S.C. 271(a), 35 U.S.C. 271(b), and/or 35 U.S.C. 271(c), the commercial manufacture, use, sale, offer for sale, and/or importation into the United States of the products that are the subject of ANDA No prior to the expiration of the 576, 580, 683, 248, 191, and 989 patents, including any regulatory extensions, will constitute an act of infringement by Defendants indirectly, including by inducement and/or contributory infringement; 23

24 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 24 of 155 PageID: 421 vi. An Order that, pursuant to 35 U.S.C. 271(e)(4)(A), 281, and 283, the effective date of any approval of the products that are the subject of ANDA No shall be no earlier than the date on which the 576, 580, 683, 248, 191, and 989 patents expire, including any regulatory extensions; vii. A Judgment pursuant to 35 U.S.C. 271(e)(4)(B), 281, and 283, preliminarily and permanently enjoining Defendants and their officers, agents, servants, employees, and attorneys, and those persons in active concert or participation or privity with them or any of them, from engaging in the commercial manufacture, use, sale, offer for sale, and/or importation in the United States any product that is the subject of ANDA No until the expiration of the 576, 580, 683, 248, 191, and 989 patents, including any regulatory extensions; viii. A Judgment awarding Supernus damages or other monetary relief, pursuant to 35 U.S.C. 271(e)(4)(C) and 284, if Defendants commercially manufacture, use, sell, offer to sell, and/or import any product that is the subject of ANDA No that infringes the 576, 580, 683, 248, 191, and/or 989 patents; ix. A Judgment declaring that infringement of the 576, 580, 683, 248, 191, and 989 patents is willful if Defendants commercially manufacture, use, sell, offer to sell, and/or import any product that is the subject of ANDA No that infringes 576, 580, 683, 248, 191, and 989 patents; x. A Judgment declaring that, pursuant to 35 U.S.C. 285, this is an exceptional case and awarding Supernus its attorneys fees and costs; and xi. Such other and further relief as this Court may deem just and proper. 24

25 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 25 of 155 PageID: 422 Dated: April 28, 2015 Respectfully submitted, By: s/ Charles M. Lizza Charles M. Lizza William C. Baton Sarah A. Sullivan SAUL EWING LLP One Riverfront Plaza, Suite 1520 Newark, NJ (973) Of Counsel: Edgar H. Haug Sandra Kuzmich, Ph.D. Elizabeth Murphy Richard F. Kurz FROMMER LAWRENCE & HAUG LLP 745 Fifth Avenue New York, NY (212) Attorneys for Plaintiff Supernus Pharmaceuticals, Inc. 25

26 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 26 of 155 PageID: 423 Exhibit A

27 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 27 of 155 PageID: 424 I IIIII US B2 c12) United States Patent Liang et al. (IO) Patent No.: US 8,298,576 B2 (45) Date of Patent: Oct. 30, 2012 (54) SUSTAINED-RELEASE FORMULATIONS OF TOPIRA~HE (75) Inventors: Likan Liang, Boyds, MD (US); Hua Wang, Clarksville, MD (US); Padmanabh P. Bhatt, Rockville, MD (US); Michael L. Vieira, Gaithersburg, MD (US) (73) Assignee: Supernus Pharmaceuticals, Inc., Rockville, MD (US) ( *) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 488 days. (21) Appl. No.: 11/941,475 (22) Filed: Nov.16, 2007 (65) Prior Publication Data US 2008/ Al May 22,2008 Related U.S. Application Data (60) Provisional application No. 60/859,502, filed on Nov. 17,2006. (51) Int. Cl. A61K ( ) A61K 9114 ( ) A61K 9124 ( ) A61K 9154 ( ) (52) U.S. Cl /458; 424/494; 424/472; 424/490; 514/455 (58) Field of Classification Search... None See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 2,528,378 A 10/1950 Mannheimer et al. 2,675,619 A 4/1954 Cone 2,677,700 A 5/1954 Jackson et a!. 2,781,354 A 2/1957 Mannheimer et al. 2,979,578 A 4/1961 Curtis 2,996,431 A 8/1961 Barry 3,036,118 A 5/1962 Jackson et a!. 3,139,383 A 6/1964 Neville eta!. 3,535,307 A 10/1970 Moss eta!. 3,811,444 A 5/1974 Heller eta!. 3,829,506 A 8/1974 Schmolka et a!. 3,962,414 A 6/1976 Michaels 3,992,518 A Chien eta!. 4,066,747 A Capozza 4,070,347 A Schmitt 4,079,038 A 3/1978 Choi eta!. 4,083,949 A 4/1978 Benedikt 4,093,709 A 6/1978 Choi eta!. 4,290,426 A 9/1981 Luschen et a!. 4,434,153 A Urquhart et a!. 4,513,006 A 4/1985 Maryanoff et a!. 4,721,613 A 1/1988 Urquhmi et a!. 4,727,064 A 2/1988 Pitha 4,752,470 A 6/1988 Mehta 4,757,128 A Domb eta!. 4,853,229 A 8/1989 Theeuwes 4,938,763 A 7/1990 Dullll et al. 4,997,904 A 3/1991 Domb 5,030,447 A 7/1991 Joshi eta!. 5,175,235 A 12/1992 Domb eta!. 5,180,589 A 1/1993 Joshi eta!. 5,225,202 A 7/1993 Hodges eta!. 5,256,440 A 10/1993 Appel eta!. 5,378,475 A 1/1995 Smith eta\. 5,478,577 A 12/1995 Sackler eta!. 5,500,227 A 3/1996 Oshlack et al. 5,576,311 A 11/1996 Guy 5,753,693 A 5/1998 Shank 5,760,007 A 6/1998 Shank eta!. 5,773,019 A 6/1998 Ashton et al. 5,935,933 A 8/1999 Shank eta!. 5,955,096 A 9/1999 Santos eta!. 5,985,312 A 11/1999 Jacob eta!. 5,998,380 A 12/1999 Ehrenberg et al. 6,123,965 A Jacob eta!. 6,156,348 A 12/2000 Santos eta!. 6,191,117 B1 2/2001 Kozachuk 6,197,346 B1 3/2001 Mathiowitz eta!. 6,201,010 B1 3/2001 Cottrell 6,217,908 B1 4/2001 Mathiowitz et a!. 6,235,311 B1 5/2001 Ullah eta!. 6,248,363 B1 6/2001 Patel et al. 6,294,192 B1 9/2001 Patel et al. 6,319,903 B Carrazana et a!. (Continued) FOREIGN PATENT DOCUMENTS CN A 9/1996 (Continued) OTHER PUBLICATIONS Lui eta!, Preparation, characterization and in vivo evaluation of formulation of baicalein with hydroxypropyl-beta-cyclodextrin. International Jomnal ofpharmaceutics, vol. 312: * Non-Final Office Action dated Apr. 14, 2009, in copending U.S. Appl. No. 11/987,806. Non-Final Office Action dated Dec. 22, 2009, in copending U.S. Appl. No. 11/987,806. US 6,103,281, 08/15/2000, DelDuca eta!. (withdrawn). International Sem ch Repmi and Written Opinion mailed Sep. 2, 2008, in PCT/US2007/19208, 10 pages. Adin et a!., "Topirmnate Serum Concentration-to-Dose Ratio," Therapeutic Dmg Monitoring, Jun. 2004; 26(3): Bahk et a!., "Topirillllate and divalproex in combination with risperidone for acute mania: a randomized open-label study," Progress in Nemopsychophm macology & Biological Psychiatry, 2005, 29(1): (Continued) Primary Examiner Suzmme Ziska (74) Attorney, Agent, or Firm Foley & Lardner LLP; Stephen B. Maebius; Sunit Talapatra (57) ABSTRACT Pharmaceutical compositions of topiramate for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediaterelease eomponent, the compositions of which ean be seleetively adjusted, respectively, to release the active ingredient along a pre-determined release profile. Method of treating or preventing pathological disorders in mmnmalian subjects comprising the administration of the novel formulations disclosed herein is also provided. 30 Claims, 6 Drawing Sheets

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Scand., 2007, 115(2): Physicians' Desk Reference 59th edition, (2005). Physician's Desk Reference, 56th ed., (2002).. Pies, Ronald M.D., "Combining Lithium and Anticonvulsants m Bipolar Disorder: A Review," Annals of Clinical Psychiatry, Dec. 2002, 14(4) Porter, Stuart C., Ph.D., "Coating of Pharmaceutical Dosage Forms," Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 90, Potter et a!., "A Double-Blind, Randomized, Placebo-Controlled, Parallel Study to Determine the Efficacy of Topiramate in the Prophylactic Treatment of Migraine," Neurology, Apr. 2000, 54(Suppl 3):A15. Rudnic eta!., "Oral Solid Dosage Forms," Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 89, Silberstein et al., ''Topiramate in Migraine Prevention," Arch. Nemol., Apr. 2004, 61(4): Siniscalchi et a!., "Combined topiramate and declorazepam therapy in a patient affected by essential tremor," Parkinsonism Relat. Disord., 2007, 13(2): Smart eta!., "An in-vitro investigation of mucosa-adhesive materials for use in controlled drug delivejy," J. Pharm. Pharmacol., 1984, 36: Sofuoglu et al., ''Effects oftopira.mate in combination with intravenous nicotine in overnight abstinent smokers," Psychopharmacology, 2006, 184(3-4): Storey eta!., "Topiramate in Migraine Prevention: A Double-Blind Placebo-Controlled Study," Headache, Nov./Dec. 2001, 41( 10): Thompson et a!., "Effects of topiramate on cognitive fimction," J. Nemol. Nemosmg and Psych., 2000; 69: Toplak eta!., "Efficacy and safety of topira.mate in combination with.metformin in the terat.ment of obese subjects with type 2 diabetes: a randomized, double-blind placebo-controlled study," Int. J. Obes., 2007, 31(1): VonSeggern et al., "Efficacy oftopira.mate in Migraine Prophylaxis: A Retrospective Chart A.nalysis," Neurology, Apr. 2000, 54(Suppl 3 ):A267 -A268. Weber, Marcus Vinicius Keche, M.D., "Topiramate for Obstmctive Sleep Apnea and Snoring," A.m. J. PsychiatJY, May 2002, 159( 5): Winkelman, John W., "Treatement of nocturnal eating syndrome and sleep-related eating disorder with topiramate," Sleep Medicine, 2003, 4(3): Dorado eta!., "Topiramato en enfennedades comorbidas: epilepsia y migrana," Rev. Neurol., 2006, 43(4) Physician's Desk Reference, 60'" Edition, 2006, pp , entty for TOPAMAX. U.S. Appl. No. 12/926,931, filed Dec. 17, 2010, Liang eta!. U.S. Appl. No. 12/926,936, filed Dec. 17, 2010, Liang eta!. * cited by examiner

30 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 30 of 155 PageID: 427 U.S. Patent Oct. 30, 2012 Sheet 1 of 6 US 8,298,576 B2 Fig.1 80% release time vs. %Wt. gain of Release-Controlling Coating For Sure/ease coated Extended Release Beads 1.4 -cu E j.: cu Ill ~ cu G) 0::?ft ~ 0.4 Cl 0...J 0.2 y = x R 2 = ~ ~ ~. ~ %Release Controlling Coating Weight Gain

31 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 31 of 155 PageID: 428 U.S. Patent Oct. 30, 2012 Sheet 2 of 6 US 8,298,576 B2 Fig. 2 80% release time vs. % Wt. gain of Release-Controlling Coating For Sure/ease! Opadry coated Extended Release Beads - "" :S 7 Q) E 6 i= ~ 5 co Q) ~ 4 ';/!. 3 0 CIO 2 y / y = 0.935x / R 2 = / / / / / %Release Controlling Coating Weight Gain

32 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 32 of 155 PageID: 429 U.S. Patent Oct. 30, 2012 Sheet 3 of 6 US 8,298,576 B2 Fig. 3 Mean (n= 16) PK Profiles from Bead Populations XR1, XR2 and XR3

33 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 33 of 155 PageID: 430 U.S. Patent Oct. 30, 2012 Sheet 4 of 6 US 8,298,576 B2 Fig. 4 Mean (n= 16) PK Profiles from the Immediate Release Formulations - -EIRBeads la Beads -Topamax :; E en 6oo..s c: 0 ~ ~ 450 (J c: 0 () m 300 fij.!l! a. I Time (hours)

34 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 34 of 155 PageID: 431 U.S. Patent Oct. 30, 2012 Sheet 5 of 6 US 8,298,576 B2 Fig.5 Dissolution Profiles of Immediate Release Formulations ~~... """"" "'""""""' ' "'"""""... """'..._.. Jlo.Vt.' ~.,._~ (.:/ "C 80 ~~ ~ Topamax Q) 2: 0 I 'If f II) 60.!e c I fl, Beads! ( ';F Topiramate IR II - - Topiramate. II! Enhanced IR Beads ll 0 l Time (min)

35 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 35 of 155 PageID: 432 U.S. Patent Oct. 30, 2012 Sheet 6 of 6 US 8,298,576 B2... '~J

36 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 36 of 155 PageID: SUSTAINED-RELEASE FORMULATIONS OF TOPIRAMATE CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims benefit of U.S. Provisional Application No. 60/859,502, filed Nov. 17, 2006, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION US 8,298,576 B2 Topiramate is a sulfamate substituted monosaccharide which under the trade name TOPAMAX (Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J., U.S.A.) has been approved for use as an antiepileptic agent, as an adjuvant 15 therapy for patients with partial onset seizures or primary generalized tonic-clonic seizures, and for the prevention of migraine. See generally, Physician's Desk Reference, 60th ed., (2006); see also, U.S. Pat. No. 4,513,006. For the treatment of epilepsy, the recommended dose of 20 TOPAMAX is 400 mg/day in one or multiple doses (Physician's Desk Reference, 60th ed., (2006)). For adults with epilepsy, treatment is initiated with a dose of mg/day, with the dose being titrated in increments of mg at weekly intervals to the recollllllended or effective 25 dose. TOPAMAX(ID is an illllllediate release formulation. Adverse effects associated with the administration of TOPAMAX include, but are not limited to, somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnomwl vision, difficulty with 30 memory, paresthesia, diplopia, renal calculi (kidney stones), hepatic failure, pancreatitis, renal tubular acidosis, acute myopia and secondary angle closure glaucoma (Physician's Desk Reference, 60th ed., (2006)). Hence, though topiramate has a relatively long half-life of hours in vivo, it has not been prescribed (or formulated) as a single, daily-dose, in part due to severe side-effects that often result with peak plasma levels of the drug when taken in high doses. Instead, TOPAMAX is typically taken in multiple, "divided" doses, usually twice-daily ("BID"). However, 40 administration of the medicament in this marmer is cumbersome and patients can forget to take their medication in a timely manner. What is more, each administration of a dose is associated with a peak in plasma concentrations of the drug, and the fluctuations associated with the peaks and valleys of 45 blood plasma levels of the drug are undesirable. Therefore, there is a need for a formulation of topiramate, which reduces or eliminates the side effects associated with peaking and fluctuating plasma levels of the drug and preferably may be administered in a once-daily regimen. New, highly soluble and bioavailable forms oftopiramate are also needed in order to increase the safety and effectiveness of the drug. The instant invention addresses these and other needs by providing a modified formulation of topiramate characterized 55 by a sustained, non-pulsatile release of an active ingredient. This invention additionally provides an effective, once-daily dosage form of topiramate or salts thereof, which not only enables an effective single daily dose regimen to improve patient compliance but may also reduce some of the side 60 effects of topiramate compared to the current or higher daily doses of immediate release topiramate formulations. SUMMARY OF THE INVENTION It is an object of the present invention to provide a sustained release fommlation of topiramate for the treatment or preven- 2 tion of a pathological condition in a manunalian subject, characterized by a sustained rate of topiramate release along a pre-determined release profile. It is yet another object of the present invention to provide topiramate formulation wherein topiramate is released at a rate which results in a reduction in the frequency or severity of at least one side effect associated with the topiramate treatment. It is a further object of the present invention to provide a 10 sustained release formulation of topiramate that can be administered orally once a day. It is an object of the present invention to provide a sustained release formulation of topiramate for oral administration to a mallllllalian subject comprising topiramate as an active ingredient, wherein the active ingredient is released from the formulation at a sustained rate along a pre-detennined release profile, and wherein the sustained release formulation comprises an extended release (XR) component and an optional inunediate release (IR) component. In one embodiment of the invention, the extended release component is contained in at least one population of beads coated with a release controlling coating. The above-mentioned coating is specific for every bead population and determines its rate of release. Thus, every given bead population included into the fonnulation is characterized by its own specific rate of release. In another embodiment of the invention, the sustained release topiramate formulation comprises an inunediate release component in addition to an extended release component. In a preferred embodiment of the invention, the illllllediate release component is an enhanced inunediate release (EIR) composition. The formulation of the present invention may be incorporated in any oral dosage fonn such as represented by, but not limited to, a tablet, a pill, a capsule, a troche, a sachet, and sprinkles. It is yet another object of the present invention to provide a method of preparation of a sustained release fommlation of topiramate, comprising an extended release component, and an optional inunediate release component, wherein topiramate is released from the fonnulation at the sustained rate along the pre-detennined release profile, the method comprising the steps of: 1. determining the desired release profile; 2. determining specific amounts of the extended release component and the immediate release component necessary to produce the pre-determined release profile; and 3. incorporating the specified amounts of the components 50 into the formulation. In one embodiment, the method of preparation additionally includes a process for providing an XR component contained in at least one population of beads, wherein every population of beads is characterized by its own rate of release. This process comprises the steps of 1. forming at least one population oftopiramate-containing beads; 2. coating each population of beads with its own coating solution; 3. curing the coating for a period of time to produce a release controlling coating specific for each bead population, and 4. incorporating the beads into the formulation. The method may optionally include a process for prepara- 65 tion of an IR component, which optionally is an enhanced inunediate release (EIR) composition. The enhanced immediate release composition includes at least one agent selected

37 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 37 of 155 PageID: 434 US 8,298,576 B2 3 from a group comprising complexing agents and enhancing agents. Without any limitations, the enhancing agents useful in the present invention may be selected from solubilizing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidmg resistance protein inhibitors or combinations thereof. It is yet another object of the present invention to provide a method of treatment or prevention of a pathological condition 1 o in a mammalian subject by orally administering to the subject a therapeutically effective amount of a sustained release topiramate formulation of the instant invention. The pathological conditions that may be treated by the method of the present invention include neurological condition, psychiatric condi- 15 tion, diabetes and related disorders, cardiovascular condition, obesity, and any other condition or disorder that may be treated or prevented by topiramate administration. Definitions: For the purposes of this invention, the term "topiramate" 20 includes topiramate or any pharmaceutically acceptable salts thereof. An "illllllediate release formulation" refers to a formulation that releases greater than or equal to about 80% of the pharmaceutical agent in less than or equal to about 1 hour. For the purposes of this application, an enhancing agent ("enhancer") is defined as any non-pham1aceutically active ingredient that improves the therapeutic potential of a formulation. The term "enhanced immediate release composition" as 30 used herein describes an illllllediate release composition improved in terms of a therapeutic potential or treatment modality. "Sustained release" is defined herein as release of a pharmaceutical agent in a continuous marmer over a prolonged period of time. By "prolonged period of time" it is meant a continuous period of time of greater than about I hour, preferably, greater than about 4 hours, more preferably, greater than about 8 hours, more preferably greater than about 12 hours, more 40 preferably still, greater than about 16 hours up to more than about 24 hours. As used herein, unless otherwise noted, "rate of release" or "release rate" of a dmg refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of dmg 45 released per hour (mg/hr) or a percentage of a total drug dose released per hour. Dmg release rates for dosage forms are typically measured as an in vitro rate of dmg release, i.e., a quantity of dmg released from the dosage form per unit time measured under appropriate conditions and in a suitable fluid. 50 The time at which a specified percentage of the dmg within a dosage fonn has been released from the dosage form is referred to as the "T.sub.x" value, where "x" is the percent of dmg that has been released. The release rates referred to herein are determined by placing a dosage form to be tested in a medium in an appropriate dissolution bath. Aliquots of the medium, collected at pre-set intervals, are then injected into a chromatographic system fitted with an appropriate detector to quantify the amounts of dmg released during the testing intervals. 60 "C" denotes the concentration of dmg in blood plasma, or serum, of a subject, and is generally expressed as mass per unit volume, for example nanograms per milliliter. For convenience, this concentration may be referred to herein as "dmg plasma concentration", "plasma dmg concentration" or 65 "plasma concentration" which is intended to be inclusive of a dmg concentration measured in any appropriate body fluid or tissue. The plasma dmg concentration at any time following dmg administration is referenced as Ctime, as in C9hr or C4hr, etc. The maximum plasma dmg concentration during the dosing period is referenced as Cmax, while Cmin refers to the minimum blood plasma dmg concentration at the end of a dosing interval; and Cave refers to an average concentration during the dosing interval. The "degree of fluctuation" is defined as a quotient (Cmax Cmin)/Cave. Persons of skill in the art will appreciate that blood plasma drug concentrations obtained in individual subjects will vary due to interpatient variability in the many parameters affecting dmg absorption, distribution, metabolism and excretion. For this reason, tmless otherwise indicated, when a dmg plasma concentration is listed, the value listed is the calculated mean value based on values obtained from a groups of subjects tested. The term "bioavailability" refers to an extent to whichand sometimes rate at which-the active moiety (drug or metabolite) enters systemic circulation, thereby gaining access to the site of action. "AUC" is the area under the plasma concentration-time curve and is considered to be the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged dmg that reaches the systemic circulation. Side effect is defined herein as a secondary and usually adverse effect of a drug. The term "beads", as used herein, includes, without any limitations on the nature and size thereof, any particles, spheres, beads, granules, pellets, particulates or any stmctural units that may be incorporated into an oral dosage form. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the time of release of 80% of the dmg vs.% wt. gain of release controlling coating for cured SURE LEASE ( ethylcellulose dispersion) coated extended release beads. FIG. 2 shows the time of release of 80% of the drug vs. % wt. gain of release controlling coating for cured SURE LEASE /OPADRY Clear (HPMC with PEG) coated extended release beads. FIG. 3 shows mean (n=16) phannacokinetic profiles for bead populations XRl, XR2 and XR3. FIG. 4 shows mean (n= 16) pharmacokinetic profiles for the innnediate release formulations. FIG. 5 shows the dissolution profiles of TOPAMAX, 55 topiramate IR beads, and topiramate enhanced innnediate release beads. FIG. 6 shows mean PK Profiles for Sustained Release Formulations A, B, and C. DETAILED DESCRIPTION OF THE INVENTION Topiramate is a sulfamate-substituted monosaccharide having the chemical name 2,3:4,5-Di-0-isopropylidenebeta-D-fructopyranose sulfamate. The molecular fommla of topiramate is Cl2H21N08S, and its chemical stmcture is represented by fommla below:

38 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 38 of 155 PageID: US 8,298,576 B2 6 the range of 80% to 125%, while minimizing the degree of fluctuation, which is preferably in the range of25% to 90%, as compared to an equivalent amount of immediate release to piramate formulation given in two divided doses (Table 5 and 6). The present invention additionally provides a sustained release topiramate formulation for the treatment or preven- Topiramate is a white crystalline powder that is soluble in tion of a pathological condition in a mammalian subject alkaline solutions containing sodium hydroxide or sodium wherein topiramate is released from the formulation at a 10 phosphate, soluble in acetone, dimethylsulfoxide and etha- sustained rate along a pre-determined release profile. Such no!. However, the solubility of topiramate in water at room release is achieved by incorporation into the fonnulation of an temperature is only about 9.8mglml. Topiramate is not exten- extended release component (XR) and an optional immediate sively metabolized and is excreted largely through the urine release component (IR). (Physician's Desk Reference, 60th ed., (2006)). 15 The relative amount of each component in the topiramate Topiramate phannacokinetics are linear, producing a dose formulation of the present invention is determined according proportional increase in blood plasma concentration levels to the purpose of administration and a pre-determined release with increased dosing, and is not significantly affected by profile, and the total amount of topiramate in the fommlation food. Patients taking topiramate over prolonged period of varies from 0.5 mg to about 3000 mg. In other words, top iratime did not develop resistance to the dmg. Following oral 20 mate or its salt is present in the composition in an amount of administration of an immediate release dosage form, topira- from about 0.5% to about 85% by weight, and preferably of mate is rapidly absorbed with plasma drug concentrations from about 2% to about 70% by weight. The term "about" has peaking in approximately 2 hours. The mean elimination been recited here and throughout the specification to account half-life is reported to be about 21 hours. for variations, which can arise from inaccuracies in measure- Currently, topiramate is administered in multiple daily 25 ment inherent and understood by those of ordinary skill in the doses in part due to the severe side effects exhibited by the chemical and phannaceutical arts. immediate release product, especially when taken in a high TheXRcomponentofthefonnulationofthepresentinvensingle dose. tion releases topiramate in a continuous mauner and is A sustained release topiramate formulation that will be adjusted in such a way that 80% of the active ingredient is suitable for once-a-day administration and will result in the 30 released in vitro in the predetennined period of time. By way diminished level or severity of side effects is needed. of example, and by no means limiting the scope of the inven- The present invention provides sustained release formula- tion, the period of time may be not more than 24 hours, not tion of topiramate wherein the total daily dose of topiramate more than 16 hours, not more than 12 hours, not more than 8 is provided in an effective once-daily dose while minimizing hours, or not more than 4 hours, depending on desired fluctuations in the blood plasma dmg concentration. 35 attributes of the final product. The current invention also provides for formulations of In one embodiment, the extended release (XR) component topiramate wherein the maximum plasma concentration of is contained in at least one population of beads coated with a topiramate is attenuated as compared to the same amount of coating that modifies and controls the release of topiramate topiramate administered as an innnediate release formulation from the beads (release controlling coating). The release con- BID; therefore some of the side effects of topiramate, such as 40 trolling coating is specific for every population of beads and CNS side effects including but not limited to dizziness, par- determines the rate of release of topiramate from the given esthesia, nervousness, psychomotor slowing, confusion, and bead population. difficulty with concentration/attention, observed when taking The beads usef'i.jl in the formulation of the present inventhe immediate release product, may be reduced or eliminated. tion comprise an inert carrier, topiramate, a binder, an afore- Formulations of the instant invention are characterized by 45 mentioned release controlling coating and optionally, an a maximum steady state plasma concentration (Cmax) of overcoat that provides additional protection from moisture, topiramate which is higher than the minimal therapeutically static charge reduction, taste masking and coloring attributes effective concentration, and is in the range of 50% to 125% of to the particulates. the maximum plasma concentration produced by the same The inert carriers useful in the present invention may be amount oftopiramate administered as an immediate release 50 selected from, but are not limited to, a group consisting of formulation BID. In one embodiment, the novel formulations cellulose spheres, silicon dioxide, starch and sugar spheres. provide for a relative Cmax in the range of 80% to 125%, as The inert carrier is present in an amount of from about 15% to compared to the same amount of topiramate administered as about 99% by weight, and preferably in an amount of from an innnediate release formulation BID. In the other embodi- about 40% to about 97% by weight. ment, the invention provides for the Cmax which is lower than 55 Topiramate is introduced to the inert carrier by techniques the maximum plasma concentration produced by the same known to one skilled in the art, such as drug layering, powder amount oftopiramate administered as an immediate release coating, extrusion/spheronization, roller compaction or formulation BID. The Cmin of the topiramate formulation of granulation. Preferably, the introduction method is drug laythe present invention is about equal or higher than a Cmin of ering by spraying a suspension of topiramate and a binder an equivalent amount of immediate release topiramate for- 60 onto the inert carrier. mulation given BID. The binder may be present in the bead formulation in an Compared to the immediate release topiramate formula- amount of from about 0.1% to about 15% by weight, and tion, the sustained release topiramate formulations attenuate preferably of from about 0.2% to about 10% by weight. the Cmax of topiramate while extending the coverage of Binders include, but are not limited to starches, microcrystalplasma concentration above the minimum plasma concentra- 65 line cellulose, hydroxypropyl cellulose, hydroxyethyl cellution required therapeutic efficacy. The formulation of the lose, hydroxypropylmethyl cellulose, or polyvinylpyrrolicurrent invention provides for a relative steady state AUC in done.

39 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 39 of 155 PageID: 436 US 8,298,576 B2 7 8 T11e release controlling coating specific for every bead population comprises a coating material, and, optionally, a pore former and other excipients. The coating material is preferably selected from a group comprising cellulosic polymers, such as ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, and cellulose acetate phthalate; polyvinyl alcohol; acrylic polymers such as polyacrylates, polymethacrylates and copolymers thereof, and other water-based or solvent-based coating materials. The release-controlling coating is popula- 10 tion-specific in the sense that the rate of release of topiramate from every bead population is controlled by at least one parameter of the release controlling coating, such as the nature of the coating, coating level, type and concentration of In some embodiments, it may be further desirable to optionally coat the XR beads with an "overcoat," to provide, e.g., moisture protection, static charge reduction, taste-masking, flavoring, coloring, and/or polish or other cosmetic appeal to the beads. Suitable coating materials for such an overcoat are kuown in the art, and include, but are not limited to, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose, or combinations thereof (for example various OPADRYriD coating materials). Topiramate-contaitling beads of the present invention may additionally contain enl1ancers that may be exemplified by, but not limited to, solubility enhancers, dissolution enhancers, absorption enhancers, penneability enhancers, stabilizers, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, and multi drug resistance protein inhibitors. Altera pore fom1er, process parameters and combinations thereof. 15 Thus, changing a parameter, such as a pore former concentration, or the conditions of the curing, as will be discussed in more details below, (see Example 5) allows to change the release oftopiramate from any given bead population and to selectively adjust the formulation to the pre-determined 20 release profile. The release profile, in its tum, may be chosen or modified in such a way as to achieve the best treatment modality depending on the specific needs of the patient population and the nature of the condition. For example, with all things being equal, there exists a mathematical relationship between the release controlling coating level among the cured beads and the 80% in vitro release time. Pre-determined target profiles can therefore be achieved by the interpolation or extrapolation of the relationship curve. For example, when the release controlling coating comprises only ethylcellulose (SURELEASEliD) as a coating material, a logarithmic relationship exists between the % weight gain with the coating and the 80% release time in an in-vitro dissolution test (FIG. 1): Log(Tso% relea,e)=a(% coating)+b. When ethylcellulose/hpmc (SURELEASBID/ OPADRY ) mixture is used, for example, 85:15mixture or 80:20 mixture, a linear relationship exists between the % weight gain with the coating and the 80% release time in an in-vitro dissolution test (FIG. 2): Tso% release =a(% coating)+b. Pore fanners suitable for use in the release controlling coating herein can be organic or inorganic agents, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. Examples of pore formers include but are not limited to organic compounds such as mono-, oligo-, and polysaccharides including sucrose, glucose, fructose, mamlitol, manuose, galactose, sorbitol, pullulan, dextran; polymers soluble in the environment of use such as water-soluble hydrophilic polymers, hydroxyalkylcelluloses, carboxyalkylcelluloses. hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, and the like, dials, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols, or block polymers thereof, polyglycols, poly( a-w )alk')'lenediols; inorganic compounds such as alkali metal salts, lithium carbonate. sodium chloride, sodimn bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, suitable calcinm salts, and the like. T11e release controlling coating in the current invention can further comprise other additives kuown in the art such as plasticizers, anti-adherents, glidants, and antifoams. natively, the fonnulation can also contain enhancers that are separated from the topiramate beads, for example in a separate population of beads or as a powder. In yet another embodiment, the enhancer( s) may be contained in a separate layer on a topiramate-containing bead either under or above the release controlling coating. The beads may fi1rther comprise other phannaceutically active agents suitable for use in combination with topiramate 25 for treatment or prevention of a pathological condition. The additional pharmaceutically active agents, without limitation, may be represented by analgesic and anti-inflammatory compounds such as COX-2 inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs ). narcotic drugs such as opiates and 30 morphinomimetics, synthetic drugs with narcotic properties such as tramadol; anticonvulsants such as valproic acid or its derivatives, carbamazepine, oxcarbazepine, gabapentin, and lamotrigine; anorectics or anti-obesity agents such as sibutramine or other, orlistat or other pancreatic lipase inllibitors, 35 diethylpropion, fiuoxetine, bupropion, amphetamine, methamphetamine, sertraline, zonisamide, andmetfonnin, as well as medications associated with weight-gain, such as sulfonylurea derivatives. insulin, and thiazolidinediones whose weight-gain effect is tempered by topiramate; anti-hyperten- 40 sive agents such as diuretics, anti-adrenergics, calcinm channel blockers, ACE inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, vasodilators, centrally acting adrenergic drugs, and adrenergic neuron blockers; mood stabilizers such as various ±onus/salts oflithium, Omega-3 fatty 45 acids and others known in the art, drugs for treatment or prevention of migraines, such as ergot derivatives or trip tans, or any other phannaceutical or nutraceutical ingredient that can be safely and beneficially combined with topiramate. A relative amount of every bead population in the complete 50 formulation is detennined on the basis of the pharmacokinetic data of the separate bead populations and the pre-determined release profile and will be discussed in more detail in Example 6. In another embodiment, the fonnulation of the present 55 invention comprises an extended release component as described above, and an inunediate release component. The IR component may be an enhanced inu11ediate release composition. The enhanced immediate release composition may be characterized by a faster in vitro topiran1ate release as 60 compared to their formulation. Preferably, at least 80% of an active compound from the enhanced immediate release composition is released in a time period of not more than 30 minutes. More preferably, at least 50% of an active compound from the enhanced immediate release composition is released 65 in a time period of not more than! 0 minutes, and at least 25% is dissolved in a time period of not more than 5 minutes after the oral administration. In the most preferred embodiment of

40 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 40 of 155 PageID: the present invention, at least 75% of the active compound is released from the EIR composition in a time period of not more than I 0 minutes. The embodiment in which the IR component is an enhanced immediate release composition will be discussed in more details below. In addition to topiramate and inactive excipients, the EIR composition of the present invention comprises at least one agent selected from a group consisting of complexing agents and enhancing agents. Without any limitation, the enhancing agents suitable for the present invention may be selected from the solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, such as non-ionic surfactants, ionic surfactants US 8,298,576 B2 or combinations thereof; stabilizers that include antioxidants, preservatives, buffering agents, bases and other known in the art; enzyme inhibitors, p-glycoprotein inhibitors, multidmg resistance protein inhibitors, or any combinations thereof. The representative, but non-limiting examples of these compounds are Vitamin E TPGS, amino acid such as glutamic acid and glycine, sorbitol, maunose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins such as maltodextrin, Cremophor RH40 (glycerol-polyethylene glycol oxystearate), Gelucire 50/13 (PEG-32 glyceryl palmitostearate), sodium Iaury! sulfate, Tween 80 (polyoxyethylene sorbitan monooleate), benzyl alcohol, Span 20 (sorbitan monolaurate), Poloxamer 407, PEG3350, PVP K25, oleic acid, Capmul GMO (glycerylmonooleate), sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, crosscam1ellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydroxypropylcellulose, microcrystalline cellulose, sodiun1 bicarbonate, calcitun citrate, sodium docusate, and menthol, among others. Enhancers can be combined to achieve multiple enhancement effects, for example, solubility enhance- 35 ment combined with permeability enhancement and p-glycoprotein inhibition, or to provide a synergistic enhancement effect to achieve greater and more efficient enhancement. For example, polyglycolized glycerides (different grades of Gelucire) can be combined with sodium Iaury! sulfate to 40 achieve higher solubility enhancement as well as faster dissolution of topiramate. 10 mate can be incremental to reduce the viscosity of the complex solution and to achieve better complexation. In a further embodiment, the EIR component of the present invention is contained in at least one bead population. To piramate EIR beads can be prepared using processes suitable for bead manufacturing, such as coating of a topiranmte suspension, dispersion or solution onto an inert carrier, or by roller compaction, granulation, extrusion/spheronization, or powder coating, and are not limited by the examples cited 1 o therein. The enhancing agents of the present invention can be incorporated into the topiramate containing beads, or may be contained in other beads separated from the topiramate containing beads. By way of a non-limiting example, topiramatecontaining EIR beads were prepared by coating topiramate 15 dispersion onto an inert carrier such as sugar spheres. The topiramate dispersion, in addition to topiramate in the micronized form or in non-micronized fom1, can contain one or more enhancers, water and optionally a binder such as hydroxypropylcellullose, hydroxypropylmethylcellulose, 20 polyvinylpyrrolidone and polyvinyl alcohol. When the formulation is enhanced with complexing agents, the agents may be first mixed with topiramate and a suitable solvent such as water to form the complex. The topiramate-containing complex is then mixed with a binder 25 solution prepared separately to give the coating dispersion. The coating dispersion is then sprayed onto the inert carrier such as sugar spheres using a fluid bed processor. In an alternative embodiment of the invention, the fornmlation comprises at least one XR bead population, and at least 30 one additional combination bead population consisting of the extended release beads that have an additional il1llllediate In one embodiment, the EIR composition comprises a highly soluble complex of topiramate with a complexing agent that is represented by, but not limited to, cyclodextrins, 45 including cyclodextrin derivatives, such as hydroxypropylbeta-cyclodextrin, beta-cyclodextrin, gal1lllla-cyclodextrin, and alpha-cyclodextrin. The ratio of cyclodextrin to topiramate in the EIR formulation is preferably less than 20: I and more preferably less than5:1. In the most preferred embodi- 50 ment, the complexing agent is hydroxypropyl beta cyclodextrin. The highly soluble complex oftopiramate and cyclodextrin is prepared by mixing topiramate and cyclodextrin together in the presence of water. The concentration of cyclodextrin is 55 preferably high to facilitate the formation oftopiramate-enhancer complex. In the case when the complexing agent is hydroxypropyl-beta-cyclodextrin, the concentration of the hydroxypropyl-beta-cyclodextrin solution nsed for mixing with topiramate is greater than 2%, preferably greater than 60 20%, and more preferably at least about 40%. The amount of topiramate is determined by a desired ratio ofhydroxypropylbeta-cyclodextrin to topiramate, which is preferably less than 20:1, and more preferably less than 5:1. The mixing time of the complex solution is from about one hour to about hours, and preferably from about 5 hours to about 24 hours. The addition ofhydroxypropyl-beta-cyclodextrin and topirarelease component layer coated on top of the release controlling coating. This layer may be formed by a suitable loading method such as solution/suspension/dispersion coating, powder coating or wet granulation. In yet another embodiment, at least part (i.e., more than 0.01 %, preferably at least 1%) of the active ingredient may be present in the formulation in a form of micronized particles with the size of from 1 ~m1 to 1000 J.tm, preferably from 2 J.tm to about 200 Jllll, more preferably from 2 Jlm to about 100 Jlm. Further, one or more enhancers may be present in the formulations covered by this embodiment. The enhancers are selected from solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, such as non-ionic surfactants, ionic surfactants or combinations thereof; stabilizers that include antioxidants, preservatives, buffering agents, bases and other known in the art; enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors, or any combinations thereof. Preferably, the enhancer is a solubility enhancer or a dissolution enhancer. The topiramate fommlation of the present invention may be formulated in a dosage form selected from a tablet, a pill, a capsule, a caplet, a troche, a sachet, a cachet, a pouch, sprinkles, or any other fonn suitable for oral administration. In one embodiment of the invention, the dosage form is a gelatin capsule containing the XR component in a form of at least one population of beads, and an optional IR component. The IR component, when present, may be in a form of a powder, or may also be contained in at least one population of beads to achieve faster dissolution oftopiramate (FIG. 5). In an alternative embodiment, part of the total amount of the active ingredient may be incorporated into the aforementioned bead populations that will be contained inside an enclosure such as a capsule, and the rest of the active ingredient can be loaded on the outside of the enclosure by a suitable loading method such as solution/suspension/disper-

41 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 41 of 155 PageID: 438 US 8,298,576 B2 11 sion coating or powder coating or wet granulation. For example, a part of the inn11ediate release topiramate formulation can be loaded by coating on the outside of a capsule that contains within it other populations of topiramate such as extended release topiramate. This dosage form can provide almost instantaneous dissolution of the initial portion of to piramate dose from the outside of the capsule, followed by a sustained release of the rest of topiramate from inside the capsule. In a further embodiment of the invention, the dosage fonn 10 is a tablet. Without imposing any limitations, this embodiment may be exemplified by a multilayered tablet that comprises at least one layer containing the extended release component, and at least one layer comprising the illllllediate release component, wherein their component may or may be 15 not an EIR composition. Tl1e last two embodiments are especially beneficial when fast onset of action followed by sustained release is preferred, as is for example in the cases of a breakthrough migraine episode. The current invention additionally encompasses a method of preparing fonnulations of topiramate, comprising an extended release component, and an optional illllllediate release component, wherein topiramate is released from the formulation at the sustained rate along the pre-determined 25 release profile. The method comprises the following steps: 1. determining the desired release profile; 2. detennining specific amounts of the extended release component and the immediate release component necessary to produce the pre-determined release profile; and 3. incorporating the specified amounts of the components into the formulation. In one embodiment, the method comprises a step for providing an immediate release component, which may be an enhanced innnediate release composition. In another embodiment, the method includes a process for providing an extended release component contained in at least one population of beads characterized by its own rate of release, wherein the process includes the steps of: 1. forming at least one population oftopiramate-containing 40 beads; 2. coating each population of beads with its own coating solution; 3. curing the coating for a period of time to produce a release controlling coating specific for each bead population, 45 and 4. incorporating the beads into the formulation. The exact amount of beads of every population incorporated into the formulation and into the final dosage form is determined using the linear superposition principle (Win- 50 NonLin) on the basis of the pharmacokinetic data of the separate bead populations and the pre-determined release profile (Example 6). Release profiles ofxr topiramate beads can be selectively adjusted, modified or stabilized by curing the beads at an 55 elevated temperature. This process is well known in the art. However, it was unexpectedly discovered that curing the beads in the curing apparatus in the presence of at least one suitable solvent dramatically reduces the curing time necessary to produce a desired release profile and a level of stabil- 60 ity. The curing process that previously required up to two weeks can be carried out by the method of current invention in several hours. The assisting solvents can be selected ±rom those solvents that can dissolve or partially dissolve the coating material, or those that can induce or assist the coalescence or molecular relaxation of the coating material, or those that can reduce 12 electrostatic charge on the dosage forms during curing and those that can facilitate curing at a higher temperature. Examples of these solvents include but are not limited to organic solvents, such as alcohols, ketones, ethers, esters, amides, amines, hydrocarbons including substituted hydrocarbons such as chlorinated hydrocarbons and aromatic hydrocarbons, furans, sulfoxides, organic acids, phenols, super-critical fluids; allllllonia; and water, buffered water, or water solutions of other inorganic or organic compounds, and their combinations. Preferably, water, water-alcohol mixture, water-ketone mixture, water-ammonia mixture, or water-organic acid (for example water-acetic acid) mixture, or combinations thereof are used as the assisting solvents. The curing of the dosage form normally is done in an apparatus that can operate at elevated temperatures and that can deliver the assisting solvents by means such as spray, injection, or vaporization. In the embodiment of the invention when the assisting solvent is sprayed or injected into the 20 curing apparatus, the stream of solvent is introduced directly onto the coated beads. The amount of the solvent necessary to produce the desired effect, such as the desired release parameters and stabilization of the coating, depends on the nature of the solvent and the method of solvent delivery. Typically, when the vaporization method is used, the organic solvents and aqueous solutions may be used in the wide range of vapor concentrations varying from2% to more than 100%, providing an unsaturated, saturated or an oversaturated atmosphere. The pure water, however, has to be 30 used in such an amount as to provide at least a saturated or, preferably, an oversaturated atmosphere in the curing apparatus. At least during the delivery of assisting solvents, the coated beads are mixed or agitated either continuously or in a 35 pulsed matmer. In an altemative embodiment of the invention, hot water steam is introduced into the curing apparatus for a pre-selected period of time. The steam serves simultaneously as a solvent and as a source of heat for the beads. Introduction of steam is followed by a drying period. This method of curing the release controlling coating results in many benefits including the dramatically shortened curing time, increased stability and modification of the release profile, and is not limited to topiramate containing beads, but includes the curing of any microparticles regardless of the dmg. Specifically, active ingredient containing beads, with or without the optional over-coat, are charged to a fluid bed processor or a pan coater and heated to a desired curing temperature range, for example 40 C. to 80 C. for sustained release dosage forms containing ethylcellulose (SURE LEASE ), and 40 C. to 70 C. for sustained release dosage forms containing acrylic polymers (EUDRAGIT RS and EUDRAGIT RL annnonio methacrylate copolymer dispersion, type A and B)). The assisting solvent or solvents, such as water or alcohol-water mixture, are sprayed onto the beads while mixing by, for example, fluidizing or rotating. Altematively, the process is carried out in an oven where hot steam is introduced as previously discussed. Solvent-assisted curing is carried out to a desired curing time length, either in one curing period or in multiple, separate curing periods. The dosage forms can be fhrther dried for a short period of time to remove residual solvents. The solvent-assisted curing process significantly accelerates the curing of release controlling coating on active ingre- 65 dient containing beads as compared to the heat-only curing of the same. In most instances, less than 4 hours of solventassisted curing resulted in more complete curing of the

42 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 42 of 155 PageID: 439 US 8,298,576 B2 13 extended release dosage forms than 2 weeks of heat-only oven curing of the same dosage forms. The present invention also presents a method of treatment or prevention of a pathological condition in a manm1alian subject, comprising orally administering to the subject a therapeutically effective amount of a novel topiran1ate formulation of the instant invention, wherein topiramate is released from the formulation at a sustained rate along the pre-detennined release profile. The method of the current invention possesses the flexibility to selectively adjust the pharmacokinetics of the administered formulations depending on the nature ofthe condition and needs of the patients due to the novel design of the topiramate formulation that comprises an extended release component and an optional inmle- 15 diate release component, and the release profiles of both components can be selectively modified during the preparation process as described above to comply with the predetermined release profile. The pathological condition that may be treated by a method of the present invention is a neurological condition, psychi- 20 atric condition, diabetes and related disorders, cardiovascular condition, obesity, and any other condition or disorder that may be treated or prevented by the topiramate administration. The neurological disorders that may be treated or prevented by a formulation of the present invention include, but 25 are not limited to, epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, perinatal hypoxia ischemia and related damage, chronic neurodegen- 30 erative disorders, acute neurodegeneration, and ALS. Psychiatric disorders that may be treated or prevented by a formulation of the present invention include, but are not limited to bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disor- 35 der, post-traumatic stress disorder, ADHD, impulse control disorders, border line personality disorder, addiction, and autism. Formulations of the present invention may be also used for the treatment and prevention of diabetes and related disor- 40 ders, such as type II diabetes mellitus, diabetic retinopathy, impaired oral glucose tolerance, diabetic skin lesions, diabetic neuropathy, Syndrome X and elevated blood glucose levels; ocular disorders, including but not limited to glaucoma and macular degeneration; cardiovascular disorders represented but not limited to elevated blood pressure and elevated lipids; obesity; asthma; autoimmune disorders; sleep apnea and sleep disorders. The formulations may be also used for inducing weight loss or promoting wound healing, or for any other condition, not specified above, wherein the use oftopiramate is indicated. The invention will be further illustrated by the following Examples, however, without restricting its scope to these embodiments. EXAMPLES Example 1 Extended Release Beads Preparation Topiramate Drug Layering on Sugar Spheres-The "Core" An aqueous suspension of 10-20% (w/w) topiramate (particle size 90% vol. NMT 30 micrometer, 50% vol. NMT 15 micrometer and 10% vol. NMT 5 micrometer) and 0.5-4% ( w /w) HPMC or other aqueous binder can be used as the drug layering coating solution. A fluid bed suited for Wursterspray is assembled and charged with inert carriers such as sugar spheres. The coating suspension is sprayed onto the bed to evenly coat the inert carriers to a desired topiramate loading level. Higher binder concentration in the coating solution may be used for smaller size inert carrier and higher topiramate loading. Inlet airflow rate and product temperature are adjusted to keep the batch from spray-drying the coating material or over-wetting the spheres. Coating of the Core with a Release Controlling Coating A dispersion of a cellulosic polymer such as ethylcellulose and methylcellulose can be used to coat the core in the current invention. Ethylcellulose dispersion (SURELEASE ) can be diluted to a final concentration of about 10% to about 20% and with or without the use of other ingredients such as pore formers. A fluid bed suited for Wurster-spray is assembled and charged with the cores prepared in Example 1. The release controlling coating dispersion is sprayed onto the bed to evenly coat the core to a desired coating level as exemplified in Table 1. TABLE 1 Composition and process Parameters for the extended Release Topiramate Beads XR1a XR1b XR1c XR2a XR2b XR2c XR2d RC* coating Ethylcellulose Ethylcellulose Ethylcellulose Ethylcellulose Ethylcellulose Ethylcellulose Ethylcellulose material (SURE- (SURE- (SURE- (SURE- (SURE- (SURE- (SURE- LEASE tid) LEASE tid) LEASE tid) LEASE tid) LEASE tid) LEASE ) LEASE ) Pore-former OPARDY OPARDY OPARDY Clear Cleax CleaJ RC coating 80:20 80:20 80:20 material to pore-former ratio RC coating 2% 4% 3% 3% 3% 6.5% 6.5% level Product 20' C.-60' c. 20' C.-60' C. 20' C.-60' c. 20' C.-60' c. 20' C.-60' c. 20' C.-60' C. 20' C.-60' C. temperature dming coating Over-coat OPARDY OPARDY OPARDY OPARDY material AMBWhite AMBWhite AMBWhite AMBWhite Over-coat 1.5% 1.5% 1.5% 1.5% coating level

43 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 43 of 155 PageID: 440 US 8,298,576 B TABLE!-continued Composition and process Parameters for the extended Release Topiramate Beads Curing Fluid bed/ Fluid bed/ Fluid bed/ Fluid bed/ method water, or water, or water, or water, or oven oven oven oven RC coating material XR3 XR4 XRS LEASE LEASE LEASE Pore-former Cellulosic Cellulosic polymers polymers (OPADRY (OPADRY Clear) Clear) RC coating material to 80:20 80:20 pore-former ratio RC coating level 3.7% 3.1% 5.2% 20' C.-60' c. 20' C.-60' C. 20' C.-60' C. Over-coat material Over-coat coating level Curing method Fluid Fluid Fluid bed/ bed/water. or bed/water. or water, or oven oven oven Fluid bed/ Fluid bed/ Fluid bed/ water, or water, or water, or oven oven oven XR6 XR7 XR8 Acrylic polymers LEASE LEASE (EUDRA.GIT RL30D/ RS30D) Cellulosic Cellulosic polymers polymers (OPADRY (OPADRY Clear) Clear) 80:20 85:15 9.5% 15% 15% 20' C.-60' C. 20' C.-60' c. 20' C.-60' c. Fluid Fluid bed/ Fluid bed/ bed/water. or water, fluid water, fluid oven bed/5% bed/5% alcohol- alcoholwater, or water, or oven oven *RC-Release Controlling Example 2 30 Example 3 Method of Topiramate-Hydroxypropyl-beta-cyelodextrin Complex Bead Preparation 35 Topiramate EIR Beads Containing Non-Complexing Enhancers Approximately half of the intended amount of topiramate was added to the water with constant mixing followed by sprinkling of hydroxypropyl-beta-cyclodextrin into the dispersion. Once the dispersion became significantly less vis- 40 cous, more drug substance was added followed by sprinkling of more hydroxypropyl-beta-cyclodextrin. The drug and hydroxypropyl-beta-cyclodextrin addition steps were repeated, and the dispersion was mixed for hours. Separately, hydroxypropylmethylcellulose was dissolved in water. The above topiramate-hydroxypropyl-beta-cyclodextrin dispersion and hydroxypropylmethylcellulose solution were mixed together for 15 to 30 minutes and the mixture was screened through an 80-mesh sieve. The resultant dispersion was sprayed onto sugar spheres using a fluid bed processor to yield the enhanced immediate release beads (Table 2). TABLE2 Hydroxypropyl-beta-cyclodextrin Topirarnate EIR Bead Com ositions Topiran1ate is dispersed in a binder solution, such as hydroxypropylmethylcellulose solution, that contains an appropriate amount of enhancer or enhancers such as d-alpha-tocopheryl polyethylene glyco!iooo succinate (vitamin E TPGS) and sodium Iaury! sulfate combination, polyoxyl hydrogenated castor oil (different grades ofcremophor RH), 45 polyglycolized glycerides (different grades of Gelucire ), polyglycolized glycerides (different grades ofgelucire) combined with sodium Iaury! sulfate, or combinations thereof. The resultant dispersion is sprayed onto an inert carrier such as sugar spheres using a fluid bed processor to achieve a desired dmg load (Table 3). Percentage (w/w) in Beads Component Topiramate Hydroxypropyl-betacyclodextrin Hydroxypropylrnethylcellulose Sugar spheres EIR-1 EIR-2 EIR-3 EIR-4 (HPBCD:Dmg = 3:2)* (HPBCD:Dmg = 3:2)* (HPBCD:Dmg = 1 :1)* (HPBCD:Dmg = 1 :2)* *HPBCD:Drug- Hydroxypropyl-beta-cyclodextrin to drug substance ratio

44 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 44 of 155 PageID: TABLE3 Enh,mced Immediate Release Topiramate Bead Compositions Percentage (w!w) in Beads Component EIR-5 EIR-6 EIR-7 Polyoxyl hydrogenated castor oil (Cr<lmophor RJ{40) Sugar spheres Example Topiramate EIR Beads Containing Micronized Particles US 8,298,576 B Miconized or non-micronized topiramate is dispersed in a solution with or without heating, optionally containing dissolution enhancing agents such as mam10se, maltose, mannito!, lactose, maltodextrin and sodium starch glucolate, and optionally containing one or more additional enhancers such as PEG3350, sodium Iaury! sulfate, sodium docusate, polyoxyethylene sorbitan monooleate and Poloxamers, under 30 such process parameters that topiramate particles that remain undissolved have a particle size of about 2micron to about 30 micron. A particle size reduction device such as a homogenizer can also be used to reduce the particle size of undis- 35 solved topiramate. The resultant topiramate dispersion is then a. Plasma concentration versus time curves for the topiramate formulations containing extended release and immediate release bead populations are simulated using WinNonlin Version based on the phannacokinetic data on the sepasprayed onto inert carriers such as sugar spheres in a coating processor such as a fluid bed processor. The formulations obtained are represented in the Table 4: TABLE4 Topiramate EIR Beads containing micronized particles Percentage (w/w) in Beads EIR- EIR- EIR- EIR-8 EIR-9 EIR Topiramate Mannose Maltrin PEG Sodium lauryl 0.5 sulfate Hydroxypropyl-beta cyclodextrin D-alpha-tocopheryl 2.0 polyethylene glycol 1000 succinate 2.0 castor (Cremophor RH40) Sugar spheres Example 5 Method of Curing Beads The topiramate beads coated with a release controlling coating, with or without an overcoat, can be cured using the above-mentioned solvent-assisted curing process, or using the heat-only curing process, to a desired curing level and preferably to complete curing. Specifically, the core is coated to a desired coating level with a solution or dispersion of the release controlling coating material, with or without the above-mentioned additives such as pore-formers, using a fluid bed processor or any other suitable apparatus for coating of the core. Product temperature is controlled at a desirable range, for example 20 C. to 60 C. for the coating of ethylcellulose (SURELEASE ) and 20 C. to 60 C. for acrylic polymers (EUDRAGIT RL and Eudragit EUDRAGIT RS grades). An optional overcoat with materials such as cellulosic polymers (various OPADRY ) is applied thereafter. Curing of the sustained release topiramate beads is carried out either in an oven at 40 C. to 80 C. for SURELEASE containing beads or at 40 C. to 70 C. for EUDRAGIT RL or RS containing beads, or in a fluid bed processor with or without 20 the use of assisting solvents at similar product temperatures. For curing that uses assisting solvents, the assisting so!vent can be delivered through top spray, bottom spray, side spray or injection, or introduced by vaporization. Preferably, water, water-alcohol mixture, water-ketone mixture, water-ammo- 25 nia mixture, or water-organic acid (for example water-acetic acid) mixture, or combinations thereof are used as the assisting solvents Example 6 Sustained Release Formulations oftopiramate rate bead populations that were generated in a comparative randomized single-dose 6-way crossover study in healthy adult volunteers. The study included administration of a mg oral dose of three extended release compositions, designated here as XRI, XR2 and XR3, two immediate release compositions ((TOPAMAX, Ortho-McNeil Neurologies, Inc.) (25 mg BID), and an immediate release bead formulation) and an enhanced il1llllediate release (IR) bead composition. The single dose topiramate plasma concentration profiles for XRI, XR2 and XR3 are shown in FIG. 3. The single dose topiramate plasma concentration profiles for IR are shown in FIG. 4. The data are projected to a steady-state (SS) with a 24 h dosing interval for the sustained release compositions and a 12 hdosinginterval fortopamax, using the linear superposition principle (WinNonlin). The extended release populations XRI, XR2 and XR3, and an immediate release (IR) population are selected in such a way as to be defined by at least one of the three following sets of conditions: 1. for the steady state, for XRI, 1.70 for XR2, 0.40 cmaxir>=cmaxxr2>=0.20 cmaxir for XR3, 0.25 cmaxir>=crnaxxr3>=0.05 crnax!r 2. for in-vitro dissolution, forxrl 1.5 h for XR2, 5 h<=t so%<=8 h for XR3, 8 h<t 80 %<=10 h 3. for a single initial dose in-vivo, for XRI, 4 h<=t max <=8.5 h forxr2, Tma,>=16 h for XR3, T max>= 16 h.

45 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 45 of 155 PageID: 442 US 8,298,576 B2 19 Optionally, the immediate release bead population is composedof enhanced immediate release (EIR) beads such that at least one condition is true: a. for the steady state, 2.40 CmaxiR>=CmaxEIR>=1.20 CmaxiR; b. for in-vitro dissolution, T80%<=30 min; c. for a single initial dose in-vivo, Tmax<=2 h. The results of the pharmacokinetic simulation for the seven exemplary fonnulations are sunnnarized in Table 5 below. These formulations are selected as examples only, and in no way limit the range, compositions or properties of the formu- 10 lations covered by the present invention. TABLES Composition and Pharmacokinetic data of Multi-bead Formulations #1 #2 #3 #4 #5 #6 #7 %XR %XR %XR %IR Rel. BA (%), ss Degree of fluctuation, SS b. based on the results ofwinnonlin simulation discussed in part (a), formulations #1 (A), #3 (B), and#4 (C) were tested in the comparative randomized multi-dose 4-way study following a once a day 50 mg oral dose of three controlled release formulations and a 25 mg twice a day oral doses of 30 TOPAMAXCRI in healthy adult volunteers. The results ofthe study are sunu11arized in Table 6 and FIG. 6: TABLE carrier particles, wherein the topiramate coated inert carrier particles are further coated with a release controlling coating material, wherein the coating material comprises 2-15% by weight of the topiramate coated inert carrier particles, and wherein the XR1 bead population releases 80% of its topiranmte in a continuous mauner over less than or equal to 4 hours; and, (c) the XR2 bead population comprises topiramate at least 80% by weight of the total ammmt oftopiramate in the fonnulation, wherein the topirmnate is a coating on inert carrier particles, wherein the topiramate coated inert carrier particles are coated with a release controlling coating material, wherein the coating material comprises 2-15% by weight of the topiramate coated inert carrier particles, and wherein the XR2 bead population releases 80% of its topiramate in a continuous mmmer over less than 8 hours; wherein the release controlling coating materials comprise methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates or copolymers thereof, and wherein the XR1 and XR2 bead populations have their own specific rates of release. 2. The sustained release foimulation according to claim1, wherein the binder is selected from the group consisting of starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone. 3. The sustained release formulation according to claim 1, wherein their bead population further comprises an enhancing agent selected from the group consisting of Vitamin E TPGS, glutajllic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dex- 35 trins, glycerol-polyethylene glycol oxystearate, polyethylene Pha.rmacok:inetic study data for Multi-bead Formulations Control glycol-32 glyceryl palmitostearate, sodium Iaury! sulfate, polyoxyethylene sorbitanmonooleate, benzyl alcohol, sorbitan monolaurate, polyethylene-polypropylene glycol, polyethylene #!A #3 B #4C (TOPAMAX ) glycol-3350, polyvinylpyrrolidone-k25, oleic acid, 40 glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose %XR %XR stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized %XR3 0 %IR 0 14 starch, hydroxypropylmethylcellulose HPMC, substituted Rel.BA(%), ss hydroxypropylcellulose, microcrystalline cellulose sodium Relative 73% 72% 66% 100% 45 bicarbonate, calcium citrate, sodium docusate, menthol, and Degree of combinations thereof. fluctuation, 4. The sustained release fommlation according to claiml, ss wherein their bead population further comprises a complexing agent selected from the group consisting of cyclodextrin, What is claimed is: so hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, 1. A sustained release formulation of topiramate for oral administration to a manm1alian subject comprising an inunediate release bead population (IR), a first extended release bead population (XR1), and a second extended release bead population (XR2), wherein: (a) their bead population comprises topiramate up to 10% by wt of the total amount oftopiramate in the formulation and % by wt of a binder, wherein the topiramate and binder form a coating on inert carrier particles, wherein the coated inert carrier particles are not coated 60 with a release controlling coating, and wherein the IR bead population releases greater than or equal to 80% of its topiramate in a continuous mmmer over less than or equal to 1 hour; (b) the XR1 bead population comprises topiramate up to 65 20% by wt of the total mnount of topiramate in the formulation, wherein the topiramate is a coating on inert ganuna-cyclodextrin, alpha-cyclodextrin, and derivatives thereof. 5. The sustained release formulation according to claim 1, wherein the XR1 and/or XR2 bead populations further com- 55 prises a pore former selected from the group consisting of glucose, fructose, maj111itol, maj111ose, galactose, sorbitol pullulan, dextran, hydroxyalk')'lcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbomer, dials, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly( a-co )alkylenediols; alkali metal salts and alkaline earth metal salts, and combinations thereof. 6. The formulation of claim 1, wherein their bead population releases greater than or equal to 80% of its topiramate in less than or equal to 30 minutes.

46 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 46 of 155 PageID: 443 US 8,298,576 B The formulation ofclaim1, wherein at least a part of the active ingredient is in a form of micronized particles. 8. The formulation of claiml, wherein said formulation is in a dosage form of a tablet a pill a capsule, a caplet, a troche, a pouch, or sprinkles. 9. The formulation of claim1, wherein the total amount of topiramate in the formulation is from 0.5 to 3000 mg. 10. The formulation of claim 1, wherein the inert carrier particles comprise cellulose spheres, silicon dioxide, starch or sugar spheres The sustainedreleasefonnulation according to claim 1, wherein the coating material comprises methylcellulose, ethylcellulose, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose. 12. The formulation of claim 1, wherein said formulation 15 provides for a maximmn steady state plasma concentration (Cmax) of topiramate which is in the range from 50% to 125% of the maximum plasma concentration produced by the same ammmt of topiramate administered as an immediate release formulation BID. 13. The formulation of claim 1, wherein said formulation provides for a relative steady state AUC in the range of 80% to 125% of the AU C of the same amount of topiramate administered as an immediate release formulation BID. 14. The formulation of claim 1, f'i.jrther comprising an additional pharmaceutically active ingredient in combination with topiramate. 15. A method of treatment of a neurological and/or psychiatric condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of the sustained release formulation of claiml. 16. The method of claim 15, wherein said condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette' s syndrome, infantile 35 spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-tralullatic stress disorder. attention deficit hyperactivity disorder, impulse control disorders, border line personality disorder, addiction, autism, chronic neurodegenerative 40 disorders, acute neurodegeneration, amyotrophic lateral sclerosis. 17. The method of claim 15, wherein the condition is epilepsy. 18. The method of claim 15. wherein the condition is migraine. 19. A sustained release formulation oftopiramate comprising: (a) a first extended release bead population (XR1) comprising up to 20% by wt of the total amount oftopiramate 50 in the formulation, wherein the topiramate is a coating on inert carrier particles and further coated with a release controlling coating material, wherein the release controlling material releases 80% of the topiramate in a continuous manner over less than or equal to 4 hours; 55 and, (b) a second extended release bead population (XR2) comprising at least 80% by weight of the total amount of topiramate in the fommlation, wherein the topiramate is coated onto inert carrier particles and further coated with 60 a release controlling coating material, wherein the release controlling material releases 80% of the topiramate in a continuous matmer over less than 8 hours; wherein the release controlling coating materials comprise 65 methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, 22 cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates or copolymers thereof; and wherein the XR1 and XR2 bead populations have their own specific rates of release. 20. The sustained release formulation according to claim 19, fhrther comprising: (c) an innnediate release (IR) bead population comprises topiramate up to 10% by wt of the total amount of topiramate in the fonnulation and % by wt of a binder, wherein the topiramate and binder form a coating on inert carrier particles, and wherein the IR bead population releases greater than or equal to 80% of its topiramate in a continuous mauner over less than or equal to 1 hour. 21. The sustained release formulation according to claim 20, wherein the IR bead population further comprises atl enhancing agent selected from the group consisting ofvitamin E TPGS, glutamic acid, glycine, sorbitol, mmmose, amy- 20 lose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, polyethylene glycol-32 glyceryl palmitostearate, sodium Iaury! sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, polyethylene-polypropylene glycol, 25 polyethylene glycol-3350, polyvinylpyrrolidone-k25, oleic acid, glycerylmonooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscannellose sodium, carboxymethylcellulose, starch, pregelatinized starch. hydroxypropylmethylcellulose, substi- 30 tuted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodilllll docusate, menthol, atld combinations thereof. 22. The sustained release formulation according to claim 19, further comprising: (c) a third extended release bead population (XR3) comprising up to 15% by weight of the total amount of topiramate in the fommlation, wherein the topirmnate is coated onto inert carrier particles and further coated with a release controlling coating material, wherein the release controlling material releases 80% of the topiramate in a continuous mmmer over less than or equal to 10 hours. 23. The sustained release formulation according to claim 19, wherein the XR1 and/or XR2 bead populations further 45 comprises a pore former selected from the group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, hydroxyalk.-ylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbomer, dials, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly( a-oj )alkylenediols; alkali metal salts and alkaline earth metal salts. and combinations thereof. 24. The sustained release formulation according to claim 19. wherein the coating material comprises methylcellulose. ethylcellulose, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose. 25. The formulation of claim19, wherein said fommlation provides for a relative steady state AUC in the range of 80% to 125% oftheauc of the same amount oftopirmnate administered as an ill1111ediate release formulation BID. 26. The formulation of claim 19, further comprising an additional pham1aceutically active ingredient in combination with topiramate. 27. A method of treatment of a neurological and/or psychiatric condition in a mann11alian subject, comprising orally

47 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 47 of 155 PageID: administering to the subject a therapeutically effective ammmt of the sustained release formulation of claim The method of claim 27, wherein said condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette' s syndrome, infantile spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-tramnatic stress disorder, attention deficit hyperactivity disorder, impulse control disorders, border line person- US 8,298,576 B2 24 ality disorder, addiction, autism, chronic neurodegenerative disorders, acute neurodegeneration, amyotrophic lateral sclerosis. 29. The method of claim 28. wherein the condition is epilepsy. 30. The method of claim 28, wherein the condition is migraine. * * * * *

48 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 48 of 155 PageID: 445 Exhibit B

49 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 49 of 155 PageID: US B2 c12) United States Patent Liang et al. (10) Patent No.: US 8,298,580 B2 (45) Date of Patent: *Oct. 30, 2012 (54) SUSTAINED-RELEASE FORMULATIONS OF TOPIRA~HE (75) Inventors: Likan Liang, Boyds, MD (US); Hua Wang, Clarksville, MD (US); Padmanabh P. Bhatt, Rockville, MD (US); Michael L. Vieira, Gaithersburg, MD (US) (73) Assignee: Supernus Pharmaceuticals, Inc., Rockville, MD (US) ( *) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (21) Appl. No.: 12/926,931 (22) Filed: Dec.17, 2010 This patent is subject to a tem1inal disclaimer. (65) Prior Publication Data US 2011/ A1 Nov. 24, 2011 Related U.S. Application Data (63) Continuation of application No. 11/941,475, filed on Nov. 16, (60) Provisional application No. 60/859,502, filed on Nov. 17,2006. (51) Int. Cl. A61K 9122 ( ) A61K 9114 ( ) A61K ( ) A61P ( ) (52) U.S. Cl /468; 424/497; 424/495; 424/494; 424/490; 424/489; 514/454 (58) Field of Classification Search... None See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 2,528,378 A 10/1950 Mannheimer eta!. 2,675,619 A 4/1954 Cone 2,677,700 A 5/1954 Jackson et a!. 2,781,354 A 2/1957 Mannheimer et a!. 2,979,578 A 4/1961 Curtis 2,996,431 A 8/1961 Barry 3,036,118 A 5/1962 Jackson et a!. 3,139,383 A 6/1964 Neville eta!. 3,535,307 A 10/1970 Moss eta!. 3,811,444 A Heller eta!. 3,829,506 A 8/1974 Schmolka et a!. 3,962,414 A 6/1976 Michaels 3,992,518 A Chien eta!. 4,066,747 A Capozza 4,070,347 A Schmitt 4,079,038 A 3/1978 Choi eta!. 4,083,949 A 4/1978 Benedikt 4,093,709 A 6/1978 Choi eta!. 4,290,426 A 9/1981 Luschen et a!. 4,434,153 A 2/1984 Urquhart et a!. 4,513,006 A 4/1985 Maryanoff et a!. CN 4,721,613 A 1/1988 Urquhart eta!. 4,727,064 A 2/1988 Pitha 4,752,470 A 6/1988 Mehta 4,757,128 A 7/1988 Domb eta!. 4,853,229 A 8/1989 Theeuwes 4,938,763 A 7/1990 Dunn eta!. 4,997,904 A 3/1991 Domb 5,030,447 A 7/1991 Joshi eta!. 5,175,235 A 12/1992 Domb eta!. 5,180,589 A 1/1993 Joshi eta!. 5,225,202 A 7/1993 Hodges eta!. 5,256,440 A 10/1993 Appel eta!. 5,378,475 A 1/1995 Smith eta!. 5,478,577 A 12/1995 Sackler et a!. 5,500,227 A 3/1996 Oshlack et a!. 5,576,311 A 11/1996 Guy 5,753,693 A 5/1998 Shank 5,760,007 A 6/1998 Shank eta!. 5,773,019 A 6/1998 Ashton et a!. 5,935,933 A 8/1999 Shank eta!. 5,955,096 A 9/1999 Santos eta!. 5,985,312 A Jacob eta!. 5,998,380 A 12/1999 Ehrenberg et a!. 6,123,965 A Jacob eta!. 6,156,348 A 12/2000 Santos eta!. 6,191,117 Bl 2/2001 Kozachuk 6,197,346 Bl 3/2001 Mathiowitz et a! Bl 3/2001 Cottrell 6,217,908 Bl 4/2001 Mathiowitz et a!. 6,235,311 Bl 5/2001 Ullah eta!. (Continued) FOREIGN PATENT DOCUMENTS A 9/1996 (Continued) OTHER PUBLICATIONS US 6, 103,281, 08/2000, DelDuca eta!. (withdrawn). Adin et a!., "Topiramate Serum Concentration-to-Dose Ratio," Therapeutic Drug Monitoring, Jun. 2004; 26(3): U.S. Appl. No. 12/926,936, filed Dec. 17, 2010, Liang eta!. Bahk et a!., "Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study," Progress in Nemopsychophannacology & Biological Psychiatry, 2005, 29(1): Beaumanoir, Anne, "The l.andau-kleffner syndrome", In: Roger et a!., Eds. Epileptic Syndromes in Infancy, Childhood, and Adolescence, 2nd Ed., London, England: John Libby, pp , Berge eta!., "Pharmaceutical Salts", J. Pharm. Sci., Jan. 1977, 66(1): (Continued) Primary Examiner- Suzarme Ziska (74) Attorney, Agent, or Firm- Foley & Lardner LLP; Stephen B. Maebius; Sunit Talapatra (57) ABSTRACT Pharmaceutical compositions of topiramate for once-a-day oral administration are provided. The fommlations comprise a sustained-release component and an optional i111111ediaterelease component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-detem1ined release profile. Method of treating or preventing pathological disorders in mammalian subjects comprising the administration of the novel formulations disclosed herein is also provided. 31 Claims, 6 Drawing Sheets

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52 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 52 of 155 PageID: 449 U.S. Patent Oct. 30, 2012 Sheet 1 of 6 US 8,298,580 B2 Fig.1 80% release time vs. %Wt. gain of Release-Controlling Coating For Sure/ease coated Extended Release Beads 1.4 -CD E i= 1.2 I 0.8 CD a; ~ 0.6 'if!. i D) 0..J 0.2 rl"' y = x R 2 = ~ ~ ~ % Release Controlling Coating Weight Gain

53 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 53 of 155 PageID: 450 U.S. Patent Oct. 30, 2012 Sheet 2 of 6 US 8,298,580 B2 Fig. 2 80% release time vs. % Wt. gain of Release-Controlling Coating For Sure/ease / Opadry coated Extended Release Beads c 7 -Q) E 6 i= Q) t/) IV Q) 'i rx: 5 4 ~ 3 0 co 2 / t?" y = 0.935x / R 2 = / / / / -- / % Release Controlling Coating Weight Gain

54 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 54 of 155 PageID: 451 U.S. Patent Oct. 30, 2012 Sheet 3 of 6 US 8,298,580 B2 Fig. 3 Mean (n= 16) PK Profiles from Bead Populations XR1, XR2 and XR3 -XR1 XR2 - -XR , 750-f ~--~--~--~--~ ~ ~ Time (hours)

55 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 55 of 155 PageID: 452 U.S. Patent Oct. 30, 2012 Sheet 4 of 6 US 8,298,580 B2 Fig.4 Mean (n= 16) PK Profiles from the Immediate Release Formulations - -EIRBeads IR Beads --Topamax :::;.E ~ 600 c:: 0 i.. c 450 2l c:: 0 (.) E soo Ill..\'!! a Time (hours)

56 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 56 of 155 PageID: 453 U.S. Patent Oct. 30, 2012 Sheet 5 of 6 US 8,298,580 B2 Fig.5 Dissolution Profiles of Immediate Release Formulations 120 "C 80 (I),_;;: I ~ /, 100 ~ _......""!!!...- _.2: 0 I f 1/) 60 1/)!/' I - - Topamax c. Beads '# Topiramate IR - - Topiramate y I Enhanced IR 1 I Beads Time {min)

57 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 57 of 155 PageID: 454

58 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 58 of 155 PageID: SUSTAINED-RELEASE FORMULATIONS OF TOPIRAMATE CROSS-REFERENCE TO RELATED APPLICATIONS TI1e present application is a Continuation of U.S. application Ser. No. 11/941,475, filed Nov. 16, 2007, which claims benefit of U.S. Provisional Application No. 60/859,502, filed Nov. 17, 2006, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION US 8,298,580 B2 Topiramate is a sulfamate substituted monosaccharide 15 which under the trade name TOPAMAX (Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J., U.S.A.) has been approved for use as an antiepileptic agent, as an adjuvant therapy for patients with partial onset seizures or primary 20 generalized tonic-clonic seizures, and for the prevention of migraine. See generally, Physician's Desk Reference, 60th ed., (2006); see also, U.S. Pat. No. 4,513,006. For the treatment of epilepsy, the recommended dose of Topamax is 400 mg/day in one or multiple doses (Physi- 25 cian's Desk Reference, 60th ed., (2006)). For adults with epilepsy, treatment is initiated with a dose of mg/day, with the dose being titrated in increments of mg at weekly intervals to the recommended or effective dose. Topamax is an immediate release fommlation. Adverse effects associated with the administration of Topamax(RJ include, but are not limited to, somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor 35 slowing, abnormal vision, difficulty with memory, paresthesia, diplopia, renal calculi (kidney stones), hepatic failure, pancreatitis, renal tubular acidosis, acute myopia and secondary angle closure glaucoma (Physician's Desk Reference, 60th ed., (2006)). 40 Hence, though topiramate has a relatively long half-life of 21 hours in vivo, it has not been prescribed (or fommlated) as specific rate of release. In another embodiment of the invention, the sustained release topiramate formulation comprises an innnediate release component in addition to an extended release component. In a preferred embodiment of the invention, the innnediate release component is an enhanced immediate release (EIR) composition. The formulation of the present invention may be incorporated in any oral dosage form such as represented by, but not limited to, a tablet, a pill, a capsule, a troche, a sachet, and sprinkles. It is yet another object of the present invention to provide a method of preparation of a sustained release fommlation of topiramate, comprising an extended release component, and an optional immediate release component, wherein topiraa single, daily-dose, in part due to severe side-effects that often result with peak plasma levels of the dmg when taken in high doses. Instead, Topamax is typically taken in multiple, 45 "divided" doses, usually twice-daily ("BID"). However, administration of the medicament in this mam1er is cumbersome and patients can forget to take their medication in a timely manner. What is more, each administration of a dose is associated with a peak in plasma concentrations of the dmg, and the fluctuations associated with the peaks and valleys of blood plasma levels of the dmg are undesirable. Therefore, there is a need for a formulation oftopiramate, which reduces or eliminates the side effects associated with peaking and fluctuating plasma levels of the dmg and preferably may be administered in a once-daily regimen. New, highly soluble and bioavailable fom1s oftopiramate are also needed in order to increase the safety and effectiveness of the dmg. TI1e instant invention addresses these and other needs by providing a modified formulation oftopiramate characterized by a sustained, non-pulsatile release of an active ingredient. This invention additionally provides an effective, once-daily dosage fom1 of topiramate or salts thereof, which not only 65 enables an effective single daily dose regimen to improve patient compliance but may also reduce some of the side 2 effects of topiramate compared to the current or higher daily doses of immediate release topiramate formulations. SUMMARY OF THE INVENTION It is an object ofthe present invention to provide a sustained release formulation of topiramate for the treatment or prevention of a pathological condition in a mammalian subject, characterized by a sustained rate of topiramate release along 10 a pre-determined release profile. It is yet another object of the present invention to provide topiramate formulation wherein topiramate is released at a rate which results in a reduction in the frequency or severity of at least one side effect associated with the topiramate treatment. It is a further object of the present invention to provide a sustained release formulation of topiramate that can be administered orally once a day. It is an object of the present invention to provide a sustained release fonnulation of topiramate for oral administration to a mammalian subject comprising topiramate as an active ingredient, wherein the active ingredient is released from the formulation at a sustained rate along a pre-determined release profile, and wherein the sustained release formulation comprises an extended release (XR) component and an optional immediate release (IR) component. In one embodiment of the invention, the extended release component is contained in at least one population of beads 30 coated with a release controlling coating. The above-mentioned coating is specific for every bead population and determines its rate of release. Thus, every given bead population included into the formulation is characterized by its own 50 mate is released from the formulation at the sustained rate along the pre-determined release profile, the method comprising the steps of: 1. determining the desired release profile; 2. determining specific amounts of the extended release 55 component and the immediate release component necessary to produce the pre-determined release profile; and 3. incorporating the specified amounts of the components into the fommlation. In one embodiment, the method of preparation additionally 60 includes a process for providing an XR component contained in at least one population of beads, wherein every population of beads is characterized by its own rate of release. This process comprises the steps of 1. forming at least one population oftopiramate-containing beads; 2. coating each population of beads with its own coating solution;

59 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 59 of 155 PageID: 456 US 8,298,580 B curing the coating for a period of time to produce a release controlling coating specific for each bead population, and 4. incorporating the beads into the formulation. The method may optionally include a process for preparation of an IR component, which optionally is an enhanced immediate release (EIR) composition. The enhanced immediate release composition includes at least one agent selected from a group comprising complexing agents and enhancing agents. Without any limitations, the enhancing agents useful 10 in the present invention may be selected from solubilizing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multi drug resistance protein inhibitors or combinations 15 thereof. It is yet another object of the present invention to provide a method of treatment or prevention of a pathological condition in a mammalian subject by orally administering to the subject 4 intervals, are then injected into a chromatographic system fitted with an appropriate detector to quantify the ammmts of drug released during the testing intervals. "C" denotes the concentration of drug in blood plasma, or serum, of a subject, and is generally expressed as mass per unit volume, for exan1ple nanograms per milliliter. For convenience, this concentration may be referred to herein as "drug plasma concentration", "plasma drug concentration" or "plasma concentration" which is intended to be inclusive of a drug concentration measured in any appropriate body fluid or tissue. The plasma drug concentration at ally time following drug administration is referenced as Ctime, as in C9 hr or C4 hr, etc. The maximtun plasma drug concentration during the dosing period is referenced as Cmax, while Cmin refers to the minimum blood plasma drug concentration at the end of a dosing interval; alld Cave refers to an average concentration during the dosing interval. The "degree of fluctuation" is defined as a quotient (Cmax Cmin)/Cave. Persons of skill in the art will appreciate that blood plasma drug concentrations obtained in individual subjects will vary due to interpatient variability in the many parameters affecta therapeutically effective amount of a sustained release topi- 20 ramate formulation of the instant invention. The pathological conditions that may be treated by the method of the present invention include neurological condition, psychiatric condition, diabetes and related disorders, cardiovascular condition, obesity, and any other condition or disorder that may be treated or prevented by topiramate administration. DEFINITIONS For the purposes of this invention, the term "topiramate" 30 includes topiramate or any pharmaceutically acceptable salts thereof. An "i111111ediate release formulation" refers to a formulation that releases greater than or equal to about 80% of the pharmaceutical agent in less than or equal to about 1 hour. For the purposes of this application, an enhancing agent ("enhancer") is defined as any non-phannaceutically active ingredient that improves the therapeutic potential of a fonnulation. The term "enhanced i111111ediate release composition" as 40 used herein describes an immediate release composition improved in terms of a therapeutic potential or treatment modality. "Sustained release" is defined herein as release of a pharmaceutical agent in a continuous malmer over a prolonged 45 period of time. By "prolonged period of time" it is meant a continuous period oftime of greater thall about 1 hour, preferably, greater than about 4 hours, more preferably, greater than about 8 hours, more preferably greater than about 12 hours, more 50 preferably still, greater than about 16 hours up to more than about 24 hours. As used herein, unless otherwise noted, "rate of release" or "release rate" of a drug refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug 55 released per hour (mg/hr) or a percentage of a total drug dose released per hour. Drug release rates for dosage forms are typically measured as an in vitro rate of drug release, i.e., a quantity of drug released from the dosage form per unit time measured under appropriate conditions and in a suitable fluid. 60 The time at which a specified percentage of the drug within a dosage form has been released from the dosage form is referred to as the "T.sub.x" value, where "x" is the percent of drug that has been released. The release rates referred to herein are detem1ined by plac- 65 ing a dosage form to be tested in a medium in an appropriate dissolution bath. Aliquots of the mediulll, collected at pre-set 25 ing drug absorption, distribution, metabolism and excretion. For tllis reason, unless otherwise indicated, when a drug plasma concentration is listed, the value listed is the calculated mean value based on values obtained from a groups of subjects tested. The term "bioavailability" refers to an extent to whichand sometimes rate at which-the active moiety (drug or metabolite) enters systemic circulation, thereby gaining access to the site of action. "AUC" is the area under the plasma concentration-time 35 curve and is considered to be the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation. Side effect is defined herein as a secondary and usually adverse effect of a drug. The term "beads", as used herein, includes, without any limitations on the nature and size thereof, any particles, spheres, beads, granules, pellets, particulates or ally structural units that may be incorporated into an oral dosage form. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the time of release of 80% of the drug vs. % wt. gain of release controlling coating for cured Surelease coated extended release beads. FIG. 2 shows the time of release of 80% of the drug vs. % wt. gain of release controlling coating for cured Surelease / Opadry coated extended release beads. FIG. 3 shows mean (n=l6) pharmacokinetic profiles for bead populations XR1, XR2 and XR3. FIG. 4 shows mean (n=16) pharmacokinetic profiles for the immediate release fommlations. FIG. 5 shows the dissolution profiles oftopamax, topiramate IR beads, and topiramate enhanced i111111ediate release beads. FIG. 6 shows mean PK Profiles for Sustained Release Fonnulations A, B, and C. DETAILED DESCRIPTION OF THE INVENTION Topiralllate is a sulfamate-substituted monosaccharide having the chemical name 2,3:4,5-Di-0-isopropylidenebeta-D-fructopyranose sulfalllate. The molecular fommla of

60 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 60 of 155 PageID: topiramate is Cl2H21N08S, and its chemical stmcture is represented by formula below: US 8,298,580 B2 Topiramate is a white crystalline powder that is soluble in alkaline solutions containing sodium hydroxide or sodium phosphate, soluble in acetone, dimethylsulfoxide and ethanol. However, the solubility of topiramate in water at room 15 temperature is only about 9.8 mg/ml. Topiramate is not extensively metabolized and is excreted largely through the urine (Physician's Desk Reference, 60th ed., (2006)). Topiramate phannacokinetics are linear, producing a dose proportional increase in blood plasma concentration levels 20 with increased dosing, and is not significantly affected by food. Patients taking topiramate over prolonged period of time did not develop resistance to the drug. Following oral administration of an immediate release dosage form, topiramate is rapidly absorbed with plasma dmg concentrations 25 peaking in approximately 2 hours. The mean elimination half-life is reported to be about 21 hours. Currently, topiramate is administered in multiple daily doses in part due to the severe side effects exhibited by the immediate release product, especially when taken in a high 30 single dose. A sustained release topiramate formulation that will be suitable for once-a-day administration and will result in the diminished level or severity of side effects is needed. The present invention provides sustained release fonnula- 35 tion oftopiramate wherein the total daily dose oftopiramate is provided in an effective once-daily dose while minimizing fluctuations in the blood plasma dmg concentration. The current invention also provides for formulations of topiramate wherein the maximum plasma concentration of 40 topiramate is attenuated as compared to the same amount of topiramate administered as an immediate release formulation BID; therefore some of the side effects oftopiramate, such as CNS side effects including but not limited to dizziness, paresthesia, nervousness, psychomotor slowing, confusion, and 45 difficulty with concentration/attention, observed when taking the immediate release product, may be reduced or eliminated. Formulations of the instant invention are characterized by a maximum steady state plasma concentration (Cmax) of topiramate which is higher than the minimal therapeutically 50 effective concentration, and is in the range of 50% to 125% of the maximum plasma concentration produced by the same ammmt oftopiramate administered as an immediate release formulation BID. In one embodiment, the novel formulations provide for a relative Cmax in the range of 80% to 125%, as 55 compared to the same amount oftopiramate administered as an innnediate release formulation BID. In the other embodiment, the invention provides for the Cmax which is lower than the maximum plasma concentration produced by the same ammmt oftopiramate administered as an immediate release formulation BID. The Cmin of the topiramate fonnulation of the present invention is about equal or higher than a Cmin of an equivalent amount of inunediate release topiramate formulation given BID. Compared to the inu11ediate release topiramate fommlation, the sustained release topiramate formulations attenuate the Cmax of topiramate while extending the coverage of 10 6 plasma concentration above the minimum plasma concentration required therapeutic efficacy. The formulation of the current invention provides for a relative steady state AUC in the range of 80% to 125%, while minimizing the degree of fluctuation, which is preferably in the range of25% to 90%, as compared to an equivalent ammmt of immediate release to piramate formulation given in two divided doses (Table 5 and 6). The present invention additionally provides a sustained release topiramate fommlation for the treatment or prevention of a pathological condition in a mammalian subject wherein topiran1ate is released from the formulation at a sustained rate along a pre-determined release profile. Such release is achieved by incorporation into the formulation of an extended release component (XR) and an optional immediate release component (IR). The relative amount of each component in the topiramate formulation of the present invention is determined according to the purpose of administration and a pre-detennined release profile, and the total amount oftopiramate in the fonnulation varies from 0.5 mg to about 3000 mg. In other words, topiramate or its salt is present in the composition in an amount of from about 0.5% to about 85% by weight, and preferably of from about 2% to about 70% by weight. The term "about" has been recited here and throughout the specification to account for variations, which can arise from inaccuracies in measurement inherent and understood by those of ordinary skill in the chemical and pharmaceutical arts. TheXR component of the fonnulationofthe present invention releases topiramate in a continuous manner and is adjusted in such a way that 80% of the active ingredient is released in vitro in the predetermined period of time. By way of example, and by no means limiting the scope ofthe invention, the period of time may be not more than 24 hours, not more than 16 hours, not more than 12 hours, not more than 8 hours, or not more than 4 hours, depending on desired attributes of the final product. In one embodiment, the extended release (XR) component is contained in at least one population of beads coated with a coating that modifies and controls the release of topiramate from the beads (release controlling coating). The release controlling coating is specific for every population of beads and determines the rate of release of topiramate from the given bead population. The beads useful in the formulation of the present invention comprise an inert carrier, topiramate, a binder, an aforementioned release controlling coating and optionally, an overcoat that provides additional protection from moisture, static charge reduction, taste masking and coloring attributes to the particulates. The inert carriers useful in the present invention may be selected from, but are not limited to, a group consisting of cellulose spheres, silicon dioxide. starch and sugar spheres. The inert carrier is present in an amount of from about 15% to about 99% by weight, and preferably in an amount of from about 40% to about 97% by weight. Topiran1ate is introduced to the inert carrier by techniques known to one skilled in the art, such as dmg layering, powder 60 coating, extmsion/spheronization, roller compaction or granulation. Preferably, the introduction method is dmg layering by spraying a suspension of topiramate and a binder onto the inert carrier. The binder may be present in the bead formulation in an 65 amount of from about 0.1% to about 15% by weight, and preferably of from about 0.2% to about 10% by weight. Binders include, but are not limited, to starches, microcrys-

61 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 61 of 155 PageID: talline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, or polyvinylpyrrolidone. The release controlling coating specific for every bead population comprises a coating material, and, optionally, a pore former and other excipients. The coating material is preferably selected from a group comprising cellulosic polymers, such as ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, and cellulose acetate phthalate; polyvinyl alcohol; acrylic polymers such as polyacrylates, polymethacrylates and copolymers thereof, and other water-based or solvent-based coating materials. The release-controlling coating is population-specific in the sense that the rate of release oftopiramate from every bead population is controlled by at least one parameter of the release controlling coating, such as the nature of the coating, coating level, type and concentration of a pore former, process parameters and combinations thereof. Thus, changing a parameter, such as a pore former concentration, or the conditions of the curing, as will be discussed in more details below, (see Example 5) allows to change the release oftopiramate from any given bead population and to selectively adjust the formulation to the pre-determined release profile. The release profile, in its tum, may be chosen or modified in such a way as to achieve the best treatment modality depending on the specific needs of the patient population and the nature of the condition. For example, with all things being equal, there exists a mathematical relationship between the release controlling coating level among the cured beads and the 80% in vitro release time. Pre-determined target profiles can therefore be achieved by the interpolation or extrapolation of the relationship curve. For example, when the release controlling coating comprises only ethylcellulose (Surelease ) as a coating material, a logaritlunic relationship exists between the % weight gain with the coating and the 80% release time in an in-vitro dissolution test (FIG. 1 ): Log(Tso% releaoe)~a(o/ocoating)+b. When ethylcellulose/hpmc (SureleaseriD/OpadryriD) mixture is used, for example, 85:15 mixture or 80:20 mixture, a linear relationship exists between the %weight gain with the coating and the 80% release time in an in-vitro dissolution test (FIG. 2): Tso% release =a(%coating)+b. US 8,298,580 B2 Pore fom1ers suitable for use in the release controlling coating herein can be organic or inorganic agents, and include materials that can be dissolved, extracted or leached from the 50 coating in the environment of use. Examples of pore formers include but are not limited to organic compounds such as mono-, oligo-, and polysaccharides including sucrose, glucose, fructose, mannitol, matmose, galactose, sorbitol pullulan, dextran; polymers soluble in the environment of use such as water-soluble hydrophilic polymers, hydroxyalh:ylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, and the like, diols, polyols, polyhydric alcohols, polyalk"ylene glycols, polyethylene glycols, polypropylene glycols, or block polymers thereof~ polyglycols, poly(a-m)alkylenediols; inorganic compounds such as alkali metal salts, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassitun sulfate, potassium phosphate, sodium acetate, sodium citrate, suitable calcium salts, and the like. 8 The release controlling coating in the current invention can further comprise other additives known in the art such as plasticizers, anti-adherents, glidants, and antifoan1s. In some embodiments, it may be further desirable to optionally coat the XR beads with an "overcoat," to provide, e.g., moisture protection, static charge reduction, taste-masking, flavoring, coloring, and/or polish or other cosmetic appeal to the beads. Suitable coating materials for such an overcoat are known in the art, atld include, but are not limited 10 to, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose, or combinations thereof (for exatnple various Opadry coating materials). Topiratnate-containing beads of the present invention may 15 additionally contain enhancers that may be exemplified by, but not limited to, solubility enhancers, dissolution enhancers, absorption enhancers, permeability enhancers, stabilizers, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, and multidmg resistance protein inhibitors. Alter- 20 natively, the formulation can also contain enhancers that are separated from the topiramate beads, for example in a separate population of beads or as a powder. In yet another embodiment, the enhancer(s) may be contained in a separate layer on a topiramate-containing bead either under or above 25 the release controlling coating. The beads may further comprise other pharmaceutically active agents suitable for use in combination with topiramate for treatment or prevention of a pathological condition. The additional pharmaceutically active agents, without limitation, 30 may be represented by analgesic and anti-inflanm1atory compounds such as COX-2 inhibitors, nonsteroidal anti-inflammatory dmgs (NSAIDs), narcotic dmgs such as opiates and morphinomimetics, synthetic dmgs with narcotic properties such as tramadol; anticonvulsants such as valproic acid or its 35 derivatives, carbamazepine, oxcarbazepine, gabapentin, and lamotrigine; anorectics or anti-obesity agents such as sibutramine or other, orlistat or other pancreatic lipase inhibitors, diethylpropion, fluoxetine, bupropion, atnphetatnine, methamphetamine, sertraline, zonisamide, andmetfom1in, as well 40 as medications associated with weight-gain, such as sulfonylurea derivatives, insulin, and thiazolidinediones whose weight-gain effect is tempered by topiramate; anti-hypertensive agents such as diuretics, anti-adrenergics, calcitun channel blockers, ACE inhibitors, angiotensin II receptor antago- 45 nists, aldosterone antagonists, vasodilators, centrally acting adrenergic dmgs, and adrenergic neuron blockers; mood stabilizers such as various forms/salts oflithium, Omega-3 fatty acids and others known in the art, dmgs for treatment or prevention of migraines, such as ergot derivatives or triptans, or any other pharmaceutical or nutraceutical ingredient that can be safely and beneficially combined with topiramate. A relative amount of every bead population in the complete formulation is determined on the basis of the pharmacokinetic data of the separate bead populations and the pre-deter- 55 mined release profile and will be discussed in more detail in Exatnple 6. In a11other embodiment, the fommlation of the present invention comprises an extended release component as described above, and an innnediate release component. The 60 IR component may be an enhanced illllllediate release composition. The enhat1ced innnediate release composition may be characterized by a faster in vitro topiratnate release as compared to their formulation. Preferably, at least 80% of an active compound from the enhanced immediate release com- 65 position is released in a time period of not more than 30 minutes. More preferably, at least 50% of an active compound from the enhanced inn11ediate release composition is released

62 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 62 of 155 PageID: 459 US 8,298,580 B2 9 in a time period of not more than 10 minutes, and at least 25% is dissolved in a time period of not more than 5 minutes after the oral administration. In the most preferred embodiment of the present invention, at least 75% of the active compound is released from the EIR composition in a time period of not more than 10 minutes. The embodiment in which the IR component is an enhanced immediate release composition will be discussed in more details below. In addition to topiramate and inactive excipients, the EIR composition of the present invention comprises at least one 10 agent selected from a group consisting of complexing agents and enhancing agents. Without any limitation, the enhancing agents suitable for the present invention may be selected from the solubility enhancing agents, dissolution enhancing agents, absorption 15 enhancing agents, penetration enhancing agents, surface active agents, such as non-ionic surfactants, ionic surfactants hydroxypropylcellullose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol. When the formulation is enhanced with complexing agents, the agents may be first mixed with topiramate and a suitable solvent such as water to fonn the complex. The topiramate-containing complex is then mixed with a binder solution prepared separately to give the coating dispersion. The coating dispersion is then sprayed onto the inert carrier such as sugar spheres using a fluid bed processor. In an altemative embodiment of the invention, the formulation comprises at least one XR bead population, and at least one additional combination bead population consisting of the extended release beads that have an additional innnediate release component layer coated on top of the release controlling coating. This layer may be fonned by a suitable loading method such as solution/suspension/dispersion coating, powder coating or wet granulation. In yet another embodiment, at least part (i.e., more than 0.01 %, preferably at least 1%) of the active ingredient may be present in the formulation in a form of micronized particles with the size of from 1 ~llll to 1000 f.lm, preferably from 2 f.lm to about 200 fllll, more preferably from2 fllll to about 100 ~llll. Further, one or more enhancers may be present in the formuor combinations thereof; stabilizers that include antioxidants, preservatives, buffering agents, bases and other known in the art; enzyme inhibitors, p-glycoprotein inhibitors, multidrug 20 resistance protein inhibitors, or any combinations thereof. The representative, but non-limiting examples of these compounds are Vitamin E TPGS, amino acid such as glutamic acid and glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins such as 25 maltodextrin, Cremophor RH40 (glycerol-polyethylene glycol oxystearate), Gelucire 50/13 (PEG-32 glyceryl palmitostearate), sodiumlauryl sulfate, Tween 80 (polyoxyethylene sorbitan monooleate), benzyl alcohol Span 20 (sorbitan monolaurate), Poloxamer 407, PEG3350, PVP K25, oleic 30 acid, Capmul GMO (glycerylmonooleate ), sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, crosscarmellose soditun, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydroxypropylcellulose, microcrystalline cellulose, sodium bicar- 35 bouate, calcium citrate, sodium docusate, and menthol, among others. Enhancers can be combined to achieve multiple enhancement effects, for example, solubility enhancement combined with permeability enhancement and p-glycoprotein inhibition, or to provide a synergistic enhancement 40 effect to achieve greater and more efficient enhancement. For example, polyglycolized glycerides (different grades of Gelucire) can be combined with sodium lauryl sulfate to achieve higher solubility enhancement as well as faster dissolution of topiramate. In one embodiment, the EIR composition comprises a highly soluble complex of topiramate with a complexing agent that is represented by, but not limited to, cyclodextrins, including cyclodextrin derivatives, such as hydroxypropylbeta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, 50 and alpha-cyclodextrin. The ratio of cyclodextrin to topiramate in the EIR fonnulation is preferably less than 20:1 and more preferably less than 5:1. In the most preferred embodiment, the complexing agent is hydroxypropyl beta cyclodextrill 55 The highly soluble complex oftopiramate and cyclodextrin is prepared by mixing topiramate and cyclodextrin together in the presence of water. The concentration of cyclodextrin is preferably high to facilitate the formation oftopiramate-enhancer complex. In the case when the complexing agent is 60 hydroxypropyl-beta-cyclodextrin, the concentration of the hydroxypropyl-beta-cyclodextrin solution used for mixing with topiramate is greater than 2%, preferably greater than 20%, and more preferably at least about 40%. The amount of topiramate is detem1ined by a desired ratio ofhydroxypropyl- 65 beta-cyclodextrin to topiramate, which is preferably less than 20:1, and more preferably less than 5:1. The mixing time of 10 the complex solution is from about one hour to about 48 hours, and preferably from about 5 hours to about 24 hours. The addition ofhydroxypropyl-beta-cyclodextrin and topiramate can be incremental to reduce the viscosity of the complex solution and to achieve better complexation. In a further embodiment, the EIR component of the present invention is contained in at least one bead population. Topiramate EIR beads can be prepared using processes suitable for bead manufacturing, such as coating of a topiran1ate suspension, dispersion or solution onto an inert carrier, or by roller compaction, granulation, extmsion/spheronization, or powder coating, and are not limited by the examples cited therein. The enhancing agents of the present invention can be incorporated into the topiramate containing beads, or may be contained in other beads separated from the topiramate containing beads. By way of a non-limiting example, topiramatecontaining EIR beads were prepared by coating topiramate dispersion onto an inert carrier such as sugar spheres. The topiramate dispersion, in addition to topiramate in the micronized form or in non-micronized form, can contain one or more enhancers, water and optionally a binder such as 45 lations covered by this embodiment. The enhancers are selected from solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, such as non-ionic surfactants, ionic surfactants or combinations thereof; stabilizers that include antioxidants, preservatives, buffering agents, bases and other known in the art; enzyme inhibitors, p-glycoprotein inhibitors, multidmg resistance protein inhibitors, or any combinations thereof Preferably, the enhancer is a solubility enhancer or a dissolution enhancer. The topiramate formulation of the present invention may be formulated in a dosage fonn selected from a tablet, a pill a capsule, a caplet, a troche, a sachet, a cachet, a pouch, sprinkles, or any other form suitable for oral administration. In one embodiment of the invention, the dosage form is a gelatin capsule containing the XR component in a form of at least one population of beads, and an optional IR component. The IR component, when present, may be in a form of a powder, or may also be contained in at least one population of beads to achieve faster dissolution oftopiramate (FIG. 5). In an alternative embodiment, part of the total amount of the active ingredient may be incorporated into the aforementioned bead populations that will be contained inside an

63 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 63 of 155 PageID: enclosure such as a capsule, and the rest of the active ingredient can be loaded on the outside of the enclosure by a suitable loading method such as solution/suspension/dispersion coating or powder coating or wet granulation. For example, a part of the immediate release topiramate fonnulation can be loaded by coating on the outside of a capsule that contains within it other populations of topiramate such as extended release topiramate. This dosage fonn can provide almost instantaneous dissolution of the initial portion of to piran1ate dose from the outside of the capsule, followed by a sustained release of the rest of topiramate from inside the capsule. In a further embodiment of the invention, the dosage fonn is a tablet. Without imposing any limitations, this embodiment may be exemplified by a multilayered tablet that comprises at least one layer containing the extended release component, and at least one layer comprising the innnediate release component, wherein their component may or may be not an EIR composition. l11e last two embodiments are especially beneficial when fast onset of action followed by sustained release is preferred, as is for example in the cases of a breakthrough migraine episode. The current invention additionally encompasses a method of preparing fonnulations of topiramate, comprising an extended release component, and an optional innnediate release component, wherein topiramate is released from the formulation at the sustained rate along the pre-determined release profile. The method comprises the following steps: 1. determining the desired release profile; 2. detennining specific amounts of the extended release component and the immediate release component necessary to produce the pre-determined release profile; and 3. incorporating the specified amounts of the components into the fonnulation. In one embodiment, the method comprises a step for providing an innnediate release component, which may be an enhanced innnediate release composition. US 8,298,580 B2 In another embodiment, the method includes a process for 40 providing an extended release component contained in at least one population of beads characterized by its own rate of release, wherein the process includes the steps of: 1. fanning at least one population oftopiramate-containing beads; 2. coating each population of beads with its own coating solution; 3. curing the coating for a period of time to produce a release controlling coating specific for each bead population, and 4. incorporating the beads into the formulation. The exact amount of beads of every population incorporated into the fonnulation and into the final dosage form is determined using the linear superposition principle (Win NonLin) on the basis of the pharmacokinetic data of the separate bead populations and the pre-determined release profile (Example 6). Release profiles ofxr topiramate beads can be selectively adjusted, modified or stabilized by curing the beads at an elevated temperature. This process is well known in the art. However, it was unexpectedly discovered that curing the beads in the curing apparatus in the presence of at least one suitable solvent dramatically reduces the curing time necessary to produce a desired release profile and a level of stability. The curing process that previously required up to two 65 weeks can be carried out by the method of current invention in several hours. 12 The assisting solvents can be selected from those solvents that can dissolve or partially dissolve the coating material, or those that can induce or assist the coalescence or molecular relaxation of the coating material or those that can reduce electrostatic charge on the dosage forms during curing and those that can facilitate curing at a higher temperature. Examples of these solvents include but are not limited to organic solvents, such as alcohols, ketones, ethers, esters, amides, amines, hydrocarbons including substituted hydro- 10 carbons such as chlorinated hydrocarbons and aromatic hydrocarbons, furans, sulfoxides, organic acids, phenols, super-critical fluids; annnonia; and water, buffered water, or water solutions of other inorganic or organic compounds, and their combinations. Preferably, water, water-alcohol mixture, 15 water-ketone mixture, water-ammonia mixture, or water-organic acid (for example water-acetic acid) mixture, or combinations thereof are used as the assisting solvents. The curing of the dosage form nonnally is done in an apparatus that can operate at elevated temperatures and that 20 can deliver the assisting solvents by means such as spray, injection, or vaporization. In the embodiment of the invention when the assisting solvent is sprayed or injected into the curing apparatus, the stream of solvent is introduced directly onto the coated beads. The amount of the solvent necessary to 25 produce the desired effect, such as the desired release parameters and stabilization of the coating, depends on the nature of the solvent and the method of solvent delivery. Typically, when the vaporization method is used, the organic solvents and aqueous solutions may be used in the 30 wide range of vapor concentrations varying from 2% to more than 100%, providing an unsaturated, saturated or an oversaturated atmosphere. The pure water, however, has to be used in such an amount as to provide at least a saturated or, preferably, an oversaturated atmosphere in the curing appa- 35 ratus. At least during the delivery of assisting solvents, the coated beads are mixed or agitated either continuously or in a pulsed mmmer. In an alternative embodiment of the invention, hot water steam is introduced into the curing apparatus for a pre-selected period of time. The steam serves simultaneously as a solvent and as a source of heat for the beads. Introduction of stemn is followed by a drying period. This method of curing the release controlling coating results in many benefits including the dramatically shortened 45 curing time, increased stability and modification of the release profile, and is not limited to topiramate containing beads, but includes the curing of any microparticles regardless of the drug. Specifically, active ingredient containing beads, with or 50 without the optional over-coat, are charged to a fluid bed processor or a pan coater and heated to a desired curing temperature range, for example 40 C. to 80 C. for sustained release dosage forms containing ethylcellulose (Surelease@), and 40 C. to 70 C. for sustained release dosage fonns 55 containing acrylic polymers (Eudragit@ RS m1d Eudragit@ RL ). The assisting solvent or solvents, such as water or alcohol-water mixture, are sprayed onto the beads while mixing by, for example, fluidizing or rotating. Alternatively, the process is carried out in an oven where hot steam is introduced as 60 previously discussed. Solvent-assisted curing is carried out to a desired curing time length, either in one curing period or in multiple, separate curing periods. The dosage forms can be further dried for a short period of time to remove residual solvents. The solvent-assisted curing process significantly accelerates the curing of release controlling coating on active ingredient containing beads as compared to the heat-only curing of

64 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 64 of 155 PageID: 461 US 8,298,580 B2 13 the same. In most instances, less than 4 hours of solventassisted curing resulted in more complete curing of the extended release dosage forms than 2 weeks of heat-only oven curing of the same dosage forms. The present invention also presents a method of treatment or prevention of a pathological condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of a novel topiramate formulation of the instant invention, wherein topiramate is 10 released from the formulation at a sustained rate along the pre-detem1ined release profile. The method of the current invention possesses the flexibility to selectively adjust the pharmacokinetics of the administered formulations depending on the nature ofthe condition and needs of the patients due betic neuropathy, Syndrome X and elevated blood glucose levels; ocular disorders, including but not limited to glaucoma and macular degeneration; cardiovascular disorders represented but not limited to elevated blood pressure and elevated lipids; obesity; asthma; autoimmune disorders; sleep apnea and sleep disorders. The formulations may be also used for inducing weight loss or promoting wound healing, or for any other condition, not specified above, wherein the use oftopiramate is indicated. The invention will be fl.jrther illustrated by the following Examples, however, without restricting its scope to these embodiments. EXAMPLES to the novel design of the topiramate formulation that com- Example 1 prises an extended release component and an optional inmlediate release component, and the release profiles of both components can be selectively modified during the preparation process as described above to comply with the predetermined release 20 profile. The pathological condition that may be treated by a method of the present invention is a neurological condition, psychiatric condition, diabetes and related disorders, cardiovascular condition, obesity, and any other condition or disorder that may be treated or prevented by the topiramate administration. The neurological disorders that may be treated or prevented by a formulation of the present invention include, but are not limited to, epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, perinatal hypoxia ischemia and related damage, chronic neurodegenerative disorders, acute neurodegeneration, and ALS. Psychiatric disorders that may be treated or prevented by a formulation of the present invention include, but are not limited to bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, ADHD, impulse control disorders, border line personality disorder, addiction, and autism. Formulations ofthe present invention may be also used for the treatment and prevention of diabetes and related disorders, such as type II diabetes mellitus, diabetic retinopathy, impaired oral glucose tolerance, diabetic skin lesions, dia- Extended Release Beads Preparation Topiramate Drug Layering on Sugar Spheres-the "Core" Au aqueous suspension of A) (w/w) topiramate (particle size 90% vol. NMT 30 micrometer, 50% vol. NMT 15micrometer and 10% vol. NMT 5 micrometer) and0.5-4% ( w /w) HPMC or other aqueous binder can be used as the drug layering coating solution. A fluid bed suited for Wurster- 25 spray is assembled and charged with inert carriers such as sugar spheres. The coating suspension is sprayed onto the bed to evenly coat the inert carriers to a desired topiramate loading level. Higher binder concentration in the coating solution may be used for smaller size inert carrier and higher topira mate loading. Inlet airflow rate and product temperature are adjusted to keep the batch from spray-drying the coating material or over-wetting the spheres. Coating of the Core with a Release Controlling Coating A dispersion of a cellulosic polymer such as ethylcellulose and methylcellulose can be used to coatthe core in the current invention. Ethylcellulose dispersion (SureleaseiRI) can be diluted to a final concentration of about 10% to about 20% and with or without the use of other ingredients such as pore formers. A fluid bed suited for Wurster-spray is assembled and charged with the cores prepared in Example 1. The release controlling coating dispersion is sprayed onto the bed to evenly coat the core to a desired coating level as exemplified in Table I. TABLE 1 Composition and process Parameters for the extended Release XR1a XR1b XR1c XR2a XR2b XR2c XR2d RC* coating Ethyl- Ethyl- Ethyl- Ethyl- Ethyl- Ethyl- Ethylmaterial cellulose cellulose cellulose cellulose cellulose cellulose cellulose (Sure lease) (Surelease) (Surelease) (Surelease) (Sure lease) (Sure lease) (Sure lease) Pore-former Opadry Opadry Opadry CleaJ Clear Clear RC coating 80:20 80:20 80:20 material to pore-former ratio RC coating 2% 4% 3% 3% 3% 6.5% 6.5% level Product 20' C.-60' C. 20' C.-60' c. 20' C.-60' c. 20' C.-60' C. 20' C.-60' C. 20' C.-60' C. 20' C.-60' C. coating Over-coat Opadry Opadry Opadry Opadry material AMBWhite AMBWhite AMBWhite AMBWhite Over-coat 1.5% 1.5% 1.5% 1.5% coating level Cming Fluid bed/ Fluid bed/ Fluid bed/ Fluid bed/ Fluid bed/ Fluid bed/ Fluid bed! method water, or water, or water, or water, or water, or water, or water. or

65 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 65 of 155 PageID: 462 US 8,298,580 B TABLE!-continued Composition and process Parameters for the extended Release oven oven oven oven oven oven oven Topiramate Beads XR3 XR4 XR5 RC coating Ethylcellulose Ethylcellulose Ethylcellulose material (Surelease) (Surelease) (Surelease) Pore-former Cellulosic Cellulosic polymers polymers (Opadry (Opadry Clear) Clear) RC coating 80:20 80:20 material to pore-former ratio RC coating 3.7% 3.1% 5.2% level Product 20' C.-60' c. 20' C.-60' c. 20' C.-60' C. temperature during coating Over-coat material Over-coat coating level Curing method Fluid bed/ Fluid bed! Fluid bed! water. or water, or water, or oven oven oven XR6 XR7 XR8 Ethylcellulose Ethylcellulose Acrylic (Sure lease) (Sure lease) polymers (Eudragit RL30D/ RS30D) Cellulosic Cellulosic polymers polymers (Opadry (Opadry Clear) Clear) 80:20 85:15 9.5% 15% 15% 20' C.-60' C. 20' C.-60' c. 20' C.-60' c. Fluid bed/ Fluid bed/ Fluid bed/ water. or water, fluid water, fluid oven bed/5% bed/5% alcohol- alcoholwater, or water. or oven oven *RC~Release Controlling Example 2 Method of Topiramate-Hydroxypropyl-Beta-Cyclodextrin Complex Bead Preparation Approximately half of the intended an10unt of topiramate was added to the water with constant mixing followed by sprinkling of hydroxypropyl-beta-cyclodextrin into the dispersion. Once the dispersion became significantly less viscous, more drug substance was added followed by sprinkling of more hydroxypropyl-beta-cyclodextrin. The drug and hydroxypropyl-beta-cyclodextrin addition steps were 40 repeated, and the dispersion was mixed for hours. Separately, hydroxypropylmethylcellulose was dissolved in water. The above topiramate-hydroxypropyl-beta-cyclodextrin dispersion and hydroxypropylmethylcellulose solution were mixed together for 15 to 30 minutes and the mixture was 45 screened through an SO-mesh sieve. The resultant dispersion was sprayed onto sugar spheres using a fluid bed processor to yield the enhanced innnediate release beads (Table 2). TABLE2 Hydroxypropyl-beta-cyclodextrin- Topiramate EIR Bead Compositions Percentage (wlw) in Beads EIR-1 EIR-2 EIR-3 EIR-4 (HPBCD:Drug (HPBCD:Drug (HPBCD:Drug (HPBCD:Drug Component 3:2)* 3:2)* 1 :!)* 1 :2)* Topiramate Hydroxypropyl-beta-cyclodextrin Hydroxypropylmethylcellulose Sugar spheres *HPBCD:Drug~Hydroxypropyl-beta-cyclodextrin to drug substance ratio

66 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 66 of 155 PageID: Example 3 US 8,298,580 B2 18 TABLE 4-continued Topiramate EIR Beads Containing Non-Complexing Enhancers ToQiramate EIR Beads containing micronized Qarticles Percentage (w/w) in Beads Topiramate is dispersed in a binder solution, such as hydroxypropylmethylcellulose solution, that contains an appropriate amount of enhancer or enhancers such as d-alpha-tocopheryl polyethylene glycollooo succinate (vitamin E TPGS) and sodium Iaury! sulfate combination, polyoxyl 10 hydrogenated castor oil (different grades of Cremophor RH), polyglycolized glycerides (different grades of Gelucire ), polyglycolized glycerides (different grades ofgelucire) combined with sodium Iaury! sulfate, or combinations thereof. The resultant dispersion is sprayed onto an inert carrier such 15 as sugar spheres using a fluid bed processor to achieve a desired drug load (Table 3 ). TABLE3 Enhanced hnmediate Release Topiramate Bead Compositions Percentage (w/w) in Beads Component EIR-5 EIR-6 EIR-7 Topiramate Sodium lauryl sulfate D-alpha-tocopheryl 7.3 polyethylene glycol 1000 succinate Polyoxyl hydrogenated castor oil (Cremophor RH40) 9.1 Polyglycolized glycerides 4.7 (Gelucire Example 4 Topiramate EIR Beads Containing Micronized Particles Miconized or non-micronized topiramate is dispersed in a solution with or without heating, optionally containing dissolution enhancing agents such as mannose, maltose, mannito!, lactose, maltodextrin and sodium starch glucolate, and 45 optionally containing one or more additional enhancers such as PEG3350, sodium Iaury! sulfate, sodium docusate, polyoxyethylene sorbitan monooleate and Poloxamers, under such process parameters that topiramate particles that remain undissolved have a particle size of about 2 micron to about micron. A particle size reduction device such as a homogenizer can also be used to reduce the particle size of midissolved topiramate. The resultant topiramate dispersion is then sprayed onto inert carriers such as sugar spheres in a coating processor such as a fluid bed processor. The formulations 55 obtained are represented in the Table 4: TABLE4 Topiramate EIR Beads containing micronized particles Percentage (w/wl in Beads EIR- EIR- EIR- EIR- EIR Topiramate Mannose EIR EIR- EIR- EIR- EIR- EIR- EIR Maltrin PEG Sodium lauryl 0.5 sulfate Hydroxypropyl-beta cyclodextrin D-alpha-tocopheryl 2.0 polyethylene glycol 1000 succinate Polyoxyl 2.0 hydrogenated castor oil ( Cremophor RH40) Sugar spheres Example 5 Method of Curing Beads The topiramate beads coated with a release controlling coating, with or without an overcoat, can be cured using the above-mentioned solvent-assisted curing process, or using the heat-only curing process, to a desired curing level and preferably to complete curing. Specifically, the core is coated to a desired coating level with a solution or dispersion ofthe release controlling coating material, with or without the above-mentioned additives such as pore-formers, using a fluid bed processor or any other suitable apparatus for coating of the core. Product temperature is controlled at a desirable range, for example 20 C. to 60 C. for the coating of ethylcellulose (SureleaseCID) and 20 C. to 60 C. for acrylic polymers (Eudragit RL and EudragitCID RS grades). An optional overcoat with materials 40 such as cellulosic polymers (various OpadryCID) is applied thereafter. Curing of the sustained release topiramate beads is carried out either in an oven at 40 C. to 80 C. for Sure lease containing beads or at 40 C. to 70 C. for Eudragit@ RL or RS containing beads, or in a fluid bed processor with or without the use of assisting solvents at similar product temperatures. For curing that uses assisting solvents, the assisting solvent can be delivered through top spray, bottom spray, side spray or injection, or introduced by vaporization. Preferably, water, water-alcohol mixture, water-ketone mixture, water-ammonia mixture, or water-organic acid (for example water-acetic acid) mixture, or combinations thereof are used as the assisting solvents. Example 6 Sustained Release Formulations oftopiramate a. Plasma concentration versus time curves for the topira- 60 mate formulations containing extended release and immediate release bead populations are simulated using WinNonlin Version based on the pharmacokinetic data on the separate bead populations that were generated in a comparative randomized single-dose 6-way crossover study in healthy 65 adult volunteers. The study included administration of a 50 mg oral dose of three extended release compositions, designated here as XRI, XR2 and XR3, two immediate release

67 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 67 of 155 PageID: compositions ((Topamax, Ortho-McNeil Neurologies, Inc.) (25 mg BID), and an immediate release bead formul~tion) and an enhanced immediate release (IR) bead c?mposltion. The single dose topiramate plasma concentratwn profiles for XR1, XR2 andxr3 are shown in FIG. 3. The single dose topiramate plasma concentration profiles for IR are shown in FIG. 4. The data are projected to a steady-state (SS) with a 24 h dosina interval for the sustained release compositions and a 12 h dosing interval for Topamax, using the linear superposition principle (WinNonlin). The extended release populations XR1, XR2 and XR3, and an immediate release (IR) population are selected in such a way as to be defined by at least one of the three following sets of conditions: 1. for the steady state, for XR1, 1.70CmaxiR>=Cm<L.:XRl>= 1.30CmaxiR for XR2, 0.40Cm<LTlR>=Cmax. R2>=0.20CmaxiR for XR3, 0.25CmaxiR>=C m<lvyr3>=0.05c maxir 2. for in-vitro dissolution, for XR1, 1.5,,,-~, OCM -.._~~.., h for XR2, 5 h<= T so% <=8 h for XR3, 8 h<t 80 %<=10 h 3. for a single initial dose in-vivo, for XRl, 4 h<=tmax<=8.5 h US 8,298,580 B2 forxr2, h 25 for XR3, Tm,_,>=16 h. Optionally, the immediate release bead population is composed of enhanced immediate release (EIR) beads such that at least one condition is true: a. for the steady state, 2.40CmaxiR>=CmaxEIR>= 1.20CmaxiR; b. for in-vitro dis- 30 solution, T80%<=30 min; c. for a single initial dose in-vivo, Tmax<=2 h. The results of the pharmacokinetic simulation for the seven exemplary fonnulations are sunnnarized in Table 5 below. These formulations are selected as examples only, and in no 35 way limit the range, compositions or properties of the formulations covered by the present invention. TABLES Composition and Pharmacokinetic data ofmnlti-bead Formulations #1 #2 #3 #4 #5 #6 #7 %XR %XR %XR %IR I) I) Rei.BA(%), ss Degree of fluctuation. SS b. Based on the results ofwinnonlin simulation discussed in part (a), formulations #1 (A), #3 (B), and #4 (C) were tested in the comparative randomized multi-dose 4-way study following a once a day 50 mg oral dose of three controlled 55 release formulations and a 25 mg twice a day oral doses of Topamax in healthy adult volunteers. The results of the study are summarized in Table 6 and FIG. 6: %XR1 %XR2 TABLE6 Pharmacokinetic study data for Multi-bead Formulations #!A #3 B 0 86 #4C Control (Toparnax ) TABLE 6-continued Pharmacokinetic study data for Multi-bead Formulations #!A #3 B #4C Control (Toparnax ) %XR3 %IR Rei. BA(%), ss Relative 73% 72% 66% 100% Degree of fluctuation, ss What is claimed is: 1. A sustained release formulation of topiramate comprising topiramate as an active ingredient, which is released from the formulation along a pre-detennined release profile, the formulation comprising: (a) at least two diflerent extended release topiramate-containing components, wherein each component comprises a release controlling coating specific for its component and comprising a coating material selected fro~ the group consisting of cellulosic polymers and aery he polymers, and, optionally, (b) an innnediate release (IR) topiramate-containing component comprising:. (i) a complexing agent selected from the group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, cyclodextrin, and cyclodextrin derivative, and/or (ii) an enhancing agent selected from the group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mam1itol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, polyethylene glycol-32 glyceryl palmitostearate, sodium Iaury! sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, polyethylene-polypropylene glycol, polyethylene glycol-3350, polyvinylpyrrolidone-k25, oleic acid, glycerylmonooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol, and combinations thereof; wherein all of the components release topiramate in a continuous manner and at least one of the two XR components releases the topiramate contained therein such that greater than or equal to about 80% of the topiramate is released in vitro in less than or equal to about 4 hours. 2. The formulation of claim 1, wherein their component exhibits a release profile such that 80% of the active ingredient is dissolved in not more than 1 hour. 3. The formulation according to claim 1, wherein at least one of the two XR components further comprises a binder 60 selected from the group consisting of starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone. 4. The formulation according to claiml, wherein at least 65 one of the two XR components further comprises a pore former selected from the group consisting of glucose, fructose, mannitol, mam1ose, galactose, sorbitol, pullulan, dext-

68 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 68 of 155 PageID: ran, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbomer, dials, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly( a.-w )alkylenediols; alkali metal salts and alkaline earth metal salts, and combinations thereof. 5. The formulation of claim1, wherein at least a part of the active ingredient is in a form of micronized particles. US 8,298,580 B2 6. The formulation of claim1, wherein the formulation is in a dosage fonn of a tablet, a pill, a capsule, a caplet, a troche, a pouch, or sprinkles. 7. The formulation of claim1, wherein the total amount of topiramate in the formulation is from 0.5 to 3000 mg The formulation of claim 1, wherein at least one of the two XR components comprises an inert carrier selected from the group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres. 9. The formulation of claim1, wherein the release control- 20 ling coating comprises ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates or copolymers thereof. 10. The formulation of claim 1, wherein the formulation 25 provides for a maximum steady state plasma concentration (Cmax) of topiramate which is in the range from 50% to 125% of the maximum plasma concentration produced by the same amount of topiramate administered as an innnediate release formulation BID The formulation of claim 1, wherein the formulation provides for a relative steady state AUC in the range of 80% to 125% oftheauc of the same amount oftopiramateadministered as an immediate release formulation BID. 12. The fonnulation of claim 1, further comprising an additional phannaceutically active ingredient in combination with topiramate. 13. A method of treatment of a neurological and/or psychiatric condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of a sustained release formulation of topiramate according to claim The method of claim 13, wherein said condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neu- 45 ralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-tratunatic stress disorder, attention deficit hyperactivity disorder (ADHD), impulse control disorders, border 50 line personality disorder, addiction, autism, chronic neurodegenerative disorders, acute neurodegeneration, amyotropic lateral sclerosis (ALS). 15. The method of claim 14, wherein the condition is epilepsy. 16. The method of claim 14, wherein the condition is migraine. 17. A sustained release formulation of topiramate comprising topiramate as an active ingredient, which is released from the formulation along a pre-determined release profile, the formulation comprising: (a) at least two different extended release topiramate-containing components, wherein each component comprises a release controlling coating specific for its component and comprising a coating material selected from 65 the group consisting of cellulosic polymers and acrylic polymers, and, optionally, 1 o (b) an innnediate release (IR) topiramate-containing component comprising: (i) a complexing agent selected from the group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, cyclodextrin, and cyclodextrin derivative, and/or (ii) an enhancing agent selected from the group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mam10se, amylose, maltose, mam1itol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, polyethylene glycol-32 glyceryl palmitostearate, sodiumlauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, polyethylene-polypropylene glycol, polyethylene glycol-3350, polyvinylpyrrolidone-k25, oleic acid, glycerylmonooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol, and combinations thereof; wherein all of the components release topiramate in a continuous manner and at least one of the two XR components releases the topiramate contained therein such that greater than or equal to about 80% of the topiramate is released in vitro in less than or equal to about 4 hours, and wherein the components in the formulation are present according to the following proportions: F. No. %XR %XR %XR %IR wherein XR1, XR2, XR3, and IR release topinnate in a continuous marmer such that: 1. for in-vitro dissolution, for XR1, 1.5 h<=t 80 %<=4 h; for XR2, 5 h<=t 80 %<=8 h; forxr3, 8h<T 80 %<=10h; forir, T 80 %<=1 h; and/or 2. for a single initial dose in vivo, for XR1, 4 h<=t max <=8.5 h; for XR2, T max>=16 h; for XR3, T m<l,>=16 h. 18. The formulation of claim17, wherein their campo- 55 nent exhibits: a. for in-vitro dissolution, T 80 %<=30 min; and/or b. for a single initial dose in vivo, T mile <=2 h. 19. The fommlation according to claim17, wherein at least one of the two XR components further comprises an binder 60 selected from the group consisting of starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone. 20. The formulation according to claim 17, wherein at least one of the two XR components further comprises a pore former selected from the group consisting of glucose, fructose, mannitol, mam1ose, galactose, sorbitol, pullulan, dext- 4

69 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 69 of 155 PageID: ran, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbomer, dials, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(a.-b)alk:ylenediols; alkali metal salts and alkaline earth metal salts, and combinations thereof. 21. The formulation of claim 17, wherein at least a part of the active ingredient is in a form of micronized particles. 22. The formulation of claim17, wherein the formulation is in a dosage form of a tablet, a pill, a capsule, a caplet, a troche, a pouch, or sprinkles. 23. The formulation of claim17, wherein the total amount oftopiramate in the formulation is from 0.5 to 3000 mg. 24. The formulation of claim 17, wherein at least one of the two XR components comprises an inert carrier selected from the group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres. 25. The fommlation of claim17, wherein the fonnulation provides for a maximum steady state plasma concentration (Cmax) of topiran1ate which is in the range from 50% to 125% of the maximum plasma concentration produced by the same amount of topiramate administered as an inm1ediate release formulation BID. 26. The formulation of claim 17, wherein the formulation provides for a relative steady state AUC in the range of 80% US 8,298,580 B2 24 to 125% oftheauc of the same amount oftopiramate administered as an inm1ediate release fommlation BID. 27. The formulation of claim 17, further comprising an additional phammceutically active ingredient in combination with topiramate. 28. A method of treatment of a neurological and/or psychiatric condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of a sustained release formulation of topiramate 1 o according to claim The method of claim 28, wherein said condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile 15 spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, ADHD, impulse control disorders, border line personality disorder, addiction, autism, chronic neurodegenerative disorders, acute neurodegenera- 20 tion, ALS. 30. The method of claim 29, wherein the condition is epilepsy. 31. The method of claim 29, wherein the condition is migraine. 25 * * * * *

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113 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 113 of 155 PageID: US B2 c12) United States Patent Liang et al. (10) Patent No.: US 8,889,191 B2 (45) Date of Patent: *Nov. 18, 2014 (54) SUSTAINED-RELEASE FORMULATIONS OF TOPIRAMATE (75) Inventors: Likan Liang, Boyds, MD (US); Hua Wang, Clarksville, MD (US); Padmanabh P. Bhatt, Rockville, MD (US); Michael L. Vieira, Gaithersburg, MD (US) (73) Assignee: Supernus Pharmaceuticals, Inc., Rockville, MD (US) ( *) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (21) Appl. No.: 12/926,936 (22) Filed: Dec.17, 2010 This patent is subject to a terminal disclaimer. (65) Prior Publication Data US 2011/ Al Nov. 24, 2011 Related U.S. Application Data (63) Continuation of application No. 11/941,475, filed on Nov. 16, 2007, now Pat. No. 8,298,576. (60) Provisional application No. 60/859,502, filed on Nov. 17,2006. (51) Int. Cl. A61K9/16 A61K9124 A61K9/50 A61K A61K B82Y5100 (52) U.S. Cl. ( ) ( ) ( ) ( ) ( ) ( ) CPC... A61K ( ); A61K ( ); A61K ( ); A61K ( ); A61K ( ); A61K ( ); B82Y 5100 ( ) USPC /490; 427/2.21; 514/25 (58) Field of Classification Search None See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 2,528,378 A 10/1950 Mannheimer et al. 2,675,619 A 4/1954 Cone 2,677,700 A 5/1954 Jackson et a!. 2,781,354 A 2/1957 Mannheimer et al. 2,979,578 A 4/1961 Curtis 2,996,431 A 8/1961 Barry CN wo 3,036,118 A 5/1962 Jackson et a!. 3,139,383 A 6/1964 Neville et al. 3,535,307 A 10/1970 Moss et al. 3,811,444 A 5/1974 Heller et al. 3,829,506 A 8/1974 Schmolka et al. 3,962,414 A 6/1976 Michaels 3,992,518 A Chien eta!. 4,066,747 A Capozza 4,070,347 A Schmitt 4,079,038 A 3/1978 Choi eta!. 4,083,949 A 4/1978 Benedikt 4,093,709 A 6/1978 Choi eta!. 4,290,426 A 9/1981 Luschen et a!. 4,434,153 A 2/1984 Urquhart et al. 4,513,006 A 4/1985 Maryanoff eta!. 4,721,613 A Urquhart et al. 4,727,064 A 2/1988 Pitha 4,752,470 A 6/1988 Mehta 4,757,128 A 7/1988 Domb eta!. 4,853,229 A 8/1989 Theeuwes 4,938,763 A 7/1990 Dunn eta!. 4,997,904 A 3/1991 Domb 5,030,447 A 7/1991 Joshi eta!. 5,175,235 A 12/1992 Domb eta!. 5,180,589 A Joshi eta!. 5,225,202 A 7/1993 Hodges eta!. 5,256,440 A 10/1993 Appel eta!. 5,378,475 A Smith eta!. 5,478,577 A 12/1995 Sackler et a!. 5,500,227 A 3/1996 Oshlack et al. 5,576,311 A Guy 5,753,693 A 5/1998 Shank 5,760,007 A 6/1998 Shank eta!. 5,773,019 A 6/1998 Ashton et al. 5,935,933 A 8/1999 Shank eta!. 5,955,096 A 9/1999 Santos eta!. 5,985,312 A Jacob eta!. (Continued) FOREIGN PATENT DOCUMENTS A 9/1996 WO 93/21906 A (Continued) OTHER PUBLICATIONS US 6, 103,281, 08/2000, DelDuca eta!. (withdrawn). (Continued) Primary Examiner- Suzanne Ziska (7 4) Attorney, Agent, or Firm -Foley & Lardner LLP; Sunit Talapatra (57) ABSTRACT Pharmaceutical compositions of topiramate for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediaterelease component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-determined release profile. Method of treating or preventing pathological disorders in mammalian subjects comprising the administration of the novel formulations disclosed herein is also provided. 24 Claims, 6 Drawing Sheets

114 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 114 of 155 PageID: 511 US 8,889,191 B2 Page 2 (56) References Cited U.S. PATENT DOCUMENTS 5,998,380 A 12/1999 Ehrenberg et al. 6,123,965 A 9/2000 Jacob eta!. 6,156,348 A 12/2000 Santos eta!. 6,159,501 A 12/2000 Skinhoj 6,191,117 Bl 2/2001 Kozachuk 6,197,346 Bl 3/2001 Mathiowitz eta!. 6,201,010 Bl 3/2001 Cottrell 6,217,908 Bl 4/2001 Mathiowitz eta!. 6,235,311 Bl 5/2001 Ullah et al. 6,248,363 Bl 6/2001 Patel eta!. 6,294,192 Bl 9/2001 Patel eta!. 6,319,903 Bl Carrazana et al. 6,344,215 Bl Bettman et a!. 6,365,187 B2 4/2002 Mathiowitz eta!. 6,368,586 Bl 4/2002 Jacob eta!. 6,479,467 Bl Buchanan et a!. 6,503,884 Bl Ehrenberg et al. 6,514,531 Bl 2/2003 Alaux eta!. 6,524,620 B2 2/2003 Cheng et al. 6,559,293 Bl * 5/2003 Almarsson et a!. 6,562,865 Bl 5/2003 Coddet a!. 6,569,463 B2 5/2003 Patel eta!. 6,696,091 B2 2/2004 Thakur eta!. 6,699,840 B2 3/2004 Almarsson et a!. 6,797,283 Bl 9/2004 Edgren eta!. 6,923,988 B2 8/2005 Patel eta!. 7,018,609 B2 3/2006 Hwang Pun et al. 7,195,778 B2 3/2007 Fleshner-Barak eta!. 7,611,722 B Lerner eta!. 7,737,133 B2 6/2010 Devane et al. 7,763,635 B2 7/2010 Kidane eta!. 2002/ Al 4/2002 Cherukuri et al. 2002/ Al 5/2002 Devane et al. 2002/ Al 5/2002 Thakur eta!. 2002/ Al 10/2002 Vandecruys 2003/ AI Pun eta!. 2003/ Al 4/2003 Patel eta!. 2003/ Al 4/2003 Cutler 2003/ Al 5/2003 Louie-Helmet a!. 2003/ Al 7/2003 Louie-Helmet a!. 2003/ Al 8/2003 Lim eta!. 2003/ AI 8/2003 Perce! eta!. 2003/ Al 9/2003 Almarsson et a!. 2003/ Al Patel eta!. 2003/ Al 12/2003 Livingstone 2004/ Al Najarian 2004/ Al 2/2004 Hasenzahl et a!. 2004/ Al 2/2004 Kositprapa 2004/ Al 3/2004 Lerner eta!. 2004/ Al 3/2004 Almarsson et a!. 2004/ Al 4/2004 Redner et al. 2004/ Al 5/2004 Edgren eta!. 2004/ AI 5/2004 Vaya eta!. 2004/ AI 6/2004 Shefer et al. 2004/ AI 6/2004 Jao eta!. 2004/ Al 6/2004 Hirsh et al. 2004/ Al 7/2004 Hirsh et al. 2004/ AI 8/2004 Thakur eta!. 2004/ AI 8/2004 Connor 2004/ AI 9/2004 Kannan eta!. 2004/ AI Legrand et a!. 2004/ Al 12/2004 Gustow eta!. 2005/ Al 3/2005 Kidane eta!. 2005/ Al 3/2005 Reyes et al. 2005/ Al 3/2005 Modi eta!. 2005/ Al 5/2005 Yan eta!. 2005/ Al 5/2005 Venkatesh eta!. 2005/ Al 6/2005 Li eta!. 2005/ Al 6/2005 Yarn eta!. 2005/ Al 8/2005 Almarssoo et a!. 2005/ Al 8/2005 Jao eta!. 2005/ Al 8/2005 Edgren eta!. 2005/ Al 9/2005 Liang 2005/ Al 10/2005 Gaedy et al. 2006/ AI Vaya eta!. 536/ / AI 2006/ Al 2006/ Al 2006/ Al 2006/ AI 2006/ Al * 2006/ Al 2006/ Al 2006/ Al 2007/ AI 2008/ Al * 2008/ Al wo wo wo wo wo wo wo wo wo wo wo Vaya eta!. 2/2006 Vaya eta!. 2/2006 Casadevall et a!. 4/2006 Vandecruys et a!. 5/2006 Buchanan et al. 6/2006 Jenkins eta! /468 7/2006 Bachmann eta!. 10/2006 Ehrenberg et al. 10/2006 Hendrix 9/2007 Fawzy eta!. 4/2008 Nangia et al /458 6/2008 Liang eta!. FOREIGN PATENT DOCUMENTS WO AI WO 02/03984 A2 WO 02/ A3 WO 2004/ Al WO Al WO A2 WO 2005/ Al WO 2005/ A2 WO 2006/ AI WO 2006/ A2 wo 2007/ /2001 1/2002 6/2002 3/2004 9/2004 9/2004 4/2005 9/ /2007 OTHER PUBLICATIONS U.S. Appl. No. 12/926,931, filed Dec. 17, 2010, Liang eta!. Adin et a!., "Topirarnate Serum Concentration-to-Dose Ratio," Therapeutic Drug Monitoring, Jun. 2004; 26(3): Bahk et a!., "Topirarnate and divalproex in combination with risperidone for acute mania: a randomized open-label study," Progress in Neuropsychopharmacology & Biological Psychiatry, 2005, 29(1): Beaumanoir, Anne, "The Landau-Kleffner syndrome", In: Roger et a!., Eds. Epileptic Syndromes in Infancy, Childhood, and Adolescence, 2nd Ed., London, England: John Libby, pp , Berge eta!., "Pharmaceutical Salts", J. Pharm. Sci., Jan. 1977, 66(1): Bertant, Jeffery L., M.D., Ph.D., "Topirarnate in Posttraumatic Stress Disorder: Preliminary Clinical Observations," J. Clin. Psychiatry, 2001, 62(Suppll7): Brandes eta!., "Topirarnate for Migraine Prevention," JAMA, Feb. 25, 2004, 291(8): Carpenter eta!., "Do obese depressed patients respond to topirarnate? A retrospective chart review," J. Affect. Disord., 2002, 69(1-3): Chen eta!., "Combination Treatement ofclozapine and Topirarnate in Resistant Rapid-Cycling Bipolar Disorder," Clin. Neuropharmacol., May-Jun. 2005, 28(3): Coleman eta!., "Polymer reviewed: A practical guide to polymer miscibility," Jul. 1990, 31: Contin et a!., "Topirarnate Therapeutic Monitoring in Patients with Epilepsy: Effect of Concomitant Anti epileptic Drugs," Ther. Drug Monit., 2002, 24(3): D'Amico eta!., "Topirarnate in migraine prophylaxis," Neurological Sciences, 2005, 26(Suppl2):S130-Sl33. Deckers et a!., "Selection of Anti epileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed," Epilepsia, 2000, 41(11): Diener et al., "Topirarnate in migrain prophylaxis: Results from a placebo-controlled trail with propranolol as an active control," J. Neurol., 2004, 251(8): Dorado eta!., "Topirarnato en enfermedades comorbidas: epilepsia y migrana," Rev. Neurol., 2006, 43(4): Duchene eta!., "Pharmaceutical and Medical Aspects ofbioadhesive Systems for Drug Administration," Drug Dev. Ind. Pharm., 1988, 14(2&3): Erfurth eta!., "Bupropion as Add-On Strategy in Difficult-to-Treat Bipolar Depressive Patients," Neuropsychobiology, 2002, 45(Suppl 1): Felmeister, Alvin Ph.D., "Powders," Remington's Pharm. Sci., 14th Ed., 1970, Chapter 86,

115 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 115 of 155 PageID: 512 US 8,889,191 B2 Page 3 (56) References Cited OTHER PUBLICATIONS Ferrari et a!., "Influence of Dosage, Age, and Co-Medication on Plasma Topiramate Concentrations in Children and Adults with Severe Epilepsy and Preliminary Observations on Correlations with Clinical Response," Therapeutic Drug Monitoring, 2003, 25(6): Ferrari eta!., "Rizatriptan: a new milestone in migraine treatment," Cephalalgia, 2000, 20(Suppl1):1. Fincher, Julian H., "Particle Size of Drugs and Its Relationship to Absorption and Activity," J. Pharm. Sci., Nov. 1968, 57(11): Fisher et al., "Synergism between Topiramate and Budipine in Refractory Status Epilepticus in the Rat," Epilepsia, 2004, 45(11): Fran~ois et a!., "The combination of topiramate and diazepam is partially neuroprotective in the hippocampus but not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy," Epilepsy Research, 2006,72: Gurny et al., "Bioadhesive intraoral release systems: design, testing and analysis," Biomaterials, Nov. 1984, 5: Hershey et a!., "Effectiveness of Topiramate in the Prevention of Childhood Headaches," Headache, Sep. 2002;42(8): Hoes eta!., "The Application of Drug-Polymer Conjugates in Chemotherapy," Drug Carrier Systems, 1989, 9: Hollander eta!., "Topiramate plus paroxetine in treatment-resistant obsessive-compulsive disorder," Int. Clin. Psychopharmacol., 2006, 21(3): International Search Report and Written Opinion mailed Sep. 2, 2008, in PCT/US2007/19208, 10 pages. Ioannides-Demos et a!., "Pharmacotherapy for Obesity," Drugs, 2005, 65(10): Johnson et al., "Oral topiramate for treatmetn of alcohol dependence: a randomised controlled trial," The Lancet, May 17, 2003, 361(9370): Kellett eta!., "Topiramate in clinical practice: first year's postlicensing experience in a specialist epilepsy clinic," J. Neurol. Neurosurg. and Psych., 1999;66: Lainez eta!., "Topiramate in the Prophylactic Treatment of Cluster Headache," Headache, Jul./Aug. 2003, 43(7): Lalonde eta!., "Additive effects of leptin and topirarnate in reducing fat deposition in lean and obese ob/ob mice," Physiology & Behavior, 2004, 80(4): Lee eta!., "The Effects of Adjunctive Topiramate on Cognitive Function in Patients with Epilepsy," Epilepsia, 2003; 44(3): Lehr eta!., "Intestinal Transit of Bioadhesive Micro spheres in an in situ Loop in the Rat-A Comparative Study with Copolymers and Blends Based on Poly( acrylic acid)," Journal of Controlled Release, 1990, 13: Leong et al., "Polymeric controlled drug delivery," Adv. Drug Delivery Rev., 1987, 1: Linhardt, Robert J. "Biodegradable Polymers for Controlled Release of Drugs," Controlled Release of Drugs, 1989, Chapter 2, Liu et a!., "Preparation, characterization and in vivo evaluation of formulation of baicalein with hydroxypropyl-beta-cyclodextrin," International Journal of Pharmaceutics, 2006,312: Longer, Mark A., Ph.D., "Sustained-Release Drug Delivery Systems," Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 91, Lu eta!., "Dimensionless presentation for drug release from a coated pure drug bead: 1. Analysis," Inter. J. ofpharm., 1994, 112: Lu eta!., "Dimensionless presentation for drug release from a coated pure drug bead: 2. Experiment," Inter. J. ofpharm., 1994, 112: Luszczki et a!., "Interactions of Lamotrigine with Topiramate and First-Generation Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis," Epilepsia, 2003, 44(8): Mathew et al., "Prophylaxis ofmigraine, Transformed Migraine, and Cluster Headache with Topiramate," Headache, Sep. 2002, 42(8): McElroy eta!., "Topiramate in the Treatment of Binge Eating Disorder Associated with Obesity: A Randomized, Placebo-Controlled Trial," Am. J. Psychiatry, Feb. 2003, 160(2): Meador et a!., "Cognitive and behavioral effects of Iamotrigine and topirarnate in healthy volunteers," Neurology, Jun. 2005, 64: Mikos eta!., "Interaction of Polymer Micro spheres with Mucin Gels as a Means of Characterizing Polymer Retention on Mucus," Journal of Colloid and Interface Science, May 1991, 143(2): Morton et a!., "Diagnosis and treatment of epilepsy in children and adolescents", Drugs, Mar. 1996, 51(3): Mosek et. a!., "Topiramate in the treatment of refractory chronic daily headache. An open trial," Journal of Headache and Pain, 2005, 6: O'Connor eta!., "Powders," Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 88, Park eta!., "Alternative Approaches to Oral Controlled Drug Delivery: Bioadhesives and In-Situ Systems," Recent Advances in Drug Delivery, Plenum Press, New York, 1984, Pascual eta!., "Testing the combination beta-blockerplus topiramate in refractory migraine," Acta Neurol. Scand., 2007, 115(2): Physician's Desk Reference, 60 1 h Edition, 2006, pp , entry for TOPAMAX. Physicians' Desk Reference 59th edition, (2005). Physician's Desk Reference, 56th ed., (2002). Pies, Ronald M.D., "Combining Lithium and Anticonvulsants in Bipolar Disorder: A Review," Annals of Clinical Psychiatry, Dec. 2002, 14(4): Porter, Stuart C., Ph.D., "Coating of Pharmaceutical Dosage Forms," Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 90, Potter et a!., "A Double-Blind, Randomized, Placebo-Controlled, Parallel Study to Determine the Efficacy of Topiramate in the Prophylactic Treatment of Migraine," Neurology, Apr. 2000, 54(Suppl 3):A15. Rudnic eta!., "Oral Solid Dosage Forms," Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 89, Silberstein et al., "Topiramate in Migraine Prevention," Arch. Neurol., Apr. 2004, 61(4): Siniscalchi et a!., "Combined topiramate and declorazepam therapy in a patient affected by essential tremor," Parkinsonism Relat. Disord., 2007, 13(2): Smart eta!., "An in-vitro investigation of mucosa-adhesive materials for use in controlled drug delivery," J. Phami. Pharmacol., 1984, 36: Sofuoglu et al., "Effects oftopiramate in combination with intravenous nicotine in overnight abstinent smokers," Psychopharmacology, 2006, 184(3-4): Storey eta!., "Topiramate in Migraine Prevention: A Double-Blind Placebo-Controlled Study," Headache, Nov./Dec. 2001, 41(10): Thompson et a!., "Effects of topiramate on cognitive function," J. Neurol. Neurosurg and Psych., 2000; 69: Toplak eta!., "Efficacy and safety oftopiramate in combination with metformin in the teratment of obese subjects with type 2 diabetes: a randomized, double-blind placebo-controlled study," Int. J. Obes., 2007, 31(1): Von Seggem eta!., "Efficacy oftopiramate in Migraine Prophylaxis: A Retrospective Chart Analysis," Neurology, Apr. 2000, 54(Suppl 3):A267-A268. Weber, Marcus Vinicius Keche, M.D., "Topirarnate for Obstructive Sleep Apnea and Snoring," Am. J. Psychiatry, May 2002, 159(5): Winkelman, John W., "Treatement of nocturnal eating syndrome and sleep-related eating disorder with topiramate," Sleep Medicine, 2003, 4(3): * cited by examiner

116 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 116 of 155 PageID: 513 U.S. Patent Nov. 18, 2014 Sheet 1 of 6 US 8,889,191 B2 Fig.1 80% release time vs. %Wt. gain of Release-Controlling Coating For Sure/ease coated Extended Release Beads Qj E j:: Cll :(! 0.8 Cll Gl 0:: 0.6 <f. 0 e o.4 Q) 0...J %Release Controlling Coating Weight Gain

117 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 117 of 155 PageID: 514 U.S. Patent Nov. 18, 2014 Sheet 2 of 6 US 8,889,191 B2 Fig.2 80% release time vs. % Wt. gain of Release-Controlling Coating For Sure/ease / Opadry coated Extended Release Beads 'C" :::. 7 G) E 6 i= G) Ill I'll G) Qj ~ 5 4 D ~ ! ~--~~--~~ % Release Controlling Coating Weight Gain

118 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 118 of 155 PageID: 515 U.S. Patent Nov. 18, 2014 Sheet 3 of 6 US 8,889,191 B2 Fig. 3 Mean (n= 16) PK Profiles from Bead Populations XR1, XR2 and XR3 --XR1 XR2 - -XR3 900~ ~ ~,'/ / 0~--r-~---T---r--~---~---r-~--~--r-~--~ Time (hours)

119 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 119 of 155 PageID: 516 U.S. Patent Nov. 18, 2014 Sheet 4 of 6 US 8,889,191 B2 Fig.4 Mean (n= 16) PK Profiles from the Immediate Release Formulations - -EIRBeads IR Beads --Topamax :I E <» 600.s c: 0 :;::; E ;: c: 0 ().. ~ 300 "' ii: Time (hours)

120 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 120 of 155 PageID: 517 U.S. Patent Nov. 18, 2014 Sheet 5 of 6 US 8,889,191 B2 Fig.S Dissolution Profiles of Immediate Release Formulations ~ /... - ;:::- - :Yf--~ "'C Tapa max G) l: 0 f/) f/) 60 --Topiramate IR i5 I. Beads #. 40 w - - Topiramate 20 0 l/.1 I _ Time (min) Enhanced IR Beads

121 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 121 of 155 PageID: 518 U.S. Patent Nov. 18, 2014 Sheet 6 of 6 US 8,889,191 B2 :;;; ~~< :~:~ ~=::. 0 $ *... "" "... 'w' ~... I ~ "" "'.,.. ~.&,... j7':)0 -~ f:~{)o.....,.. : :::~~:;o 1 {)()

122 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 122 of 155 PageID: SUSTAINED-RELEASE FORMULATIONS OF TOPIRAMATE CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a Continuation of U.S. application Ser. No. 11/941,475, filed Nov. 16,2007, which claims benefit ofu.s. Provisional Application No. 60/859,502, filed Nov. 17, 2006, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION US 8,889,191 B2 Topiramate is a sulfamate substituted monosaccharide which under the trade name TOPAMAX (Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J., U.S.A.) has been approved for use as an antiepileptic agent, as an adjuvant therapy for patients with partial onset seizures or primary 20 generalized tonic-clonic seizures, and for the prevention of migraine. See generally, Physician's Desk Reference, 60th ed., (2006); see also, U.S. Pat. No. 4,513,006. For the treatment of epilepsy, the recommended dose of Topamax is 400 mg/day in one or multiple doses (Physi- 25 cian's Desk Reference, 60th ed., (2006)). For adults with epilepsy, treatment is initiated with a dose of mg/day, with the dose being titrated in increments of mg at weekly intervals to the recommended or effective sia, diplopia, renal calculi (kidney stones), hepatic failure, pancreatitis, renal tubular acidosis, acute myopia and secondary angle closure glaucoma (Physician's Desk Reference, 60th ed., (2006)). Hence, though topiramate has a relatively long half-life of 21 hours in vivo, it has not been prescribed (or formulated) as a single, daily-dose, in part due to severe side-effects that often result with peak plasma levels of the drug when taken in high doses. Instead, Topamax is typically taken in multiple, 45 "divided" doses, usually twice-daily ("BID"). However, administration of the medicament in this manner is cumbersome and patients can forget to take their medication in a timely manner. What is more, each administration of a dose is associated with a peak in plasma concentrations of the drug, 50 and the fluctuations associated with the peaks and valleys of blood plasma levels of the drug are undesirable. Therefore, there is a need for a formulation of topiramate, which reduces or eliminates the side effects associated with peaking and fluctuating plasma levels of the drug and preferably may be 55 administered in a once-daily regimen. New, highly soluble and bioavailable forms oftopiramate are also needed in order to increase the safety and effectiveness of the drug. The instant invention addresses these and other needs by providing a modified formulation oftopiramate characterized by a sustained, non-pulsatile release of an active ingredient. This invention additionally provides an effective, once-daily dosage form of topiramate or salts thereof, which not only 65 enables an effective single daily dose regimen to improve patient compliance but may also reduce some of the side 2 effects of topiramate compared to the current or higher daily doses of immediate release topiramate formulations. SUMMARY OF THE INVENTION It is an object of the present invention to provide a sustained release formulation oftopiramate for the treatment or prevention of a pathological condition in a mammalian subject, characterized by a sustained rate of topiramate release along 10 a pre-determined release profile. It is yet another object of the present invention to provide topiramate formulation wherein topiramate is released at a rate which results in a reduction in the frequency or severity of at least one side effect associated with the topiramate treat- 15 ment. It is a further object of the present invention to provide a sustained release formulation of topiramate that can be administered orally once a day. It is an object of the present invention to provide a sustained release formulation of topiramate for oral administration to a mammalian subject comprising topiramate as an active ingredient, wherein the active ingredient is released from the formulation at a sustained rate along a pre-determined release profile, and wherein the sustained release formulation comprises an extended release (XR) component and an optional immediate release (IR) component. In one embodiment of the invention, the extended release component is contained in at least one population of beads 30 coated with a release controlling coating. The above-mentioned coating is specific for every bead population and determines its rate of release. Thus, every given bead population included into the formulation is characterized by its own dose. Topamax is an immediate release formulation. Adverse effects associated with the administration of Topamax include, but are not limited to, sonmolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor 35 slowing, abnormal vision, difficulty with memory, paresthespecific rate of release. In another embodiment of the invention, the sustained release topiramate formulation comprises an immediate release component in addition to an extended release component. In a preferred embodiment of the invention, the immediate 40 release component is an enhanced immediate release (EIR) composition. The formulation of the present invention may be incorporated in any oral dosage form such as represented by, but not limited to, a tablet, a pill, a capsule, a troche, a sachet, and sprinkles. It is yet another object of the present invention to provide a method of preparation of a sustained release formulation of topiramate, comprising an extended release component, and an optional immediate release component, wherein topiramate is released from the formulation at the sustained rate along the pre-determined release profile, the method comprising the steps of: 1. determining the desired release profile; 2. determining specific amounts of the extended release component and the immediate release component necessary to produce the pre-determined release profile; and 3. incorporating the specified amounts of the components into the formulation. In one embodiment, the method of preparation additionally 60 includes a process for providing an XR component contained in at least one population of beads, wherein every population of beads is characterized by its own rate of release. This process comprises the steps of 1. forming at least one population of topiramate-containing beads; 2. coating each population of beads with its own coating solution;

123 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 123 of 155 PageID: 520 US 8,889,191 B curing the coating for a period of time to produce a release controlling coating specific for each bead population, and 4. incorporating the beads into the formulation. The method may optionally include a process for preparation of an IR component, which optionally is an enhanced immediate release (EIR) composition. The enhanced immediate release composition includes at least one agent selected from a group comprising complexing agents and enhancing agents. Without any limitations, the enhancing agents useful 10 in the present invention may be selected from solubilizing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multi drug resistance protein inhibitors or combinations 15 The maximum plasma drug concentration during the dosing period is referenced as Cmax, while Cmin refers to the minimum blood plasma drug concentration at the end of a dosing interval; and Cave refers to an average concentration during the dosing interval. The "degree of fluctuation" is defined as a quotient ( Cmax Cmin)/Cave. Persons of skill in the art will appreciate that blood plasma drug concentrations obtained in individual subjects will vary due to interpatient variability in the many parameters affect- thereof. It is yet another object of the present invention to provide a method of treatment or prevention of a pathological condition in a mammalian subject by orally administering to the subject a therapeutically effective amount of a sustained release topi- 20 ramate formulation of the instant invention. The pathological conditions that may be treated by the method of the present invention include neurological condition, psychiatric condition, diabetes and related disorders, cardiovascular condition, obesity, and any other condition or disorder that may be treated or prevented by topiramate administration. DEFINITIONS For the purposes of this invention, the term "topiramate" 30 includes topiramate or any pharmaceutically acceptable salts thereof. An "immediate release formulation" refers to a formulation that releases greater than or equal to about 80% of the pharmaceutical agent in less than or equal to about 1 hour. For the purposes of this application, an enhancing agent ("enhancer") is defined as any non-pharmaceutically active ingredient that improves the therapeutic potential of a formulation. The term "enhanced immediate release composition" as 40 used herein describes an immediate release composition improved in terms of a therapeutic potential or treatment modality. "Sustained release" is defined herein as release of a pharmaceutical agent in a continuous manner over a prolonged 45 period of time. By "prolonged period of time" it is meant a continuous period of time of greater than about 1 hour, preferably, greater than about 4 hours, more preferably, greater than about 8 hours, more preferably greater than about 12 hours, more 50 preferably still, greater than about 16 hours up to more than about 24 hours. As used herein, unless otherwise noted, "rate of release" or "release rate" of a drug refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug 55 released per hour (mg/hr) or a percentage of a total drug dose released per hour. Drug release rates for dosage forms are typically measured as an in vitro rate of drug release, i.e., a quantity of drug released from the dosage form per unit time measured under appropriate conditions and in a suitable fluid. 60 The time at which a specified percentage of the drug within a dosage form has been released from the dosage form is referred to as the "T.sub.x" value, where "x" is the percent of drug that has been released. The release rates referred to herein are determined by plac- 65 ing a dosage form to be tested in a medium in an appropriate dissolution bath. Aliquots of the medium, collected at pre-set 4 intervals, are then injected into a chromatographic system fitted with an appropriate detector to quantify the amounts of drug released during the testing intervals. "C" denotes the concentration of drug in blood plasma, or serum, of a subject, and is generally expressed as mass per unit volume, for example nanograms per milliliter. For convenience, this concentration may be referred to herein as "drug plasma concentration", "plasma drug concentration" or "plasma concentration" which is intended to be inclusive of a drug concentration measured in any appropriate body fluid or tissue. The plasma drug concentration at any time following drug administration is referenced as Ctime, as in C9 hr or C4 hr, etc. 25 ing drug absorption, distribution, metabolism and excretion. For this reason, unless otherwise indicated, when a drug plasma concentration is listed, the value listed is the calculated mean value based on values obtained from a groups of subjects tested. The term "bioavailability" refers to an extent to whichand sometimes rate at which-the active moiety (drug or metabolite) enters systemic circulation, thereby gaining access to the site of action. "AUC" is the area under the plasma concentration-time 35 curve and is considered to be the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation. Side effect is defined herein as a secondary and usually adverse effect of a drug. The term "beads", as used herein, includes, without any limitations on the nature and size thereof, any particles, spheres, beads, granules, pellets, particulates or any structural units that may be incorporated into an oral dosage form. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the time of release of 80% of the drug vs. % wt. gain of release controlling coating for cured Surelease coated extended release beads. FIG. 2 shows the time of release of 80% of the drug vs. % wt. gain of release controlling coating for cured Surelease / Opadry coated extended release beads. FIG. 3 shows mean (n=16) pharmacokinetic profiles for bead populations XR1, XR2 and XR3. FIG. 4 shows mean ( n= 16) pharmacokinetic profiles for the immediate release formulations. FIG. 5 shows the dissolution profiles oftopamax, topiramate IR beads, and topiramate enhanced immediate release beads. FIG. 6 shows mean PK Profiles for Sustained Release Formulations A, B, and C. DETAILED DESCRIPTION OF THE INVENTION Topiramate is a sulfamate-substituted monosaccharide having the chemical name 2,3:4,5-Di-0-isopropylidenebeta-D-fructopyranose sulfamate. The molecular formula of

124 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 124 of 155 PageID: topiramate is C12H21N08S, and its chemical structure is represented by formula below: Topiramate is a white crystalline powder that is soluble in alkaline solutions containing sodium hydroxide or sodium phosphate, soluble in acetone, dimethylsulfoxide and ethanol. However, the solubility of topiramate in water at room temperature is only about 9.8 mg/ml. Topiramate is not extensively metabolized and is excreted largely through the urine (Physician's Desk Reference, 60th ed., (2006)). Topiramate pharmacokinetics are linear, producing a dose proportional increase in blood plasma concentration levels with increased dosing, and is not significantly affected by food. Patients taking topiramate over prolonged period of time did not develop resistance to the drug. Following oral administration of an immediate release dosage form, topiramate is rapidly absorbed with plasma drug concentrations peaking in approximately 2 hours. The mean elimination half-life is reported to be about 21 hours. US 8,889,191 B2 Currently, topiramate is administered in multiple daily doses in part due to the severe side effects exhibited by the 30 immediate release product, especially when taken in a high single dose. A sustained release topiramate formulation that will be suitable for once-a-day administration and will result in the diminished level or severity of side effects is needed. The present invention provides sustained release formulation oftopiramate wherein the total daily dose oftopiramate is provided in an effective once-daily dose while minimizing fluctuations in the blood plasma drug concentration. The current invention also provides for formulations of topiramate wherein the maximum plasma concentration of topiramate is attenuated as compared to the same amount of topiramate administered as an immediate release formulation BID; therefore some of the side effects oftopiramate, such as CNS side effects including but not limited to dizziness, paresthesia, nervousness, psychomotor slowing, confusion, and difficulty with concentration/attention, observed when taking the immediate release product, may be reduced or eliminated. Formulations of the instant invention are characterized by a maximum steady state plasma concentration (Cmax) of topiramate which is higher than the minimal therapeutically effective concentration, and is in the range of 50% to 125% of the maximum plasma concentration produced by the same amount oftopiramate administered as an immediate release formulation BID. In one embodiment, the novel formulations provide for a relative Cmax in the range of 80% to 125%, as compared to the same amount oftopiramate administered as an immediate release formulation BID. In the other embodiment, the invention provides for the Cmax which is lower than the maximum plasma concentration produced by the same amount oftopiramate administered as an immediate release formulation BID. The Cmin of the topiramate formulation of the present invention is about equal or higher than a Cmin of an equivalent amount of immediate release topiramate formulation given BID. Compared to the immediate release topiramate formulation, the sustained release topiramate formulations attenuate 10 6 the Cmax of topiramate while extending the coverage of plasma concentration above the minimum plasma concentration required therapeutic efficacy. The formulation of the current invention provides for a relative steady state AUC in the range of 80% to 125%, while minimizing the degree of fluctuation, which is preferably in the range of25% to 90%, as compared to an equivalent amount of immediate release to piramate formulation given in two divided doses (Table 5 and 6). The present invention additionally provides a sustained release topiramate formulation for the treatment or prevention of a pathological condition in a mammalian subject wherein topiramate is released from the formulation at a sustained rate along a pre-determined release profile. Such 15 release is achieved by incorporation into the formulation of an extended release component (XR) and an optional immediate release component (IR). The relative amount of each component in the topiramate formulation of the present invention is determined according 20 to the purpose of administration and a pre-determined release profile, and the total amount of topiramate in the formulation varies from 0.5 mg to about 3000 mg. In other words, topiramate or its salt is present in the composition in an amount of from about 0.5% to about 85% by weight, and preferably of 25 from about 2% to about 70% by weight. The term "about" has been recited here and throughout the specification to account for variations, which can arise from inaccuracies in measurement inherent and understood by those of ordinary skill in the chemical and pharmaceutical arts. TheXR component of the formulationofthe present invention releases topiramate in a continuous mauner and is adjusted in such a way that 80% of the active ingredient is released in vitro in the predetermined period of time. By way of example, and by no means limiting the scope of the inven- 35 tion, the period of time may be not more than 24 hours, not more than 16 hours, not more than 12 hours, not more than 8 hours, or not more than 4 hours, depending on desired attributes of the final product. In one embodiment, the extended release (XR) component 40 is contained in at least one population of beads coated with a coating that modifies and controls the release of topiramate from the beads (release controlling coating). The release controlling coating is specific for every population of beads and determines the rate of release of topiramate from the given 45 bead population. The beads useful in the formulation of the present invention comprise an inert carrier, topiramate, a binder, an aforementioned release controlling coating and optionally, an overcoat that provides additional protection from moisture, 50 static charge reduction, taste masking and coloring attributes to the particulates. The inert carriers useful in the present invention may be selected from, but are not limited to, a group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres. 55 The inert carrier is present in an amount of from about 15% to about 99% by weight, and preferably in an amount of from about 40% to about 97% by weight. Topiramate is introduced to the inert carrier by techniques known to one skilled in the art, such as drug layering, powder 60 coating, extrusion/spheronization, roller compaction or granulation. Preferably, the introduction method is drug layering by spraying a suspension of topiramate and a binder onto the inert carrier. The binder may be present in the bead formulation in an 65 amount of from about 0.1% to about 15% by weight, and preferably of from about 0.2% to about 10% by weight. Binders include, but are not limited to starches, microcrystal-

125 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 125 of 155 PageID: line cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, or polyvinylpyrrolidone. The release controlling coating specific for every bead population comprises a coating material, and, optionally, a pore former and other excipients. The coating material is preferably selected from a group comprising cellulosic polymers, such as ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, and cellulose acetate phthalate; polyvinyl alcohol; acrylic polymers such as polyacrylates, polymethacrylates and copolymers thereof, and other water-based or solvent-based coating materials. The release-controlling coating is population-specific in the sense that the rate of release oftopiramate from every bead population is controlled by at least one parameter of the release controlling coating, such as the nature of the coating, coating level, type and concentration of a pore former, process parameters and combinations thereof. Thus, changing a parameter, such as a pore former concentration, or the conditions of the curing, as will be discussed in more details below, (see Example 5) allows to change the release oftopiramate from any given bead population and to selectively adjust the formulation to the pre-determined release profile. The release profile, in its tum, may be chosen or modified in such a way as to achieve the best treatment modality depending on the specific needs of the patient population and the nature of the condition. For example, with all things being equal, there exists a mathematical relationship between the release controlling coating level among the cured beads and the 80% in vitro release time. Pre-determined target profiles can therefore be achieved by the interpolation or extrapolation of the relationship curve. For example, when the release controlling coating comprises only ethylcellulose (Surelease ) as a coating material, a logarithmic relationship exists between the % weight gain with the coating and the 80% release time in an in-vitro dissolution test (FIG. 1): Log(Tso% releaoe)~a(% coating)+b. When ethylcellulose/hpmc (Surelease /Opadry ) mixture is used, for example, 85:15 mixture or 80:20 mixture, a linear relationship exists between the %weight gain with the coating and the 80% release time in an in-vitro dissolution test (FIG. 2): Tso% release =a(% coating)+b. Pore formers suitable for use in the release controlling coating herein can be organic or inorganic agents, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. Examples of pore formers include but are not limited to organic compounds such as mono-, oligo-, and polysaccharides including sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran; polymers soluble in the environment of use such as water-soluble hydrophilic polymers, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, Carbowaxes, Carbopol, and the like, dials, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols, or block polymers thereof, polyglycols, poly(a-w)alkylenediols; inorganic compounds such as alkali metal salts, lithium carbonate, sodinm chloride, sodinm bromide, potassinm chloride, potassinm sulfate, potassium phosphate, sodinm acetate, sodium citrate, suitable calcinm salts, and the like. US 8,889,191 B2 8 The release controlling coating in the current invention can further comprise other additives known in the art such as plasticizers, anti-adherents, glidants, and antifoams. In some embodiments, it may be further desirable to optionally coat the XR beads with an "overcoat," to provide, e.g., moisture protection, static charge reduction, taste-masking, flavoring, coloring, and/or polish or other cosmetic appeal to the beads. Suitable coating materials for such an overcoat are known in the art, and include, but are not limited 10 to, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose, or combinations thereof (for example various Opadry coating materials). Topiramate-containing beads of the present invention may 15 additionally contain enhancers that may be exemplified by, but not limited to, solubility enhancers, dissolution enhancers, absorption enhancers, permeability enhancers, stabilizers, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, and multi drug resistance protein inhibitors. Alter- 20 natively, the formulation can also contain enhancers that are separated from the topiramate beads, for example in a separate population of beads or as a powder. In yet another embodiment, the enhancer( s) may be contained in a separate layer on a topiramate-containing bead either under or above 25 the release controlling coating. The beads may further comprise other pharmaceutically active agents suitable for use in combination with topiramate for treatment or prevention of a pathological condition. The additional pharmaceutically active agents, without limitation, 30 may be represented by analgesic and anti-inflmatory compounds such as COX-2 inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs ), narcotic drugs such as opiates and morphinomimetics, synthetic drugs with narcotic properties such as tramadol; anticonvulsants such as valproic acid or its 35 derivatives, carbamazepine, oxcarbazepine, gabapentin, and lamotrigine; anorectics or anti-obesity agents such as sibutramine or other, orlistat or other pancreatic lipase inhibitors, diethylpropion, fluoxetine, bupropion, amphetamine, methamphetamine, sertraline, zonisamide, andmetformin, as well 40 as medications associated with weight-gain, such as sulfonylurea derivatives, insulin, and thiazolidinediones whose weight-gain effect is tempered by topiramate; anti-hypertensive agents such as diuretics, anti-adrenergics, calcinm channel blockers, ACE inhibitors, angiotensin II receptor antago- 45 nists, aldosterone antagonists, vasodilators, centrally acting adrenergic drugs, and adrenergic neuron blockers; mood stabilizers such as various forms/salts oflithium, Omega-3 fatty acids and others known in the art, drugs for treatment or prevention of migraines, such as ergot derivatives or triptans, 50 or any other pharmaceutical or nutraceutical ingredient that can be safely and beneficially combined with topiramate. A relative amount of every bead population in the complete formulation is determined on the basis of the pharmacokinetic data of the separate bead populations and the pre-deter- 55 mined release profile and will be discussed in more detail in Example 6. In another embodiment, the formulation of the present invention comprises an extended release component as described above, and an immediate release component. The 60 IR component may be an enhanced immediate release composition. The enhanced immediate release composition may be characterized by a faster in vitro topiramate release as compared to their formulation. Preferably, at least 80% of an active compound from the enhanced immediate release com- 65 position is released in a time period of not more than 30 minutes. More preferably, at least 50% of an active compound from the enhanced immediate release composition is released

126 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 126 of 155 PageID: in a time period of not more than 10 minutes, and at least 25% is dissolved in a time period of not more than 5 minutes after the oral administration. In the most preferred embodiment of the present invention, at least 75% of the active compound is released from the EIR composition in a time period of not more than 10 minutes. The embodiment in which the IR component is an enhanced immediate release composition will be discussed in more details below. In addition to topiramate and inactive excipients, the EIR composition of the present invention comprises at least one agent selected from a group consisting of complexing agents and enhancing agents. Without any limitation, the enhancing agents suitable for the present invention may be selected from the solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, such as non-ionic surfactants, ionic surfactants US 8,889,191 B2 or combinations thereof; stabilizers that include antioxidants, preservatives, buffering agents, bases and other known in the art; enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors, or any combinations thereof. The representative, but non-limiting examples of these compounds are Vitamin E TPGS, amino acid such as glutamic acid and glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins such as maltodextrin, Cremophor RH40 (glycerol-polyethylene glycol oxystearate), Gelucire 50/13 (PEG-32 glyceryl palmitostearate), sodium Iaury! sulfate, Tween 80 (polyoxyethylene sorbitan monooleate), benzyl alcohol, Span 20 (sorbitan monolaurate), Poloxamer 407, PEG3350, PVP K25, oleic acid, Capmul GMO (glyceryl monooleate ), sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, crosscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydroxypropylcellulose, microcrystalline cellulose, sodium bicar- 35 bonate, calcium citrate, sodium docusate, and menthol, among others. Enhancers can be combined to achieve multiple enhancement effects, for example, solubility enhancement combined with permeability enhancement and p-glycoprotein inhibition, or to provide a synergistic enhancement 40 effect to achieve greater and more efficient enhancement. For example, polyglycolized glycerides (different grades of Gelucire) can be combined with sodium Iaury! sulfate to achieve higher solubility enhancement as well as faster dissolution oftopiramate. In one embodiment, the EIR composition comprises a highly soluble complex of topiramate with a complexing agent that is represented by, but not limited to, cyclodextrins, including cyclodextrin derivatives, such as hydroxypropylbeta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, 50 and alpha-cyclodextrin. The ratio of cyclodextrin to topiramate in the EIR formulation is preferably less than 20:1 and more preferably less than 5:1. In the most preferred embodiment, the complexing agent is hydroxypropyl beta cyclodextrin. 55 The highly soluble complex oftopiramate and cyclodextrin is prepared by mixing topiramate and cyclodextrin together in the presence of water. The concentration of cyclodextrin is preferably high to facilitate the formation oftopiramate-enhancer complex. In the case when the complexing agent is hydroxypropyl-beta-cyclodextrin, the concentration of the hydroxypropyl-beta-cyclodextrin solution used for mixing with topiramate is greater than 2%, preferably greater than 20%, and more preferably at least about 40%. The amount of topiramate is determined by a desired ratio ofhydroxypropyl- 65 beta-cyclodextrin to topiramate, which is preferably less than 20:1, and more preferably less than 5:1. The mixing time of 10 the complex solution is from about one hour to about 48 hours, and preferably from about 5 hours to about 24 hours. The addition ofhydroxypropyl-beta-cyclodextrin and topiramate can be incremental to reduce the viscosity of the complex solution and to achieve better complexation. In a further embodiment, the EIR component of the present invention is contained in at least one bead population. Topiramate EIR beads can be prepared using processes suitable for bead manufacturing, such as coating of a topiramate sus- 10 pension, dispersion or solution onto an inert carrier, or by roller compaction, granulation, extrusion/spheronization, or powder coating, and are not limited by the examples cited therein. The enhancing agents of the present invention can be incorporated into the topiramate containing beads, or may be 15 contained in other beads separated from the topiramate containing beads. By way of a non-limiting example, topiramatecontaining EIR beads were prepared by coating topiramate dispersion onto an inert carrier such as sugar spheres. The topiramate dispersion, in addition to topiramate in the 20 micronized form or in non-micronized form, can contain one or more enhancers, water and optionally a binder such as hydroxypropylcellullose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol. When the formulation is enhanced with complexing 25 agents, the agents may be first mixed with topiramate and a suitable solvent such as water to form the complex. The topiramate-containing complex is then mixed with a binder solution prepared separately to give the coating dispersion. The coating dispersion is then sprayed onto the inert carrier 30 such as sugar spheres using a fluid bed processor. In an alternative embodiment of the invention, the formulation comprises at least one XR bead population, and at least one additional combination bead population consisting of the extended release beads that have an additional immediate release component layer coated on top of the release controlling coating. This layer may be formed by a suitable loading method such as solution/suspension/dispersion coating, powder coating or wet granulation. In yet another embodiment, at least part (i.e., more than 0.01 %, preferably at least 1%) of the active ingredient may be present in the formulation in a form of micronized particles with the size of from 1 f.ull to 1000 f.tm, preferably from 2 f.tm to about 200 f.ull, more preferably from 2 f.tm to about 100 f.tm. Further, one or more enhancers may be present in the formu- 45 lations covered by this embodiment. The enhancers are selected from solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, such as non-ionic surfactants, ionic surfactants or combinations thereof; stabilizers that include antioxidants, preservatives, buffering agents, bases and other known in the art; enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors, or any combinations thereof. Preferably, the enhancer is a solubility enhancer or a dissolution enhancer. The topiramate formulation of the present invention may be formulated in a dosage form selected from a tablet, a pill, a capsule, a caplet, a troche, a sachet, a cachet, a pouch, sprinkles, or any other form suitable for oral administration. In one embodiment of the invention, the dosage form is a 60 gelatin capsule containing the XR component in a form of at least one population of beads, and an optional IR component. The IR component, when present, may be in a form of a powder, or may also be contained in at least one population of beads to achieve faster dissolution oftopiramate (FIG. 5). In an alternative embodiment, part of the total amount of the active ingredient may be incorporated into the aforementioned bead populations that will be contained inside an

127 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 127 of 155 PageID: enclosure such as a capsule, and the rest of the active ingredient can be loaded on the outside of the enclosure by a suitable loading method such as solution/suspension/dispersion coating or powder coating or wet granulation. For example, a part of the immediate release topiramate formulation can be loaded by coating on the outside of a capsule that contains within it other populations of topiramate such as extended release topiramate. This dosage form can provide almost instantaneous dissolution of the initial portion of to piramate dose from the outside of the capsule, followed by a sustained release of the rest of topiramate from inside the capsule. In a further embodiment of the invention, the dosage form is a tablet. Without imposing any limitations, this embodiment may be exemplified by a multilayered tablet that comprises at least one layer containing the extended release component, and at least one layer comprising the immediate release component, wherein their component may or may be not an EIR composition. The last two embodiments are especially beneficial when fast onset of action followed by sustained release is preferred, as is for example in the cases of a breakthrough migraine episode. The current invention additionally encompasses a method of preparing formulations of topiramate, comprising an extended release component, and an optional immediate release component, wherein topiramate is released from the formulation at the sustained rate along the pre-determined release profile. The method comprises the following steps: 1. determining the desired release profile; 2. determining specific amounts of the extended release component and the immediate release component necessary to produce the pre-determined release profile; and 3. incorporating the specified amounts of the components into the formulation. In one embodiment, the method comprises a step for providing an immediate release component, which may be an enhanced immediate release composition. In another embodiment, the method includes a process for providing an extended release component contained in at least one population of beads characterized by its own rate of release, wherein the process includes the steps of: 1. forming at least one population oftopiramate-containing beads; 2. coating each population of beads with its own coating solution; 3. curing the coating for a period of time to produce a release controlling coating specific for each bead population, and 4. incorporating the beads into the formulation. The exact amount of beads of every population incorporated into the formulation and into the final dosage form is determined using the linear superposition principle (Win NonLin) on the basis of the pharmacokinetic data of the separate bead populations and the pre-determined release profile (Example 6). US 8,889,191 B2 Release profiles ofxr topiramate beads can be selectively adjusted, modified or stabilized by curing the beads at an elevated temperature. This process is well known in the art. However, it was unexpectedly discovered that curing the beads in the curing apparatus in the presence of at least one suitable solvent dramatically reduces the curing time necessary to produce a desired release profile and a level of stability. The curing process that previously required up to two 65 weeks can be carried out by the method of current invention in several hours. 12 The assisting solvents can be selected from those solvents that can dissolve or partially dissolve the coating material, or those that can induce or assist the coalescence or molecular relaxation of the coating material, or those that can reduce electrostatic charge on the dosage forms during curing and those that can facilitate curing at a higher temperature. Examples of these solvents include but are not limited to organic solvents, such as alcohols, ketones, ethers, esters, amides, amines, hydrocarbons including substituted hydro- 10 carbons such as chlorinated hydrocarbons and aromatic hydrocarbons, furans, sulfoxides, organic acids, phenols, super-critical fluids; ammonia; and water, buffered water, or water solutions of other inorganic or organic compounds, and their combinations. Preferably, water, water-alcohol mixture, 15 water-ketone mixture, water-ammonia mixture, or water-organic acid (for example water-acetic acid) mixture, or combinations thereof are used as the assisting solvents. The curing of the dosage form normally is done in an apparatus that can operate at elevated temperatures and that 20 can deliver the assisting solvents by means such as spray, injection, or vaporization. In the embodiment of the invention when the assisting solvent is sprayed or injected into the curing apparatus, the stream of solvent is introduced directly onto the coated beads. The amount of the solvent necessary to 25 produce the desired effect, such as the desired release parameters and stabilization of the coating, depends on the nature of the solvent and the method of solvent delivery. Typically, when the vaporization method is used, the organic solvents and aqueous solutions may be used in the 30 wide range of vapor concentrations varying from 2% to more than 100%, providing an unsaturated, saturated or an oversaturated atmosphere. The pure water, however, has to be used in such an amount as to provide at least a saturated or, preferably, an oversaturated atmosphere in the curing appa- 35 ratus. At least during the delivery of assisting solvents, the coated beads are mixed or agitated either continuously or in a pulsed mauner. In an alternative embodiment of the invention, hot water steam is introduced into the curing apparatus for a pre-se- 40 lected period of time. The steam serves simultaneously as a solvent and as a source of heat for the beads. Introduction of steam is followed by a drying period. This method of curing the release controlling coating results in many benefits including the dramatically shortened 45 curing time, increased stability and modification of the release profile, and is not limited to topiramate containing beads, but includes the curing of any microparticles regardless of the drug. Specifically, active ingredient containing beads, with or 50 without the optional over-coat, are charged to a fluid bed processor or a pan coater and heated to a desired curing temperature range, for example 40 C. to 80 C. for sustained release dosage forms containing ethylcellulose (Surelease ), and 40 C. to 70 C. for sustained release dosage forms 55 containing acrylic polymers (Eudragit RS and Eudragit RL). The assisting solvent or solvents, such as water or alcohol-water mixture, are sprayed onto the beads while mixing by, for example, fluidizing or rotating. Alternatively, the process is carried out in an oven where hot steam is introduced as 60 previously discussed. Solvent-assisted curing is carried out to a desired curing time length, either in one curing period or in multiple, separate curing periods. The dosage forms can be further dried for a short period of time to remove residual solvents. The solvent-assisted curing process significantly accelerates the curing of release controlling coating on active ingredient containing beads as compared to the heat-only curing of

128 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 128 of 155 PageID: the same. In most instances, less than 4 hours of solventassisted curing resulted in more complete curing of the extended release dosage forms than 2 weeks of heat-only oven curing of the same dosage forms. The present invention also presents a method of treatment or prevention of a pathological condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of a novel topiramate formulation of the instant invention, wherein topiramate is released from the formulation at a sustained rate along the pre-determined release profile. The method of the current invention possesses the flexibility to selectively adjust the pharmacokinetics of the administered formulations depend US 8,889,191 B2 ing on the nature of the condition and needs of the patients due to the novel design of the topiramate formulation that com- 15 prises an extended release component and an optional immediate release component, and the release profiles of both components can be selectively modified during the preparation process as described above to comply with the predetermined release profile. The pathological condition that may be treated by a method of the present invention is a neurological condition, psychiatric condition, diabetes and related disorders, cardiovascular condition, obesity, and any other condition or disorder that may be treated or prevented by the topiramate administration. 25 The neurological disorders that may be treated or prevented by a formulation of the present invention include, but are not limited to, epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, perinatal 30 hypoxia ischemia and related damage, chronic neurodegenerative disorders, acute neurodegeneration, and ALS. Psychiatric disorders that may be treated or prevented by a formulation of the present invention include, but are not limited to bipolar disorder, dementia, depression, psychosis, 35 mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, ADHD, impulse control disorders, border line personality disorder, addiction, and autism. Formulations of the present invention may be also used for the treatment and prevention of diabetes and related disorders, such as type II diabetes mellitus, diabetic retinopathy, impaired oral glucose tolerance, diabetic skin lesions, diabetic neuropathy, Syndrome X and elevated blood glucose levels; ocular disorders, including but not limited to glaucoma and macular degeneration; cardiovascular disorders represented but not limited to elevated blood pressure and elevated lipids; obesity; asthma; autoimmune disorders; sleep apnea and sleep disorders. The formulations may be also used for inducing weight loss or promoting wound healing, or for any other condition, not specified above, wherein the use oftopiramate is indicated. The invention will be further illustrated by the following Examples, however, without restricting its scope to these embodiments. EXAMPLES Example 1 Extended Release Beads Preparation 20 Topiramate Drug Layering on Sugar Spheres-The "Core" An aqueous suspension of A) (w/w) topiramate (particle size 90% vol. NMT 30 micrometer, 50% vol. NMT 15 micrometer and 10%vol. NMT 5 micrometer) and0.5-4% ( w /w) HPMC or other aqueous binder can be used as the drug layering coating solution. A fluid bed suited for Wursterspray is assembled and charged with inert carriers such as sugar spheres. The coating suspension is sprayed onto the bed to evenly coat the inert carriers to a desired topiramate loading level. Higher binder concentration in the coating solution may be used for smaller size inert carrier and higher topiramate loading. Inlet airflow rate and product temperature are adjusted to keep the batch from spray-drying the coating material or over-wetting the spheres. Coating of the Core with a Release Controlling Coating A dispersion of a cellulosic polymer such as ethylcellulose and methy!cellulose can be used to coat the core in the current invention. Ethylcellulose dispersion (Surelease ) can be diluted to a final concentration of about 10% to about 20% and with or without the use of other ingredients such as pore 40 formers. A fluid bed suited for Wurster-spray is assembled and charged with the cores prepared in Example 1. The release controlling coating dispersion is sprayed onto the bed to evenly coat the core to a desired coating level as exemplified in Table 1. TABLE 1 Composition and process Parameters for the extended Release XR1a XR1b XR1c XR2a XR2b XR2c XR2d RC* coating Etbyl- Ethyl- Etbyl- Etbyl- Ethyl- Etbyl- Etbylmaterial cellulose cellulose cellulose cellulose cellulose cellulose cellulose (Surelease) (Sure lease) (Surelease) (Surelease) (Sure lease) (Surelease) (Surelease) Pore-former Opadry Opadry Opadry Clear Clear Clear RC coating 80:20 80:20 80:20 material to pore-former ratio RC coating 2% 4% 3% 3% 3% 6.5% 6.5% level Product 20 C.-60 c. 20 C.-60 C. 20 C.-60 C. 20 C.-60 c. 20 C.-60 C. 20 C.-60 C. 20 C.-60 c. temperature during coating Over-coat Opadry Opadry Opadry Opadry material AMBWhite AMBWhite AMBWhite AMBWhite Over-coat 1.5% 1.5% 1.5% 1.5% coating level Curing Fluid bed/water, Fluid bed/water, Fluid bed/water, Fluid bed/water, Fluid bed/water, Fluid bed/water, Fluid bed/water,

129 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 129 of 155 PageID: 526 US 8,889,191 B TABLE!-continued method or oven or oven or oven or oven or oven or oven or oven RC coating material Topiramate Beads XR3 XR4 XR5 XR6 XR7 XR8 Ethylcellulose Ethylcellulose Ethylcellulose Ethylcellulose Ethylcellulose Acrylic (Surelease) (Surelease) (Surelease) (Surelease) (Surelease) polymers (Eudragit RL30D/RS30D) Pore-former Cellulosic Cellulosic Cellulosic Cellulosic polymers polymers polymers polymers (Opadry (Opadry (Opadry (Opadry RC coating Material to pore-former ratio RC coating level Product temperature dming coating Over-coat material Over-coat coating level Curing method *RC-Release Controlling 3.7% Clear) 80:20 3.1% Clear) 80:20 5.2% Clear) Clear) 80:20 85:15 9.5% 15% 15% 20 C.-60 C. 20 C.-60 C. 20 C.-60 C. 20 C.-60 C. 20 C.-60 C. 20 C.-60 C. Fluid bed/water, or oven Fluid bed/water, or oven Fluid bed/water, or oven Fluid bed/water, or oven Fluid bed/water, fluid bed/5% alcohol-water, or oven Fluid bed/water, fluid bed/5% alcohol-water, or oven Example 2 30 TABLE 2-continued Method of Topiramate-Hydroxypropy 1-Beta-Cyclodextrin Complex Bead Preparation Approximately half of the intended amount oftopiramate was added to the water with constant mixing followed by sprinkling of hydroxypropyl-beta-cyclodextrin into the dispersion. Once the dispersion became significantly less viscous, more drug substance was added followed by sprinkling of more hydroxypropyl-beta-cyclodextrin. The drug and hydroxypropyl-beta-cyclodextrin addition steps were repeated, and the dispersion was mixed for hours. Separately, hydroxypropylmethylcellulose was dissolved in water. The above topiramate-hydroxypropyl-beta-cyclodextrin dispersion and hydroxypropylmethylcellulose solution were mixed together for 15 to 30 minutes and the mixture was screened through an 80-mesh sieve. The resultant dispersion was sprayed onto sugar spheres using a fluid bed proces- 50 sor to yield the enhanced immediate release beads (Table 2). TABLE Hydroxypropyl-beta-cyclodextrin- Topiramate EIR Bead Compositions Percentage (w/w) in Beads EIR-1 EIR-2 EIR-3 EIR-4 (HPBCD: (HPBCD: (HPBCD: (HPBCD: Component Drug~ 3:2)* Drug~ 3:2)* Drug~ 1:1)* Drug~ 1:2)* Sugar spheres *HPBCD: Drug-Hydroxypropyl-beta-cyclodextrin to drug substance ratio Example 3 Topiramate EIR Beads Containing Non-Complexing Enhancers Hydroxypropyl-beta-cyclodextrin- Topiramate EIR Bead Com ositions Percentage (w/w) in Beads EIR-1 EIR-2 EIR-3 EIR-4 (HPBCD: (HPBCD: (HPBCD: (HPBCD: Component Drug~ 3:2)* Drug~ 3:2)* Drug~ 1:1)* Drug~ 1:2)* Topirarnate Hydroxy propylbetacyclodextrin Hydroxypropyl methylcellulose Topiramate is dispersed in a binder solution, such as hydroxypropylmethylcellulose solution, that contains an appropriate amount of enhancer or enhancers such as d-alpha-tocopheryl polyethylene glycollooo succinate (vitamin E TPGS) and sodium Iaury! sulfate combination, polyoxyl hydrogenated castor oil (different grades ofcremophor RH), polyglycolized glycerides (different grades of Gelucire ), polyglycolizedglycerides (different grades ofgelucire) combined with sodium Iaury! sulfate, or combinations thereof. The resultant dispersion is sprayed onto an inert carrier such as sugar spheres using a fluid bed processor to achieve a desired drug load (Table 3).

130 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 130 of 155 PageID: TABLE3 Enhanced Immediate Release Topirarnate Bead Compositions Percentage (w/w) in Beads Component EIR-5 EIR-6 EIR-7 Topirarnate Sodium lauryl sulfate D-alpha-tocopheryl 7.3 polyethylene glycol 1000 succinate Polyoxyl hydrogenated castor 9.1 oil (Cremophor RH40) Polyglycolized glycerides 4.7 (Gelucire 50/13) Hydroxypropylmethylcellulose Sugar spheres Example 4 Topiramate EIR Beads Containing Micronized Particles Miconized or non-micronized topiramate is dispersed in a solution with or without heating, optionally containing dissolution enhancing agents such as mannose, maltose, mannito!, lactose, maltodextrin and sodium starch glucolate, and optionally containing one or more additional enhancers such US 8,889,191 B2 as PEG3350, sodium Iaury! sulfate, sodium docusate, polyoxyethylene sorbitan monooleate and Poloxamers, under 30 such process parameters that topiramate particles that remain undissolved have a particle size of about 2 micron to about 30 micron. A particle size reduction device such as a homogenizer can also be used to reduce the particle size of undissolved topiramate. The resultant topiramate dispersion is then 35 sprayed onto inert carriers such as sugar spheres in a coating processor such as a fluid bed processor. The formulations obtained are represented in the Table 4: TABLE4 To12irarnate EIR Beads containing micronized 12articles Percentage (w/w) in Beads EIR-8 EIR-9 EIR-10 EIR-11 EIR-12 EIR-13 Topirarnate Mannose Maltrin PEG Sodium lauryl 0.5 sulfate Hydroxypropyl-beta cyclodextrin D-alpha-tocopheryl 2.0 polyethylene glycol 1000 succinate Polyoxyl 2.0 hydrogenated castor oil (Cremophor RH40) Sugar spheres Example 5 Method of Curing Beads The topiramate beads coated with a release controlling coating, with or without an overcoat, can be cured using the above-mentioned solvent-assisted curing process, or using the heat-only curing process, to a desired curing level and preferably to complete curing. Specifically, the core is coated to a desired coating level with a solution or dispersion of the release controlling coating material, with or without the above-mentioned additives such as pore-formers, using a fluid bed processor or any other suitable apparatus for coating of the core. Product temperature is controlled at a desirable range, for example 20 C. to 60 C. for the coating of ethylcellulose (Surelease ) and 20 C. to 60 C. for acrylic polymers (Eudragit RL and Eudragit RS grades). An optional overcoat with materials such as cellulosic polymers (various Opadry ) is applied thereafter. Curing of the sustained release topiramate beads is carried out either in an oven at 40 C. to 80 C. for Surelease containing beads or at 40 C. to 70 C. for Eudragit RL or RS containing beads, or in a fluid bed processor with or without the use of assisting solvents at similar product temperatures. For curing that uses assisting solvents, the assisting solvent can be delivered through top spray, bottom spray, side spray or injection, or introduced by vaporization. Preferably, water, water-alcohol mixture, water-ketone mixture, water-ammonia mixture, or water-organic acid (for example water-acetic 25 acid) mixture, or combinations thereof are used as the assisting solvents Example 6 Sustained Release Formulations oftopiramate a. Plasma concentration versus time curves for the topiramate formulations containing extended release and immediate release bead populations are simulated using Wiri.Nonlin Version based on the pharmacokinetic data on the separate bead populations that were generated in a comparative randomized single-dose 6-way crossover study in healthy adult volunteers. The study included administration of a 50 mg oral dose of three extended release compositions, desig nated here as XR1, XR2 and XR3, two immediate release compositions ((Topamax, Ortho-McNeil Neurologies, Inc.) (25 mg BID), and an immediate release bead formulation) and an enhanced immediate release (IR) bead composition. The single dose topiramate plasma concentration profiles for XR1, XR2 and XR3 are shown in FIG. 3. The single dose topiramate plasma concentration profiles for IR are shown in FIG. 4. The data are projected to a steady-state (SS) with a 24 h dosing interval for the sustained release compositions and a 12 h dosing interval for Topamax, using the linear superposition principle (WinNonlin). The extended release populations XR1, XR2 and XR3, and an immediate release (IR) population are selected in such a way as to be defined by at least one of the three following sets of conditions 1. for the steady state, for XR3, 0.25CmaxiR>~CmaxXR3>~0.05CmaxiR 2. for in-vitro dissolution, for XR1, 1.5 h<~t8 0o/,<~ h for XR3, 8 h<t 80 %<~10 h

131 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 131 of 155 PageID: for a single initial dose in-vivo, for XR3, Tmax>~I6 h. Optionally, the innnediate release bead population is composed of enhanced immediate release (EIR) beads such that at least one condition is true: a. for the steady state, 2.40CmaxiR>=CmaxEIR>=1.20CmaxiR; b. for in-vitro dissolution, T80%<=30 min; c. for a single initial dose in-vivo, Tmax<=2h. The results of the pharmacokinetic simulation for the seven exemplary formulations are sunnnarized in Table 5 below. These formulations are selected as examples only, and in no way limit the range, compositions or properties of the formulations covered by the present invention. %XR1 %XR2 %XR3 %IR Rel. BA (%), ss Degree of fluctuation, SS TABLES Composition and Pharmacokinetic data of Multi-bead Formulations #1 #2 #3 #4 # US 8,889,191 B2 #6 # b. based on the results ofwinnonlin simulation discussed in part (a), formulations #1 (A), #3 (B), and#4 (C) were tested in the comparative randomized multi-dose 4-way study following a once a day 50 mg oral dose of three controlled release formulations and a 25 mg twice a day oral doses of Topamax in healthy adult volunteers. The results of the study are sunnnarized in Table 6 and FIG. 6: TABLE6 Pharmacokinetic study data for Multi-bead Formulations Control #!A #3 B #4C (Topamax ) %XR %XR %XR %IR 0 14 Rel.BA(%), ss Relative 73% 72% 66% 100% Degree of fluctuation, ss What is claimed is: 1. A method of treatment of a neurological and/or psychiatric condition in a mannnalian subject, comprising orally 60 administering to said subject in need thereof a therapeutically effective amount of a sustained release formulation of 2,3 :4, 5-Di -0-isopropylidene-beta-D-fructopyranose sulfamate (topiramate), wherein all of the topiramate is released in a continuous manner from the formulation, wherein at least 85% by weight of the total topiramate in the formulation is contained in an extended release (XR) component compris- 20 ing at least two populations of beads coated with a release controlling coating and each having its own rate of release, and wherein at least one of the at least two XR populations releases 80% of the topiramate contained therein in vitro in not more than 4 hours. 2. The method of claim 1, wherein said formulation provides for a maximum steady state plasma concentration (Cmax) oftopiramate which is in the range of 50% to 125% of the maximum plasma concentration produced by the same 10 amount oftopiramate administered as an innnediate release formulation BID. 3. The method of claim 2, wherein said Cmax is higher than the minimal therapeutically effective concentration, but lower than the maximum plasma concentration produced by 15 the same amount oftopiramate administered as an innnediate release formulation BID. 4. The method of claim 2, wherein said Cmax is in the range of 80% to 125% of the maximum plasma concentration pro- 20 duced by the same amount oftopiramate administered as an innnediate release formulation BID. 5. The method of claim 1, wherein said formulation provides for a relative steady state AUC in the range of 80% to 125%, as compared to the same amount oftopiramate administered as an innnediate release formulation BID The method of claim 1, wherein said formulation provides for a degree offluctuationin the range of25% to 90% as compared to the same amount oftopiramate administered as an innnediate release formulation BID The method of claim 1, wherein said beads comprise an inert carrier, topiramate, an optional enhancer, and a release controlling coating that comprises a coating material and optionally a pore former. 8. The method of claim 7, wherein said inert carrier is 35 selected from the group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres. 9. The method of claim 7, wherein said pore former is selected from the group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, water- 40 soluble hydrophilic polymers, hydroxyalkylcelluloses, car boxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, carbomers, dials, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly( a-w )alkylenediols; inorganic compounds; alkali metal salts and alkaline earth metal salts, and combinations thereof. 10. The method of claim 7, wherein said enhancer is selected from the group consisting of solubility enhancers, dissolution enhancers, permeability enhancers, stabilizing agents, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof. 11. The method of claim 1, wherein a specific amount of each bead population is determined according to a pre-determined release profile. 12. The method of claim 1, wherein the sustained release is after an initial innnediate release. 13. The method of claim 1, wherein said formulation is administered orally once a day. 14. The method of claim 1, having a reduced level of undesirable CNS side effects as compared to the same amount oftopiramate administered as an innnediate release formula- 65 tion BID. 15. The method of claim 1, wherein the total amount of topiramate in the formulation is from 0.5 mg to 3000 mg.

132 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 132 of 155 PageID: 529 US 8,889,191 B The method of claim 1, wherein said formulation is in a dosage form of a tablet, a pill, a capsule, a caplet, a troche, a pouch, or sprinkles. 17. The formulation of claim 1, further comprising an immediate release (IR) component. 18. The method of claim 17, wherein said IR component comprises topiramate and (a) a complexing agent selected from the group consisting ofhydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, and cyclodextrin derivative and/or (b) an enhancing 10 agent selected from the group consisting of solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and com- 15 binations thereof. 19. The method of claim 18, wherein said IR component exhibits a release profile such that 80% of the active ingredient is dissolved in not more than 30 min. 20. The method of claim 19, wherein said IR component exhibits a release profile selected from the group consisting of: a) a dissolution of at least 50% of the active ingredient in not more than 10 minutes; b) a dissolution of at least 70% of the active ingredient in not more than 10 minutes; c) a dissolution of at least 25% of the active ingredient in not more than 5 minutes; d) a dissolution of at least 40% of the active ingredient in not more than 5 minutes; and e) a dissolution of at least 55% of the active ingredient in not more than 5 minutes. 21. The method of claim 7, wherein said coating material is selected from the group consisting of ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates and copolymers thereof. 22. The method of claim 1, wherein the condition is selected from the group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, impulse control disorders, border line personality disorder, addiction, autism, chronic neurodegenerative disorders, acute neurodegeneration, and amyotrophic lateral sclerosis. 23. The method of claim 22, wherein the condition is epilepsy. 24. The method of claim 22, wherein the condition is migraine. * * * * *

133 Case 2:14-cv SDW-SCM Document 28 Filed 04/28/15 Page 133 of 155 PageID: 530 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. APPLICATION NO. DATED INVENTOR(S) : 8,889,191 B2 : 12/ :November 18, 2014 : Likan Liang et al. Page 1 of 1 It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below: In the Claims Col. 21, claim 17, line 4, "formulation" should be --method--. Col. 21, claim 17, line 4, "further comprising" should be --wherein the formulation further comprises--. Signed and Sealed this Thirtieth Day of December, 2014 Michelle K. Lee Deputy Director of the United States Patent and Trademark Office

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