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Avanir Pharmaceuticals, Inc. v. Actavis South Atlantic LLC

United States District Court, D. Delaware

May 2, 2014

AVANIR PHARMACEUTICALS, INC., AVANIR HOLDING COMPANY, AND CENTER FOR NEUROLOGIC STUDY, Plaintiffs,
v.
ACTAVIS SOUTH ATLANTIC LLC, ACTAVIS, INC., PAR PHARMACEUTICAL, INC., PAR PHARMACEUTICAL COMPANIES, INC., IMPAX LABORATORIES, INC., WOCKHARDT, LTD., WOCKHARDT USA, LLC, WATSON PHARMACEUTICALS, INC., WATSON LABORATORIES, INC., AND WATSON PHARMA, INC., Defendants

Decided Date: April 30, 2014.

Page 476

Jack B. Blumenfeld, Maryellen Noreika, MORRIS, NICHOLS, ARSHT & TUNNELL, LLP, Wilmington, DE; F. Dominic Cerrito, Eric Stops, Daniel Wiesner, QUINN EMANUEL URQUHART & SULLIVAN, LLP, New York, NY, Attorneys for Plaintiffs.

Steven J. Fineman, RICHARDS, LAYTON & FINGER P.A., Wilmington, DE; Richard J. Berman, Janine A. Carlan, Aziz Burgy, Amy E.L. Schoenhard, Timothy W. Bucknell, Taniel E. Anderson, ARENT FOX LLP, Washington, D.C., Attorneys for Defendants Par Pharmaceutical, Inc. and Par Pharmaceutical Companies, Inc.

John C. Phillips, Jr., Megan C. Haney, PHILLIPS, GOLDMAN & SPENCE, P.A., Wilmington, DE; Eric H. Weisblatt, Mark A. Pacella, Robert J. Scheffel, WILEY REIN LLP, Washington, D.C., Attorneys for Defendant Impax Laboratories, Inc.

Page 477

MEMORANDUM OPINION

Leonard P. Stark, UNITED STATES DISTRICT JUDGE.

Avanir Pharmaceuticals, Inc., Avanir Holding Company, and Center for Neurologic Study (" CNS" ) (collectively, " Avanir" or " Plaintiffs" ) allege that Par Pharmaceutical, Inc., Par Pharmaceutical Companies, Inc., and Impax Laboratories, Inc. (collectively, " Defendants" ) infringe United States Patent Nos. RE38,115 (" the '115 patent" ), 7,659,282 (" the '282 patent" ), and 8,227,484 (" the '484 patent" ) (collectively, the " patents-in-suit" ).[1] (C.A. No. 11-704-LPS D.I. 1; C.A. No. 11-705-LPS D.I. 1; C.A. No. 11-757-LPS D.I. 1; C.A. No. 12-1123-LPS D.I. 1; C.A. No. 12-1298-LPS D.I. 1) The '115 patent relates to formulations containing dextromethorphan (" DM" ) and quinidine (" Q" ) for the treatment of chronic or intractable pain. The '282 and '484 patents relate to the use of DM and Q for the treatment of a neurological disorder known as pseudobulbar affect (" PBA" ).[2] DM and Q are the active ingredients of Avanir's Nuedexta® product.

Page 478

In December 2012, the Court construed the disputed terms of the patents-in-suit. (D.I. 256, 257)[3] The Court conducted a six-day bench trial in September and October of 2013. ( See D.I. 463-70) (hereinafter, " Tr." ) The parties completed post-trial briefing on November 15, 2013. (D.I. 429, 432, 444, 446, 449, 450) In connection with the briefing, the parties submitted proposed findings of fact and conclusions of law. (D.I. 430, 431, 443, 445, 447, 451)

Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire record in this case and the applicable law, the Court concludes that: (1) Defendants have stipulated that their proposed products infringe claims 1-9 of the '282 patent; (2) Defendants have stipulated that their proposed products infringe claims 1-9, 12, 13, 15, and 17 of the '484 patent; (3) Plaintiffs have not proven by a preponderance of the evidence that Defendants infringe claims 18-21 of the '115 patent; (4) Defendants have failed to prove by clear and convincing evidence that claims 1-9 of the '282 patent are invalid; (5) Defendants have failed to prove by clear and convincing evidence that claims 1-9, 12, 13, 15, and 17 of the '484 patent are invalid; and (6) Defendants have failed to prove by clear and convincing evidence that claims 18-21 of the '115 patent are invalid. The Court's findings of fact and conclusions of law are set forth in detail below.

I. FINDINGS OF FACT

This section contains the Court's findings of fact for issues raised by the parties during trial. Certain findings of fact are also provided in connection with the Court's conclusions of law.

A. The Parties

1. Plaintiff Avanir Pharmaceuticals, Inc. is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 20 Enterprise, Suite 200, Aliso Viejo, California 92656. (D.I. 443 (Joint Findings of Fact (" JFF" )) at ¶ 1)

2. Plaintiff Avanir Holding Company is a corporation organized and existing under the laws of the State of California, having a principal place of business at 20 Enterprise, Suite 200, Aliso Viejo, California 92656. ( Id. at ¶ 2)

3. Avanir Holding Company is a wholly-owned subsidiary of Avanir Pharmaceuticals. ( Id. at ¶ 3)

4. Plaintiff CNS is a not-for-profit corporation organized and existing under the laws of the State of California, having a principal place of business at 7950 Fay Avenue, Suite 517, La Jolla, California 92037. ( Id. at ¶ 4)

5. Defendant Par Pharmaceutical, Inc. is a Delaware corporation with a principal place of business at One Ram Ridge Road, Spring Valley, New York 10977. ( Id. at ¶ 5)

6. Defendant Par Pharmaceutical Companies, Inc. is a Delaware corporation with a principal place of business at One Ram Ridge Road, Spring Valley, New York 10977. ( Id. at ¶ 6)

7. Defendant Impax Laboratories, Inc. is a corporation organized and existing under the laws of Delaware and having a principal place of business at 30831 Huntwood Avenue, Hayward, California 94544. ( Id. at ¶ 7)

Page 479

B. U.S. Patent 7,659,282

8. The '282 patent, entitled " Pharmaceutical Compositions Comprising Dextromethorphan and Quinidine for the Treatment of Neurological Disorders," issued on February 9, 2010. (PTX-1; JFF at ¶ 8)

9. The '282 patent issued from U.S. Patent Application No. 11/035,213, filed on January 12, 2005, and claims priority to U.S. Provisional application No. 60/396,661, filed on July 17, 2002. (PTX-1)

10. Gerald Yakatan, James Berg, Laura E. Pope, and Richard A. Smith are the named inventors of the '282 Patent. ( Id. ; JFF at ¶ 9)

11. Plaintiffs assert that Defendants' proposed generic product and/or manufacturing process infringe claims 1-9 of the '282 patent. (JFF at ¶ 10) Claim 1 is the only independent claim asserted. The asserted claims are reproduced below:

1. A method for treating pseudobulbar affect or emotional lability, the method comprising administering to a patient in need thereof dextromethorphan in combination with quinidine, wherein the amount of dextromethorphan administered comprises from about 20 mg/day to about 80 mg/day and wherein the amount of quinidine administered comprises from about 10 mg/day to less than about 30 mg/day with the proviso that the weight to weight ratio of dextromethorphan to quinidine is 1:0.5 or less.
2. The method of claim 1, wherein the pseudobulbar affect or emotional lability is caused by a neurodegenerative disease or condition or a brain injury.
3. The method of claim 1, wherein the dextromethorphan and the quinidine are administered as one combined dose per day.
4. The method of claim 1, wherein the dextromethorphan and the quinidine are administered as at least two combined doses per day.
5. The method of claim 1, wherein the amount of quinidine administered comprises from about 20 mg/day to about 30 mg/day.
6. The method of claim 1, wherein the amount of dextromethorphan administered comprises from about 20 mg/day to about 60 mg/day.
7. The method of claim 1, wherein at least one of the quinidine and the dextromethorphan is in a form of a pharmaceutically acceptable salt.
8. The method of claim 1, wherein at least one of the quinidine and the dextromethorphan is in a form of a pharmaceutically acceptable salt selected from the group consisting of salts of free acids, inorganic salts, salts of sulfate, salts of hydrochloride, and salts of hydrobromide.
9. The method of claim 1, wherein about 20 mg quinidine sulfate is administered per day.

C. U.S. Patent 8,227,484

12. The '484 patent, entitled " Pharmaceutical Compositions Comprising Dextromethorphan and Quinidine for the Treatment of Neurological Disorders," issued on July 24, 2012. (PTX-2; JFF at ¶ 20)

13. The '484 patent issued from U.S. Patent Application No. 13/415,067, filed on March 8, 2012, and claims priority to U.S. Provisional application No. 60/396,661, filed on July 17, 2002. (PTX-2)

14. Gerald Yakatan, James Berg, Laura Pope, and Richard Alan Smith are the named inventors of the '484 Patent. ( Id. ; JFF at ¶ 21)

15. Plaintiffs assert that Defendants' proposed generic product and/or manufacturing process infringe claims 1-9, 12, 13, 15, and 17 of the '484 patent. (JFF at ¶ 22)

Page 480

Claim 1 is the only independent claim asserted. The asserted claims are reproduced below:

1. A method for treating pseudobulbar affect or emotional lability, the method comprising administering to a patient in need thereof dextromethorphan in combination with quinidine, wherein the amount of dextromethorphan administered comprises from about 20 mg/day to about 60 mg/day and wherein the amount of quinidine administered comprises from about 10 mg/day to about 30 mg/day with the proviso that the weight-to-weight ratio of dextromethorphan to quinidine is 1:0.75 or less of quinidine.
2. The method of claim 1, wherein the pseudobulbar affect or emotional lability is caused by a neurodegenerative disease or condition or a brain injury.
3. The method of claim 1, wherein the dextromethorphan and the quinidine are administered as one combined dose per day.
4. The method of claim 1, wherein the dextromethorphan and the quinidine are administered as at least two combined doses per day.
5. The method of claim 1, wherein the amount of quinidine administered comprises from about 20 mg/day to 30 mg/day.
6. The method of claim 1, wherein the amount of dextromethorphan administered comprises from about 40 mg/day to 60 mg/day.
7. The method of claim 1, wherein at least one of the quinidine and the dextromethorphan is in a form of a pharmaceutically acceptable salt.
8. The method of claim 1, wherein at least one of the quinidine and the dextromethorphan is in a form of a pharmaceutically acceptable salt selected from the group consisting of salts of free acids, inorganic salts, salts of sulfate, salts of hydrochloride, and salts of hydrobromide.
9. The method of claim 1, wherein about 20 mg quinidine sulfate is administered per day.
* * *
12. The method of claim 1, wherein the weight-to-weight ratio of dextromethorphan to quinidine is 1:0.65 or less of quinidine.
13. The method of claim 1, wherein about 40 mg dextromethorphan hydrobromide is administered per day.
* * *
15. The method of claim 1, wherein about 40 mg of dextromethorphan and about 20 mg of quinidine is administered per day.
* * *
17. The method of claim 1, wherein about 40 mg of dextromethorphan hydrobromide and about 20 mg of quinidine sulfate is administered per day.

D. U.S. Patent RE38,115

16. The '115 patent, entitled " Dextromethorphan and an oxidase inhibitor for treating intractable conditions," issued on May 6, 2003. (PTX-3; JFF at ¶ 36)

17. The '115 patent issued from U.S. Patent Application Serial No. 10/052,698, filed on January 18, 2002, which was an application for reissuance of U.S. Patent No. 5,863,927, which issued from U.S. Patent Application Serial No. 08/464,792, filed on September 19, 1996, which was the national stage application of PCT International Application No. PCT/US94/10771, filed on September 22, 1994, and claims priority back to U.S. Patent Application Serial No. 08/114,845 (" the '845 application" ), filed on September 2, 1993. ( See D.I. 441) (considering priority date)

Page 481

18. Richard Alan Smith and Jonathan M. Licht are the named inventors of the '115 Patent. (PTX-3; JFF at ¶ 37)

19. Plaintiffs assert that Defendants' proposed generic product and/or manufacturing process infringe claims 18-21 of the '115 patent. (JFF at ¶ 38) Claim 18 is the only independent claim asserted. The asserted claims are reproduced below:

18. A unit dosage formulation for treatment of chronic or intractable pain, comprising:
(a) dextromethorphan or a pharmaceutically acceptable salt thereof, and,
(b) a debrisoquin hydroxylase inhibitor, in a combined form that is designed for oral ingestion by humans, wherein the dextromethorphan or salt thereof and the debrisoquin hydroxylase inhibitor are present at a combined dosage which renders the dextromethorphan therapeutically effective in substantially reducing chronic or intractable pain, without causing unacceptable side effects.
19. The unit dosage formulation of claim 18, comprising a digestible capsule which encloses the dextromethorphan or pharmaceutically acceptable salt thereof and the debrisoquin hydroxylase inhibitor.
20. The unit dosage formulation of claim 18, wherein the debrisoquin hydroxylase inhibitor is selected from the group consisting of quinidine, quinine, and pharmaceutically acceptable salts thereof.
21. The unit dosage formulation of claim 20, wherein the dosage of quinidine is 300 milligrams/day or less.

E. Nuedexta®

20. Avanir Pharmaceuticals, Inc. holds approved New Drug Application (" NDA" ) No. 21-879 under Section 505(a) of the Federal Food Drug and Cosmetic Act (" FFDCA" ), 21 U.S.C. § 355(a), for 20 mg dextromethorphan hydrobromide/10 mg quinidine sulfate capsules, which it sells under the trade name Nuedexta® . (D.I. 1 at ¶ 16; JFF at ¶ 44) The Nuedexta® capsule is taken once a day for the first week and twice a day thereafter for the treatment of PBA. (PTX-105 at AVAN-0207640; Tr. at 273-74)

21. Nuedexta® was approved by the FDA in October 2010 for the treatment of PBA. (DTX-40; JFF at ¶ 45)

22. Avanir Pharmaceuticals, Inc. has been marketing and selling Nuedexta® since February 2011. (PTX-150 at AVAN-0319386; JFF at ¶ 46)

23. Nuedexta® is the only drug product approved by the FDA for treatment of PBA. (JFF at ¶ 47)

F. Defendants' Generic Products

1. Par's Abbreviated New Drug Application (" ANDA" )

24. Par filed ANDA No. 202-993 (" Par's ANDA" ), pursuant to Section 505 of the FFDCA, seeking approval to engage in the commercial use, manufacture, sale, offer for sale, or importation of 20 mg dextromethorphan hydrobromide/10 mg quinidine sulfate capsules (" Par's Generic Product" ) before the patents-in-suit expire. ( Id. at ¶ 48)

25. In connection with the filing of its ANDA, Par provided written certifications to the FDA, pursuant to Section 505 of the FFDCA, alleging that the claims of the patents-in-suit are invalid, unenforceable, and/or will not be infringed by the activities described in Par's ANDA. ( Id. at ¶ 49)

26. No earlier than June 29, 2011, Par sent written notice of its ANDA certification relating to the '282 and '115 patents to Avanir (" Par's First Notice Letter" ), informing

Page 482

Avanir that Par seeks approval to market Par's Generic Product before the expiration of the '282 and '115 Patents. ( Id. at ¶ 50)

27. No earlier than August 22, 2012, Par sent written notice of its ANDA certification relating to the '484 Patent to Avanir (" Par's Second Notice Letter" ), informing Avanir that Par seeks approval to market Par's Generic Product before the expiration of the '484 patent. ( Id. at ¶ 51)

2. Impax's ANDA

28. Impax filed ANDA No. 203-061 (" Impax's ANDA" ), pursuant to Section 505 of the FFDCA, seeking approval to engage in the commercial use, manufacture, sale, offer for sale, or importation of 20 mg dextromethorphan hydrobromide/10 mg quinidine sulfate capsules (" Impax's Generic Product" ) before the patents-in-suit expire. ( Id. at ¶ 52)

29. In connection with the filing of its ANDA, Impax provided written certifications to the FDA, pursuant to Section 505 of the FFDCA, alleging that the claims of the patents-in-suit are invalid, unenforceable, and/or will not be infringed by the activities described in Impax's ANDA. ( Id. at ¶ 53)

30. No earlier than July 19, 2011, Impax sent written notice of its ANDA certification relating to the '282 and '115 Patents to Avanir (" Impax's First Notice Letter" ), informing Avanir that Impax seeks approval to market Impax's Generic Product before the expiration of the '282 and '115 Patents. ( Id. at ¶ 54)

31. No earlier than September 20, 2012, Impax sent written notice of its ANDA certification relating to the '484 Patent to Avanir (" Impax's Second Notice Letter" ), informing Avanir that Impax seeks approval to market Impax's Generic Product before the expiration of the '484 Patent. ( Id. at ¶ 55)

G. The Expert Witnesses at Trial

32. Dr. Stanley H. Appel testified as an expert " in the field of neurology; in particular, ALS [Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease] and the treatment of PBA and the prescribing of drugs in his specialty," on behalf of Plaintiffs. (Tr. at 264)

33. Dr. Mark C. Rainey testified as an expert " in the field of economics in the pharmaceutical industry and in particular in the field of industrial organization in the pharmaceutical industry," on behalf of Plaintiffs. ( Id. at 775)

34. Dr. Edward M. Sellers testified as an expert " in clinical psychopharmacology and CNS [Central Nervous System] drug development," on behalf of Plaintiffs. ( Id. at 856)

35. Dr. Daniel R. Wynn testified as an expert " in the field of neurology. In particular, MS [Multiple Sclerosis] and the treatment of PBA and chronic, intractable pain in the prescribing of drugs in this specialty," on behalf of Plaintiffs. ( Id. at 1092)

36. Dr. Alan Boobis testified as an expert " in the area of clinical pharmacology," on behalf of Defendants. ( Id. at 343)

37. Dr. Henrik Poulsen testified as an expert " in clinical pharmacology," on behalf of Defendants. ( Id. at 493)

38. Dr. Timothy R. Deer testified as an expert " in the treatment and evaluation of therapies for chronic or [in]tractable pain," on behalf of Defendants. ( Id. at 679)

39. Dr. William T. Dauer testified as an expert " in diagnosis and treatment of neurological disease and associated symptoms," on behalf of Defendants. ( Id. at 723-24)

40. Dr. Gordon Rausser testified as an expert " in the fields of economics, finance,

Page 483

and statistics," on behalf of Defendants. ( Id. at 813)

41. Dr. John Kelly testified by deposition as an expert " in the diagnosis and treatment of neurologic conditions, including PBA and the treatment of neuropathic pain," on behalf of Defendants. ( Id. at 1040)

H. Person Having Ordinary Skill in the Art

42. The Court has determined that a person having ordinary skill in the art relating to the inventions claimed by the '282 and '484 patents, at the time that the claimed inventions were made, would have at least an M.D. or Ph.D. in an area relevant to pharmacokinetics (" PK" ) and/or drug interactions, or a Bachelor's degree and at least five years of relevant industry or academic experience in the area of PK and/or drug interactions. ( Id. at 496-97)

43. The Court has determined that a person having ordinary skill in the art relating to the inventions claimed by the '115 patent, at the time that the claimed invention was made, would have at least an M.D. with knowledge of or five years experience in treating pain or patients with neurologic conditions including pain. ( Id. at 680)

I. Facts Relating to Infringement of the '282 and '484 Patents

44. Both Impax and Par have stipulated that their proposed ANDA products infringe each asserted claim of the '282 and '484 patents. (D.I. 238, 411)

J. Facts Relating to Infringement of the '115 Patent

45. The Court construed " chronic pain" to mean " long-term pain resulting from conditions such as stroke, cancer and trauma, as well as neuropathic pain due to deterioration of nerve tissue such as postherpetic neuralgia (PHN) resulting from herpes zoster infection, and diabetic neuropathy resulting from long-time diabetes. The conditions are not an exclusive list." (D.I. 257 at ¶ 3)

46. The Court construed " intractable pain" to mean " pain which failed to respond adequately to conventional treatments." ( Id. at ¶ 4)

47. The Court determined " a combined dosage which renders the dextromethorphan therapeutically effective in substantially reducing chronic or intractable pain, without causing unacceptable side effects" did not require construction and is given its plain and ordinary meaning. ( Id. at ¶ 5)

48. On November 20, 2012, Impax stipulated that, with the exception of the language of the preamble of Claim 18 of the '115 Patent (" A unit dosage formulation for the treatment of chronic or intractable pain" ), as well as the claim term " are present at a combined dosage which renders the dextromethorphan therapeutically effective in substantially reducing chronic or intractable pain, without causing unacceptable side effects," Impax's Generic Product falls within the literal scope of claims 18-21 of the '115 patent. (D.I. 238 at 13; JFF at ¶ 58) Although Par filed no similar stipulation, the only limitation of the '115 patent Par disputed at trial or in its post-trial briefing ( see D.I. 450 at 19-22) is the same limitation challenged by Impax. Defendants do not challenge Plaintiffs' contention that, at least for purposes of infringement of the '115 patent, Par's and Impax's Generic Products are identical to Nuedexta® , such that if Nuedexta® is an embodiment of the '115 patent, then Par's and Impax's Generic Products infringe the '115 patent. (PTX-50; DTX-105; D.I. 446 at 41)

Page 484

49. Avanir clinical studies AVR-106 (" Study 106" ) and AVR-107 (" Study 107" ) tested substantially higher dosages of DM and Q than what is contained in the Nuedexta® product. (Tr. at 1141-42)

50. Avanir's clinical study AVR-123 (" STAR Study" ) was not designed to look at pain. ( Id. at 1142-43) The STAR Study concluded that there was no statistically significant difference in pain level between patients who received Nuedexta® and patients who received a placebo, when pain was measured as a secondary endpoint. ( Id. at 1142-47)

51. On December 10, 2013, Avanir disclosed the results of its Phase II PRIME Study for the treatment of central neuropathic pain in patients with multiple sclerosis. Avanir reported that " there was no difference between the treatment arms [using AVP-923, which included '20mg DM/10mg Q'] and placebo," and further that " the treatment of central neuropathic pain in patients with multiple sclerosis did not meet the primary efficacy endpoint." (D.I. 458 Ex. 1) (" JTX-1" )

52. Dr. Wynn testified that the patients to whom he has prescribed Nuedexta® are sometimes on more than a dozen medications, including, sometimes, other pain medications. He also testified that it is not uncommon for patients who are taking Nuedexta® for ...


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