Avanir Pharmaceuticals, Inc. v. Actavis South Atlantic LLC (36 F. Supp. 3d 475, 2014)

United States District Court for the District of Delaware 2014-04-30

Citations

Full opinion text

MEMORANDUM OPINION

STARK, U.S. District Judge:

Avanir Pharmaceuticals, Inc., Avanir Holding Company, and Center for Neuro-logic 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”). (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”). DM and Q are the active ingredients of Avanir’s Nuedexta® product.

In December 2012, the Court construed the disputed terms of the patents-in-suit. (D.I.256, 257) 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 Hunt-wood Avenue, Hayward, California 94544. (Id. at ¶ 7)

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

8. The ’282 patent, entitled “Pharmaceutical Compositions Comprising Dextro-methorphan 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 dextrome-thorphan 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 dex-tromethorphan is in a form of a pharma-ceutically acceptable salt.

8. The method of claim 1, wherein at least one of the quinidine and the dex-tromethorphan is in a form of a pharma-ceutically acceptable salt selected from the group consisting of salts of free acids, inorganic salts, salts of sulfate, salts of hydrochloride, and salts of hy-drobromide.

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 Dextro-methorphan 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) 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 quinidme 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 dex-tromethorphan is in a form of a pharma-ceutically acceptable salt.

8. The method of claim 1, wherein at least one of the quinidme and the dex-tromethorphan is in a form of a pharma-ceutically acceptable salt selected from the group consisting of salts of free acids, inorganic salts, salts of sulfate, salts of hydrochloride, and salts of hy-drobromide.

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 dextromethor-phan to quinidine is 1:0.65 or less of quinidine.

13. The method of claim 1, wherein about 40 mg dextromethorphan hydro-bromide 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 hy-drobromide and about 20 mg of quini-dine sulfate is administered per day.

D. U.S. Patent RE38,115

16. The ’115 patent, entitled “Dextro-methorphan 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)

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 pharma-ceutically 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 hy-droxylase 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 hy-droxylase 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 quini-dine 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 T15 patents to Avanir (“Par’s First Notice Letter”), informing 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 Ava-nir (“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, Im-pax 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, 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 posth-erpetic neuralgia (PHN) resulting from herpes zoster infection, and diabetic neuro-pathy 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 dextromethor-phan 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 ¶ 3; 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 Nue-dex® 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)

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 Nue-dexta® 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 1142^7)

51. On December 10, 2013, Avanir disclosed the results of its Phase II PRIME Study for the treatment of central neuro-pathic pain in patients with multiple sclerosis. Avanir reported that “there was no difference between the treatment arms [using AVP-923, which included ’20mg DM/lOmg 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 Nuedex-ta® 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 pain to take other pain medications regularly as well. (Tr. at 1156-58)

53. None of the examples in the ’115 patent use the 20/10 mg/day dose of DWQ found in Nuedexta®. (Id. at 689-91,1166)

54. Neither the labels for Nuedexta® nor any of Defendants’ products provide any indication that the 20/10 formulation of DM/Q can be used to treat pain. (Id. at 1171-73)

55. Pre- and post-treatment pain scores are important for making any judgment as to the efficacy of the drug. (Id. at 695) In prescribing medication to reduce pain, physicians rely on data reporting a measureable pain score reduction resulting from the drug, on a scale that has been validated. (Id. at 684)

56. There are no peer-reviewed publications or prospective studies reporting that Nuedexta® is therapeutically effective in treating chronic or intractable pain. (Id. at 685) Nuedexta® has not been the subject of any presentation at any of the major conferences related to pain. (Id. at 685-86) Nuedexta® is not mentioned in comprehensive pain treatment text books. (Id. at 686-87)

57. Nuedexta® has not been approved to treat chronic' or intractable pain. Nue-dexta® has only been approved by the FDA for the treatment of PBA. (DTX-40; Tr. at 687)

58. A person of ordinary skill in the art would consider unacceptable side effects to be those that cause limitations in the patient’s daily function or those that cause other comorbidities or other disease states. (Tr. at 691)

59. Given the. comorbidities that are often found in patients with chronic pain, it is difficult to understand the side effects of treating chronic or intractable pain with Nuedexta® without performing a study involving a sample of patients who all suffer from chronic or intractable pain. (Id. at 692-93)

60. Dr. Wynn’s patient interviews do not provide measurements or information on the patients’ pre- and post-treatment pain scores, do not control for any possible confounding variables, including placebo effect, do not control for patient activity— which is standard practice in pain research, due to the possibility of false-positives as a result of differences in patient activity level — and do not control for other medications that the patients may have been taking at the same time as their Nuedexta® treatment. (DTX-267; DTX-478; Tr. at 695, 697-99)

61. In his experience, Dr. Wynn has seen patients discontinue Nuedexta® due ■ to side effects. (Tr. at 1168)

K. Facts Relating to Validity of the ’282 and ’484 Patents

62. Neither DM nor Q was a new chemical entity in July 2002. (Id. at 442, 888-84)

68.DM is rapidly metabolized by a liver enzyme known as cytochrome P450-2D6 enzyme (or “CYP2D6”) into dextror-phan (“DX”) and eliminated from the body. (DTX-10 at 2:30-37, 2:59-66)

64. In July 2002, Q was a known inhibitor of CYP2D6. (DTX-6 at 7:27-29)

65. Phenotypically, maximum inhibition of CYP2D6 can convert an “extensive me-tabolizer” (“EM”) to a “poor metabolizer” (“PM”). (Tr. at 359) “Poor metabolizers” of drugs have a deficiency in CYP2D6 activity. (Id. at 353-54; DTX-124 at AVAN-0379192) All other individuals who do not exhibit reduced activity of the enzyme are called “extensive metabolizers.” (Tr. at 354)

1. Scope and teachings of the prior art

a. ’248 patent

66. U.S. Patent No. 5,206,248 (hereinafter, “the ’248 patént”) was admitted at trial as DTX-6. The ’248 patent issued on April 27, 1993. The ’248 patent is entitled “Method for reducing emotional lability” and discloses the combination of 30-120 mg/day of DM and 150 mg/day of Q for treatment of PBA. (DTX-6 at 11:10-15, 11:39-41)

67. Example 2 of the ’248 patent taught that a patient receiving 60 mg/day of DM and 150 mg/day of Q had blood concentrations of DM that “usually averaged” between 43-55 ng/mL, and the patient’s PBA symptoms faded away. (Id. at 12:8-24)

68. Example 3 of the ’248 patent taught that a patient who received 90 mg/ day of DM and 150 mg/day of Q achieved DM blood levels of between 130-180 ng/mL and saw improvement in his PBA symptoms. (Id. at 12:27-56)

69. From the disclosures in Example 2, a person of ordinary skill would not have known when the reported blood samples were drawn, or how they were stored. (Tr. at 582-83, 867-68) A person of ordinary skill would also not have known how many blood samples were drawn, whether the patient had reached a steady state level of DM, and — even if he had — whether his blood levels were measured at Cmax or trough levels. (Id. at 582-84) From the single patient of Example 2, a person of ordinary skill would not be able to conclude, with any statistical significance, that the 43-55 ng/mL DM blood levels treated PBA or determine any analytical errors. (Id. at 583-84) Example 2 gives no information about the patient’s medical history or his pre-Q-dosing level of CYP2D6 activity, e.g., whether he was an EM or PM. (Id. at 867)

70. The patient in Example 3 was stopped and started on DM/Q several times, supporting causality between administration of the DM/Q and improvement in the patient’s symptoms. (DTX-6 at 12:33-48; Tr. at 869) No causality was established for the patient in Example 2. (Tr. at 584, 867, 910)

71. When no causality is established, a placebo effect, or a false positive — which is known to be very common in CNS drugs— cannot be ruled out as the reason for the apparent efficacy. (Id. at 698-99, 858)

b.Smith abstract

72. PTX-100 is an abstract by Smith, R.A., et al., entitled “The treatment of affective lability with dextromethorphan,” published in Neurology in April 1995 (hereinafter, “the Smith Abstract”). The Smith Abstract reports a double-blind, placebo-controlled crossover trial reporting that 12 ALS patients’ PBA episodes were safely and effectively treated with 60/150 mg/day DM/Q, resulting in DM blood concentrations of 100-200 ng/mL. (PTX-100; DTX-11; Tr. at 475-77, 519, 606-07)

c.Yakatan abstract

73. DTX-135 is an abstract published in the Journal of Clinical Pharmacology by Yakatan, G., et al., entitled “Low Dose Quinidine Inhibition of Dextromethorphan Metabolism by CYP 2D6” (hereinafter, “the Yakatan Abstract”). The Yakatan Abstract was published in September 1999. (DTX-135 at AVAN-0210414-415; DTX-499; Tr. at 120-22)

74. The Yakatan Abstract discloses a dose-response PK study, which explored the blood levels of DM obtained by giving subjects DM (60 mg/day) and Q (0, 5, 20, 50, 100, or 150 mg/day). (DTX-135 at AVAN-0210415; DTX-499; Tr. at 123-24, 380, 520)

d.Yakatan poster

75. DTX-144 is a poster Dr. Pope presented at the American College of Clinical Pharmacology (“ACCP”) meeting in September 1999 (hereinafter, “the Yakatan Poster”). (DTX-134; DTX-141; DTX-142; DTX-143; DTX-144; Tr. at 120, 205) The Yakatan Poster discloses similar teachings to those disclosed in the Yakatan Abstract. (DTX-135; DTX-144)

e.Other PK studies

76. DTX-21 is a paper by Nielsen, M, fet al., entitled “A Dose-Effect Study of the in vivo Inhibitory Effect of Quinidine on Sparteine Oxidation in Man,” published in the British Journal of Clinical Pharmacology in 1990 (hereinafter, “the Nielsen reference”). The Nielsen reference teaches that 5 mg Q has some effect on CYP2D6 inhibition. (DTX-21; Tr. at 376-78)

77. DTX-4 is a paper by Boobis, A, et • al., entitled “The Contribution of Polymorphic Isozymes of Cytochrome P-450 to the Pharmacokinetics and Toxicity of Foreign Compounds in Man,” published in Microsomes and Drug Oxidations. Proceedings of the 7th International Symposium (1987) (hereinafter, the “Boobis reference”). The Boobis reference teaches 5 mg Q can produce effects on CYP2D6 inhibition. (DTX-4 at Fig. 1)

78. DTX-8 is a paper by Desmeules, J, et al, entitled “Contribution of Cytochrome P-4502D6 Phenotype to the Neuromodulatory Effects of Dextrome-thorphan,” published in the Journal of Pharmacology and Experimental Therapeutics in 1999 (hereinafter, “the Des-meules reference”). The Desmeules reference discloses that 50 mg Q converted five out of five extensive metabolizers of DM into poor metabolizers. (DTX-8 at Fig. 1; Tr. at 378, 903)

f.’053 application

79. DTX-32 is U.S. Patent Application No. 07/896,053 (hereinafter, “the ’053 application”). The ’053 application was filed in 1992. The ’053 application teaches that the combination of DM and Q is effective in treating PBA. (DTX-32 at AVAN-0403504; Tr. at 517-18)

80. The ’053 application discloses a large range of DM doses (20-400 mg/day). (DTX-32 at AVAN-0403512; Tr. at 517-18, 872)

81. The ’053 application does not disclose the specific ranges of Q used in the asserted claims or any weight-to-weight ratios of DM to Q. (Tr. at 872-73) The ’053 application does not disclose or suggest using doses of less than 150 mg/ day Q for the treatment of PBA. (DTX-32 at AVAN-0403512-13)

g. ’927 patent

82. DTX-20 is U.S. Patent No. 5,863,-927 (hereinafter, “the ’927 patent”). The ’927 patent issued on January 26, 1999. The ’927 patent was in front of the PTO during prosecution of the ’282 and ’484 patents. (PTX-1; PTX-2) The ’927 patent is entitled “Dextromethor-phan and an oxidase inhibitor for treating intractable conditions” and discloses a large range of DM doses (20-200 mg/day), in combination with Q at a range of 300 mg/day or less, with a preferred Q range of 50-150 mg/day, to treat intractable conditions. (DTX-20 at 3:67-4:1, 4:16-20; Tr. at 873)

83. The ’927 patent’s disclosures do not concern PBA. (Tr. at 911-12; see also id. at 351 (Boobis testifying: “[T]he dose of drug that’s effective in one condition may be completely ineffective or much less effective in another condition.”))

84. Claim 21 of the ’927 patent states that the dose of Q is “300 mg/day or less” to treat chronic or intractable pain, not PBA. (DTX-20 at claim 21; Tr. at 911)

85. The ’927 patent does not disclose any weight-to-weight ratios of DM to Q. (Tr. at 873)

h. Additional findings regarding prior árt

86. As of July 2002, a person of ordinary skill would not have been able to predict efficacy of CNS drugs based on in vivo or in vitro pharmacokinetic studies when the dose-effect relationship was unknown. (Id. at 96, 458, 593-94, 857-62, 1055-57)

87. The prior art did not disclose any relationship between DM plasma levels and therapeutic efficacy for the treatment of specific disease states, such as PBA. Therefore, as of July 2002, persons of skill in the art were unaware of any dose-effect relationship for DM/Q in the treatment of PBA. (Id. at 99-100, 458, 593-94, 904-07, 1046)

88. Persons of ordinary skill seeking to develop a treatment for PBA would focus on dose, not concentration. (Id. at 906:1-12 (Sellers testifying: “I wouldn’t be using serum drug concentrations for anything, especially in a situation where I was looking for something that was merely efficacious. I would always go with the dose that was reported to be effective.”); id. at 99 (Yakatan testifying)) DM plasma levels do “not predict! ] response, they are merely an observation in the context of observed efficacy.” (Id. at 904-07)

89. As of July 2002, persons of skill in the art would not have attempted to develop PBA treatments based on DM concentrations alone. Instead, one of skill in the art developing a DM/Q treatment for PBA would have focused on the doses of DM and Q that proved effective in treating PBA. (Id. at 99-100, 904-07)

2. Motivation to combine or modify

a. Safety concerns

90. In the early 1990s, a neurologist named Dr. Richard Smith, relying on prior publications, speculated that DM might treat Lou Gehrig’s Disease (“ALS”). (DTX-10 at 1:59-66; Tr. at 512-13)

91. Dr. Smith first ran a PK study which found that a dose of 150 mg/day of Q could maximally inhibit DM’s metabolism by CYP2D6 and concluded that, at the 150 mg dose, Q was unlikely to cause any adverse side effects except in patients who are allergic to the drug. (DTX-60 at AVAN-0207765, 207768; Tr. at 164-66)

92. Dr. Smith subsequently ran a test in ALS patients which showed that DM/Q did not have any effect on ALS, but appeared to ameliorate symptoms of PBA in certain ALS patients. (DTX-10 at 2:25-27, 3:47-52; Tr. at 513-14)

93. Dr. Smith then ran a double-blind, placebo-controlled, crossover clinical trial in twelve patients, using a dose of 60 mg/ day DM and 150 mg/day Q to treat PBA. On average, patients showed improvement in conditions; Smith did not identify safety concerns or a lack of efficacy. The patients had DM blood plasma levels of 100-200 ng/mL. (DTX-11; PTX-100; Tr. at 476, 519, 607, 869, 871) These results were reported in the Smith Abstract. (PTX-100)

94. Through a series of PK studies in healthy volunteers, Avanir determined that doses of Q below 150 mg/day could also maximally inhibit DM’s metabolism by CYP2D6, and that the lowest dose that provided maximal inhibition was approximately 60 mg/day. (PTX-165 at AVAN-0214985; Tr. at 172-73,176)

95. In 2001, Avanir conducted its first efficacy study, known as Study 102, with a 60/60 mg/day dosage of DM/Q in 140 ALS patients with PBA. (PTX-196A; PTX-322; Tr. at 180)

96. Study 102 concluded that the 60/60 dosage of DM/Q was efficacious in treating PBA, with a “p-value” of less than 0.001, meaning that 'the probability that the results of the study were due to chance was less than 1 in 1000. (PTX-1 at 53:48-59; PTX-196A; PTX-322; Tr. at 100-01, 183-84)

97. At the time Study 102 was conducted using the 60/60 mg/day dosage of DM/Q, persons of skill in the art did not expect that doses of Q below the maximal inhibition level could be effective in a DM/Q product for the treatment of PBA. (Tr. at 195) Nothing in the prior art taught nor suggested using less than maximally-inhibiting doses of Q with DM to treat PBA. (PTX-3 at 4:30-32; Tr. at 579-80, 864-65, 871, 877-78, 882-83, 885-86,1045^7)

98. On July 17, 2002, shortly after receiving the Study 102 results, the inventors filed the priority application for the ’282 and ’484 patents. (PTX-1; PTX-2; Tr. at 184)

99. In December 2002, Avanir began a second efficacy study, known as Study 106, with the same 60/60 dose, this time in 150 MS patients with PBA. (PTX-199A) The study concluded the 60/60 mg/day dosage of DM/Q was safe and effective. (M; PTX-323; Tr. at 104,188-89)

100. In 2006, the FDA sent Avanir a letter informing Avanir that it had not approved the 60/60 dosage. (DTX-86; Tr. at 195) The FDA’s concerns were based on newly-issued (in 2005) FDA guidance on cardiac QT prolongation and on a 2005 QT study conducted by Avanir. (Tr. at 195-96)

101. In response to the 2006 FDA letter, Avanir conducted a third .efficacy study in PBA patients, between 2007 and 2009, known as Study 123, using DM/Q doses of 60/20 and 40/20. (PTX-104; PTX-213A, PTX-213B; Tr. at 196-97)

102. Study 123 surprisingly showed that both of the lower doses provided efficacy that was comparable to that of Study 102 and 106, and that both doses provided better safety than the 60/60 dosage. (PTX-285A at AVAN-0206633; Tr. at 197-99)

103. Based on Study 123, the FDA approved Nuedexta® at the 40/20 dose of DM/Q. (Tr. at 199)

104. Prior to July 2002, persons of skill in the art would have considered 60 mg/ day of DM combined with 150 mg/day of Q to be safe and effective in treating PBA. (DTX-6 at 12:8-24; DTX-11; PTX-100; Tr. at 368, 476-77, 515-16, 519, 579-80, 587, 871, 877, 879, 883-84)

105. Outside the context of PBA, there were many reported instances in the prior art of the safe administration of DM and 150 mg Q in human subjects. {See, e.g., DTX-6 at 12:6-56;' DTX-13; DTX-20; DTX-26; PTX-100; DTX-60 at AVAN-0207768 (“[T]he absence of any serious problems at this low quinidine dose [150 mg/day] led to its adoption for the subsequent studies.”); Tr. at 883-84)

106. The only known side effects in the prior art certain to be related to Q were associated with the higher doses of Q (600-1600 mg/day) used to treat cardiac ar-rhythmias. (Tr. at 431-32, 435-36, 618-19, 879-80)

107. Before July 17, 2002, a person of skill in the art would not have had safety concerns at doses of 150 mg/day of Q, which were much lower than the already-approved antiarrhythmic doses of Q. (PTX-3 at 4:30-32; Tr. at 97, 423-27, 476-77, 515-16, 580, 596-97, 877, 879-80, 1047)

108. DTX-152 is a letter the FDA sent to Avanir in 2001. The 2001 FDA letter stated “quinidine may alter the QTc [corrected QT] interval at the dose administered.” (DTX-152 at Point 3) To the extent it cautioned about the potential effect of Q on the QTc interval, the FDA letter relied on what Avanir had already explained to the FDA about Q at the much higher antiarrhythmic level doses (600-1600 mg/day) only. (PTX-194 at AVAN-0025277; see also PTX-195A at AVAN-0025395; Tr. at 244-46)

109. DTX-123 is a National Institutes of Health application (hereinafter, “NIH application”) filed by Dr. Yakatan on behalf of IriSys in 1996 regarding the proposed clinical trials to test the discovery that DM and Q could be used to treat PBA. (DTX 123 at CNS-0000131;Tr. at 127-28)

110. The NIH application noted that DM and Q posed some risk of adverse events or drug-to-drug interactions (“DDIs”); however, the application provided no reason to go below a maximally inhibiting dose. The application suggested using clinical trials to identify the lowest sub-therapeutic dose of Q that still accomplished maximal inhibition so that “the safety of the combination product would be maximized without compromising the therapeutic benefits of DM.” (DTX-123 at CNS-0000133)

111. DTX-10 is U.S. Patent No. 5,366,-980 (hereinafter, “the ’980 patent”). The ’980 patent issued on November 22, 1994. The ’980 patent is entitled, “Use of dextromethorphan and an oxidase inhibitor to treat dermatitis” and discloses the combination of DM and Q to treat severe itching and pain associated with dermatitis, not to treat PBA. (DTX-10 at 7:5-18)

112. Dr. Smith reported in the ’980 patent that, at the 150 mg/day Q dose, “the large majority of ALS patients (and all control subjects who were not afflicted with ALS) reported no adverse side effects.” (Id. at 10:2-4)

113. The side effects reported in the ’980 patent resulted in the discontinuation of medications, not a lowering of the dose of Q to the claimed dosage range. (M at 9:44-62)

114. As of July 2002, the prior art did not report any clinically meaningful adverse events at maximally-inhibiting doses of Q (50-150 mg/day). (See, e.g., DTX-4; DTX-8; DTX-21; PTX-100; Tr. at 879-82)

b. Industry practice

115. The typical drug development process for new chemical entities starts with low doses and titrates up, beginning “experimentally in animal models” before “going into human subjects,” i.e., pharmacoki-netic studies in healthy volunteers. (Tr. at 348-49, 400, 865-66) This is not the typical process for testing chemical entities already known to be safe and effective for treating humans. (Id. at 866, 888-84)

116. A person of ordinary skill would have wanted to balance the risk-benefit ratio when determining what dose of Q to use in combination with DM for the treatment of PBA. (Id. at 174 (Pope testifying it is “typical to optimize the risk/benefit ratio”); see also id. at 136-37, 573-74)

117. In the context of developing a DM/Q product that had already been shown to be safe and effective at a dose of 60/150 m^day DM/Q, optimization of the risk/benefit ratio would not have led one of ordinary skill to use less than a maximally inhibiting dose of Q. (Id. at 90, 95-99, 573-74, 863-65, 877-78, 882-84, 895)

3. Reasonable expectation of success

118. A person of ordinary skill in the art in 2002 would not have expected the 60/20 and 40/20 doses of DM/Q to be effective in treating PBA because the 20 mg/ day dose of Q would not maximally inhibit the metabolism of DM. (Id. at 195, 198-99, 864-65, 877-78, 882-83)

119. CNS drug development is challenging and inherently unpredictable, especially in relation to the treatment of PBA, as the mechanism by which PBA is treated remains unknown. (Id. at 593-94, 857-61)

120. The etiology of many CNS diseases, including PBA, are not known and, therefore, the development of a treatment cannot be driven by an understanding of the disease mechanism. Instead, studies must be conducted. (PTX-105 at AVAN-0207649; Tr. at 857)

121. CNS response measures are often subjective and variable, and placebo response can be very large for CNS diseases — making it impossible to draw firm conclusions from information about one patient or even a small number of patients. (Tr. at 857-58)

122. Development of a drug containing DM and Q is particularly unpredictable because of the complex kinetics of DM and Q, resulting in an inability to predict clinical efficacy of new dosage combinations based on PK data. (Id. at 858-59, 862)

L. Facts Relating to Validity of the ’115 Patent

123. Because the asserted claims of the ’115 patent include the “therapeutically effective” limitation, the parties’ positions make it unnecessary for the Court to make additional findings of fact regarding the validity of the 115 patent.

M. Facts Relating to Secondary Considerations of Nonobviousness

1. Unexpected results

124. Before July 17, 2002, the only doses of DM and Q used for treating PBA were standard antitussive (cough suppressant) doses of DM together with maximally-inhibiting doses of Q. (DTX-6; DTX-11; PTX-100; Tr. at 160, 519, 869, 871, 926) The maximally inhibiting dose of Q used with DM to treat PBA was 150- mg/ day Q; nothing in the prior art taught or suggested using less than maximally-inhibiting doses of Q with DM to treat PBA. (PTX-3 at 4:30-32; Tr. at 160, 579-80, 864-65, 871, 877-78, 882-83, 885-86, 1045-47)

125. As of July 17, 2002, a person of ordinary skill in the art would have expected that DM blood levels greater than 100 ng/mL were necessary to effectively treat neurological disorders such as PBA. (PTX-100; PTX-138; DTX-13 at 4:29-37; Tr. at 478-79, 577-79, 607, 870-71, 885-86)

126. In Study 123, conducted between 2007 and 2009, the average DM blood plasma level for the 20/10 DM/Q treatment group (n=107) was 47.76 ng/mL. (PTX-213A; PTX-213B; PTX-104; Tr. at 196-98)

127. In terms of efficacy, as of July 17, 2002, it would have been surprising to a person of ordinary skill in the art that the claimed lower-dose DM/Q combination, 20 mg DM/10 mg Q, which provides DM plasma levels of around 50 ng/mL, exhibited therapeutic efficacy comparable to that of DM/Q combinations providing DM blood levels above 100 ng/mL. (DTX-13 at 4:29-37; PTX-100; Tr. at 161-64, 172, 174-75, 197-99, 478-79, 577-78, 607, 870-71, 885-86)

128. As of July 17, 2002, a person of ordinary skill in the art would have expected that using a partially inhibiting dose of 10-30 mg/day of Q with DM would result in decreased DM plasma levels compared to maximal inhibition. A person of ordinary skill would expect substantially decreased therapeutic efficacy and increased variability, due to the corresponding increased metabolism of DM. (Tr. at 864-65, 877-78, 882-83, 885-86)

129. In terms of safety, a person of ordinary skill in the art as of July 17, 2002 would have expected the claimed partially-inhibiting doses of Q to increase the potential for unacceptable side effects compared to maximally-inhibiting doses of Q because a reduction in the dose of Q would reduce the inhibition of DM’s metabolism into DX, thereby increasing unwanted DX plasma levels. (Id. at 882-83, 885-86, 935-36, 1045-47)

130. As of July 17, 2002, it was well known that DX caused side effects, such as depression, and had a potential for abuse. (Id. at 883,1045-46)

2. Long-felt need and failure of others

131. Before July 2002, numerous published sources in the peer-reviewed medical literature reported successes in treating PBA with tricyclic antidepressants (“TCAs”), selective serotonin reuptake inhibitors (“SSRIs”), and other medications (e.g., levodopa, reboxetine, venlafaxine, mirtazapine, lamotrigine, methylphenidate, dexamfetamine, and amantadine). (DTX-50; DTX-53; DTX-185; DTX-191; DTX-192; DTX-194; DTX-195; PTX-1; PTX-2; Tr. at 729-44,1177-79)

132. As early as 1985, amitriptyline was shown, through a double-blind, placebo-controlled, crossover study reported in The New England Journal of Medicine, to treat PBA within days with only mild side effects. (DTX 194; Tr. at 731-33)

133. However, off-label use of drugs such as dopaminergic drugs (e.g., levodo-pa), TCAs, and SSRIs, among others, were not always considered effective treatments for PBA as of July 2002. (DTX-49; DTX-129; DTX-185; DTX-191; DTX-192; DTX-193; DTX-194; Tr. at 269,287-88,-293-301)

134. There was no long-felt need or failure of others to develop a safe and effective treatment for PBA. (Tr. at 743-44, 746)

3. Commercial success

135. Avanir has marketed and sold Nuedexta® since February 2011. (PTX-150)

136. Nuedexta® had net sales of $93.6 million from its launch in February 2011 through June 2013 and its net sales have increased in every quarter, including 265% growth from year one to year two. (PTX-305; Tr. at 672, 796-97)

137. Nuedexta®’s prescription totals were over 240,000 through early August 2013 and Nuedexta® has exhibited prescription growth every quarter since launch, including 257% from year one to year two. (PTX-326; Tr. at 778-79)

138. Nuedexta®’s profits were over $88 million through June 2013, with a consistent 94% gross profit margin, and Nue-dexta®’s revenues have been growing faster than its expenses. (PTX-305; Tr. at 673-77)

139. [Redacted]

140. Five pharmaceutical companies have filed ANDAs seeking to market generic versions of Nuedexta®. (PTX-81; PTX-168; Tr. at 787-88,1037-39)

141. Each of the asserted claims of the ’282 and ’484 patents covers the use of Nuedexta® according to its package insert to treat PBA. (PTX-1; PTX-2; PTX-105; Tr. at 271-85, 788)

142. There exists a nexus between Nuedexta®’s commercial success and the claimed inventions. (Tr. at 788-94)

143. Nuedexta® is promoted only as a treatment for PBA, and the record suggests that Nuedexta® is primarily used to treat PBA. (PTX-150; PTX-167; Tr. at 787, 789, 791-92)

II. INFRINGEMENT

A. Legal Standards

A patent is infringed when a person “without authority makes, uses, offers to sell, or sells any patented invention, within the United States ... during the term of the patent.” 35 U.S.C. § 271(a). Courts employ a two-step analysis in making an infringement determination. See Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed.Cir.1995). First, a court must construe the asserted claims. See id. Next, the trier of fact must compare the properly construed claims with the accused infringing product. See id. If an accused product does not infringe an independent claim, it also does not infringe any claim depending from that independent claim. See Wahpeton Canvas Co. v. Frontier, Inc., 870 F.2d 1546, 1553 (Fed.Cir.1989). However, “[o]ne may infringe an independent claim and not infringe a claim dependent on that claim.” Id. at 1552 n. 9.

In order to establish literal infringement, “every limitation set forth in a claim must be found in an accused product, exactly.” Southwall Techs., Inc. v. Cardinal IG Co., 54 F.3d 1570, 1575 (Fed.Cir.1995). The patent owner has the burden of proving infringement by a preponderance of the evidence. See SmithKline Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878, 889 (Fed.Cir.1988).

B. Infringement of the ’282 and ’484 Patents

Plaintiffs assert that Defendants’ proposed generic products and/or manufacturing processes infringe claims 1-9 of the ’282 patent and claims 1-9, 12, 13, 15, and 17 of the ’484 patent. Both Impax and Par have stipulated that their proposed ANDA products literally infringe each asserted claim of the ’282 and ’484 patents. (D.I.238, 411)

Therefore, the Court concludes that Defendants infringe claims 1-9 of the ’282 patent and claims 1-9, 12, 13, 15, and 17 of the ’484 patent.

C. Infringement of the ’115 Patent 1. Defendants’ ANDA products do not meet the “therapeutically effective” limitation

Plaintiffs assert that Defendants’ ANDA products infringe claims 18-21 of the ’115 patent because they are identical to Nuedexta®. At trial, the parties’ dispute focused on whether Nuedexta® contains a combined unit dosage of DM and Q that is “therapeutically effective in substantially reducing chronic or intractable pain, without unacceptable side- effects.” Plaintiffs contend the daily dose of DM/Q' in Nuedexta® meets the “therapeutically effective” limitation because the drug is capable of treating chronic pain without unacceptable side effects. Defendants assert that Nuedexta® fails to meet the disputed limitation because (i) there is no evidence Nuedexta® is therapeutically effective in substantially reducing chronic or intractable pain, and (ii) there is no evidence Nuedexta® can do so without “unacceptable side effects.” The Court agrees with Defendants.

a. “Therapeutically effective in substantially reducing chronic or intractable pain”

Claim 18 of the T15 patent requires a unit dosage formulation of either DM or a pharmaceutically acceptable salt thereof and a debrisoquin hydroxylase inhibitor, such as Q, in a combined dosage that renders the DM “therapeutically effective in substantially reducing chronic or intractable pain, without causing unacceptable side effects.” During claim construction, the Court held that this “therapeutically effective” limitation is given its plain and ordinary meaning. (D.I. 257 at ¶ 5) Plain and ordinary meaning is the meaning a term would have to a person of ordinary skill in the art at the time of the invention. See Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed.Cir.2005). A person of ordinary skill at the time of the effective filing date of the claimed invention would have had at least an M.D. degree as well as knowledge of or 5 years experience in treating pain or patients with neurological conditions including pain. The Court also 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 posther-petic neuralgia (PHN) resulting from herpes zoster infection, and diabetic neu-ropathy resulting from long-time diabetes. The conditions are not an exclusive list.” (D.I. 257 at ¶ 3) Finally, the Court construed “intractable pain” to mean “pain which failed to respond adequately to conventional treatments.” (Id. at ¶ 4)

It is undisputed that Nuedexta® has been approved by the FDA only to treat PBA. (DTX-40; JFF at ¶ 45) Plaintiffs’ expert, Dr. Wynn, explained that Nuedex-ta®’s package insert provides no statement that Nuedexta® can treat pain — let alone that it is “therapeutically effective” in treating long-term pain from other conditions, neuropathic pain from nerve tissue deterioration, or pain not responding to conventional treatments. (Tr. at 1172; see also id. (Wynn testifying: “There is nothing about pain in the labels in Par or Impax’s package insert.”)) It is also undisputed that there are no peer-reviewed publications, no presentations at major annual conferences, and no pain treatment textbooks that discuss the 20/10 mg/day dosage of DM/Q for the treatment of chronic pain. {Id. at 685-87)

To support its position that Nuedexta® is therapeutically effective for these forms of pain, Plaintiffs primarily rely on a recently completed clinical study by Avanir testing the dosage used in Nuedexta®, prior clinical trials testing doses of DM and Q higher than those used in Nuedex-ta®, and testimony from Dr. Wynn regarding those studies and his own observations. Avanir’s evidence is unpersuasive.

Plaintiffs’ cited clinical studies do not establish that Nuedexta® is “therapeutically effective” in substantially reducing chronic pain. During the pendency of this action, the 20/10 mg/day DM/Q formulation was being tested in a Phase II double-blind, randomized, placebo-controlled study, called the PRIME Study, to evaluate the safety and efficacy of the drug in the treatment of central neuropathic pain in patients with MS. {Id. at 192-93, 1088, 1091) The final study report itself has not been offered into evidence. Plaintiffs, however, rely on a recent Avanir press release reporting the results, which stated that “the treatment of central neuropathic pain in patients with multiple sclerosis did not meet the primary efficacy endpoint.” (D.I. 458 Ex. A) The press release further stated that while some pain reduction from baseline levels was observed, “there was no difference between the treatment arms [ (one of which used 20/10 mg/day DM/Q) ] and placebo.” {Id.) The record does not show what the baseline is, nor the margin the patients’ pain scores were reduced from that baseline. ■ Most significantly, whatever that reduction, there was no difference between Nuedexta® and placebo. A person of ordinary skill in the art would require some difference between Nuedex-ta® and placebo to conclude that the 20/10 mg/day dose renders the DM “therapeutically effective” in substantially reducing chronic or intractable pain, as required by Claim 18.

The remaining earlier publications and clinical studies on which Plaintiffs rely are also unavailing. Dr. Wynn admitted that Studies 106 and 107 concerned dosages of DM and Q at higher levels than Nuedexta®. (Tr. at 1141-42; PTX-199A (Study 106 testing 30/30 mg/day of DM/ Q)) Beyond the fact that those studies did not use the Nuedexta® dose (20/10 mg/day of DM/Q), Defendants’ expert Dr. Deer testified that a publication discussing the results of Study 106 showed efficacy was actually dropping at the dose closest to Nuedexta®. (Tr. at 711) (“[P]atients didn’t do as well on 30/30 as they did on 45/30. Therefore, there appeared to be a linear regression downward as you ■ lowered the dose.”) Study 123, the STAR Study, did use the same 20/10 mg/day dose of DM/Q as in Nuedexta® but examined only the drug’s efficacy in treating PBA, not its efficacy in treating pain — as Dr. Wynn admitted. (Id. at 1143) (“The trial was not designed to look at pain.”) Dr. Wynn also admitted that the STAR Study concluded the 20/10 mg/day DM/Q dose did not have a statistically significant p-value versus the placebo when pain treatment was measured as a secondary endpoint. (Id. at 1146)

Plaintiffs also elicited testimony from Dr. Wynn recounting his own clinical experience using Nuedexta®, testimony he based on patient interviews, which he opined are reliable as “the most important aspect of treating pain” from the perspective of a clinical physician. (Id. at 1165) (“[W]e don’t have a so-called pain-o-meter where I can stick an individual’s] finger in and find out if they have pain.”)

In the circumstances presented here, these patient interviews, which are undocumented and lack objective measures of efficacy, provide little evidence that Nue-dexta® is therapeutically effective in substantially reducing chronic or intractable pain. Dr. Wynn’s observations did not establish that administering Nuedexta® to a patient was the cause of any observed reduction in pain, especially given that Dr. Wynn did not record the patient’s medical history or other medications being taken, which is of particular concern since Dr. Wynn admitted it “wouldn’t be uncommon” for patients being treated with Nuedexta® in his practice also to be taking other pain medications. (Id. at 1157) Relatedly, Dr. Wynn provided no explanation as to how the patient interviews controlled for placebo effect. (See id. at 1168-69) Dr. Wynn’s observations also lacked any measurement of patient parameters, pre- and post-treatment pain scores, and statistical analysis, all of which are important factors for determining efficacy. (See id. at 695) Dr. Deer persuasively testified that “the definition of being therapeutically effective means we can measure improvement by pain score reduction on a scale that’s been validated and proven functional.” (Id. at 684) Thus, the Court concludes that, to a person of ordinary skill in the treatment of chronic or intractable pain, Dr. Wynn’s patient interviews, and his testimony about them, fail to provide reliable indicia that Nuedexta® is therapeutically effective in treating such pain.

Dr. Wynn’s remaining testimony concerned other neurologists in his practice, as well as physicians he knows around the country, many of whom “have also noted marked improvement with the treatment of chronic or intractable pain with Nuedex-ta[®].” (Id. at 1107) However, Dr. Wynn displayed little to no familiarity with the experiences of these other physicians; the only physician Dr. Wynn identified by name was Dr. Licht, an Avanir employee to whom he had never spoken nor ever met. (Id. at 1169) Dr. Wynn admitted he did not know whether Dr. Licht was prescribing Nuedexta® to patients with just PBA or patients with PBA and pain, what type of pain (if any) Dr. Licht’s patients were experiencing, the patients’ pain scores, and whether or not these patients were taking other pain medications simultaneously. (Id. at 1170) Therefore, the Court finds that Dr. Wynn’s testimony regarding other physicians’ experience provides little evidence that Nuedexta® is “therapeutically effective” in treating chronic or intractable pain.

b. “Without causing unacceptable side effects”

To satisfy the claim limitation, therapeutic efficacy must be achieved “without unacceptable side effects.” Dr. Wynn opined that “unacceptable side effects” are determined by each clinician, based on his or her experience treating patients with pain disorders, and are present when it appears the patient is “unable to continue taking medication and the patient stopped the medication” because he or she exhibited a “sign or symptom” of a possible side effect. (Id. at 1106, 1167-68) Dr. Wynn admitted to taking patients off of Nuedexta® due to such adverse reactions. (Id. at 1168) (“I have had some patients discontinue medication [i.e., Nuedexta® because of side effects.”) The record does not establish whether Dr. Wynn’s colleagues using Nue-dexta® to treat pain have also found it necessary to take patients off of it.

Furthermore, the studies upon which Avanir relies offer little evidence that Nue-dexta® Can treat chronic pain without unacceptable side effects because those studies, with the exception of the PRIME Study, do not examine Nuedexta® in a chronic pain population. Dr. Deer, who has been a pain specialist for over 20 years and annually sees approximately 1,000 patients who suffer from chronic or intractable pain, appropriately described “unacceptable side effects” as those side effects that “‘cause[ ] limitations in [a patient’s] daily function or ... cause [the patient] to have other comorbidities or other disease states.” (Id. at 676-79, 691) For several reasons, Dr. Deer explained, chronic pain patients are especially at risk for experiencing unacceptable side effects from a new drug. First, unlike healthy patients, patients afflicted with chronic pain often suffer from other conditions or comorbidities simultaneously, such as immobili