STARK, U.S. 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").
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.
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.
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)
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:
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
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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)
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:
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)
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
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)
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-insuit 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)
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,
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)
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)
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)
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 ¶ 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 Nuedex® 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)
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 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 DM/Q 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. Nuedexta® 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
61. In his experience, Dr. Wynn has seen patients discontinue Nuedexta® due to side effects. (Tr. at 1168)
62. Neither DM nor Q was a new chemical entity in July 2002. (Id. at 442, 883-84)
63. DM is rapidly metabolized by a liver enzyme known as cytochrome P450-2D6 enzyme (or "CYP2D6") into dextrorphan ("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 metabolizer" ("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)
66. U.S. Patent No. 5,206,248 (hereinafter, "the '248 patent") 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 C
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)
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)
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)
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)
76. DTX-21 is a paper by Nielsen, M, et 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 Dextromethorphan," published in the Journal of Pharmacology and Experimental Therapeutics in 1999 (hereinafter, "the Desmeules 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)
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
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 "Dextromethorphan 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)
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
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)
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, 1045-47)
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. (Id.; 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)
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 arrhythmias. (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. (Id. at 9:44-62)
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., pharmacokinetic 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, 883-84)
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 mg/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)
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)
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.
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
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)
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., levodopa), 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)
135. Avanir has marketed and sold Nuedexta® since February 2011. (PTX-150)
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 Nuedexta®'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)
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).
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.
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.
Claim 18 of the '115 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."
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 Nuedexta®'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
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 Nuedexta®, 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 remaining earlier publications and clinical studies on which Plaintiffs rely are also unavailing. Dr. Wynn
Plaintiffs also elicited testimony from Dr. Wynn
In the circumstances presented here, these patient interviews, which are undocumented and lack objective measures of efficacy, provide little evidence that Nuedexta® 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)
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 Nuedexta[®]."
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 Nuedexta® 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 Nuedexta® 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 immobility, which lead to obesity, trouble with blood sugars, and hypertension. (Id. at 692) Second, in order to address these other disease states, chronic pain patients take other drugs, which means they are particularly at risk for adverse interactions among medications. (Id. at 691-92) For example, other medications could lead to cardiac arrhythmia disturbances when combined with Nuedexta®. (Id.) Therefore, studies measuring the response to Nuedexta® among normal subjects experiencing pain—such as the bulk of the studies identified by Plaintiffs—are only minimally relevant to whether Nuedexta® can effectively treat patients with chronic or intractable pain without causing unacceptable side effects.
For the reasons explained, the Court concludes that Avanir has failed to prove by a preponderance of the evidence that Nuedexta® satisfies the "therapeutically effective" limitation of independent Claim 18 of the '115 patent. Consequently, Avanir
Defendants contend that both the '282 and '484 patents are invalid due to obviousness and lack of written description. Defendants also assert that if the Court finds the asserted claims of the '115 patent do not contain the "therapeutically effective" limitation, then the '115 patent is invalid as obvious. The Court addresses each asserted basis for invalidity below.
An issued patent is presumed to be valid. See 35 U.S.C. § 282. Therefore, to invalidate a patent, a party must carry its burden of proof by "clear and convincing evidence." See Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed.Cir.2009) (obviousness); Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1354 (Fed.Cir.2010) (written description). Clear and convincing evidence is evidence that "proves in the mind of the trier of fact an abiding conviction that the truth of [the] factual contentions [is] highly probable." Intel Corp. v. ITC, 946 F.2d 821, 830 (Fed.Cir.1991) (internal quotation marks omitted).
A patent may not issue "if' the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains." 35 U.S.C. § 103(a). Obviousness is a question of law based on underlying factual findings concerning: (1) the scope and content of the prior art; (2) the differences between the claims and the prior art; (3) the level of ordinary skill in the art; and (4) objective considerations of nonobviousness. See Graham v. John, Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966).
To prove that a patent is obvious, a party must demonstrate "that a skilled artisan would have had reason to combine the teaching of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success from doing so." In re Cyclobenzaprine, 676 F.3d 1063, 1069 (Fed.Cir.2012), cert. denied, ___ U.S. ___, 133 S.Ct. 933, 184 L.Ed.2d 725 (2013) (citing Procter & Gamble, 566 F.3d at 994); see also Amgen, Inc. v. F. Hoffman-LA Roche Ltd., 580 F.3d 1340, 1362 (Fed.Cir.2009) ("An obviousness determination requires that a skilled artisan would have perceived a reasonable expectation of success in making the invention in light of the prior art."). While an analysis of any teaching, suggestion, or motivation to combine known elements is useful to an obviousness analysis, the overall obviousness inquiry must be expansive and flexible. See KSR Int'l Co. v. Teleflex, Inc., 550 U.S. 398, 415, 419, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). In addition, the use of hindsight is not permitted when determining whether a claim would have been obvious to one of ordinary skill in the art. See id. at 421, 127 S.Ct. 1727 (cautioning
"[D]ependent claims are nonobvious if the independent claims from which they depend are nonobvious." In re Fritch, 972 F.2d 1260, 1266 (Fed.Cir.1992); see also Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1365 (Fed.Cir.2008).
The written description requirement is set forth in 35 U.S.C. § 112, ¶ 1. A patent's written description must "clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed." Ariad, 598 F.3d at 1351. Accordingly, "the test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Id.
Defendants contend that the asserted claims of the '282 and '484 patents are invalid as obvious over the prior art because: (1) it would have been obvious to a person of ordinary skill to lower the dose of Q to the claimed ranges, (2) there was motivation to do so because of safety concerns and industry practice, and (3) there would have been a reasonable expectation of success that low doses of Q combined with DM would be effective in treating PBA. Avanir responds that the evidence shows: (1) the prior art did not teach the claimed sub-maximally inhibiting dose of Q in combination with DM to treat PBA, (2) Defendants' "motivation" and "obvious to try" theories are improperly based entirely on hindsight using the '282 and '484 patents as a blueprint, and (3) a person having ordinary skill in the art would not have reasonably expected doses of Q below maximal inhibition could be combined with DM to safely and effectively treat PBA. Avanir also argues that secondary considerations of nonobviousness support a finding of validity. (See D.I. 432, 449)
For the reasons explained below, the Court agrees with Avanir that Defendants have failed to establish, by clear and convincing evidence, that the claimed inventions would have been obvious to a person of ordinary skill at the time the '282 and '484 patents were filed.
According to Defendants, "[t]he only difference between the prior art and the asserted claims of the '282 and '484 patents is the dose ranges of Q." (D.I. 429 at 5; D.I. 444 at 10 n.11; D.I. 450 at 15) Plaintiffs respond that focusing on Q alone "improperly urges the Court to ignore the subject matter of the claims as a whole, including the claimed amounts of DM and the claimed weight to weight ratios of DM to Q." (D.I. 449 at 13 n.12)
The Court finds that the differences between the asserted claims and the prior art are the lower doses of Q, at the 10-30 mg/day range,
Defendants advance several theories as to why the prior art teachings allegedly made it obvious to lower the dose of Q from the 150 mg/day used with DM in the prior art to the claimed range of 10-30 mg/day of Q to treat PBA. Specifically, Defendants contend that the asserted claims of the '282 and '484 patents are obvious over the following prior art references: (1) the '248 patent; (2) the Yakatan Abstract, Yakatan Poster, and other PK studies; (3) the '053 application; and (4) the '927 patent. The Court addresses this prior art below.
It is undisputed that the '248 patent does not disclose a 10-30 mg/day Q dose and does not suggest employing a Q dose lower than the maximally inhibiting 150 mg/day dose. However, Defendants contend that "a skilled artisan would have been motivated to achieve the effective 43-55 ng/mL DM blood levels from Example 2 of the '248 patent with as low a dose of Q as possible, utilizing the Q dose/DM blood level correlations from the Yakatan Poster or Abstract," rendering the claimed dose ranges obvious. (D.I. 429 at 14)
Example 2 teaches that for a single patient, PBA symptoms faded away when he was given 60 mg/day of DM and a
Even if a person of ordinary skill were to focus on blood concentrations, Defendants failed to prove that reliable efficacy conclusions could be drawn from the limited information disclosed in Example 2. Defendants also failed to prove that one of ordinary skill would select the 43-55 ng/mL blood concentration disclosed in a single patient over more reliable disclosures in the prior art as of July 2002, including Example 3 in the same patent and the results reported in the Smith Abstract. Example 3 of the '248 patent disclosed the safe and effective treatment of a patient's PBA at DM blood levels of 130-180 ng/mL, using a 90/150 mg/day combination of DM/Q. (DTX-6 at 11:39-43, 12:33-50) As Dr. Sellers testified, a person of ordinary skill would have considered the data reported in Example 3 to be more reliable than the data set forth in Example 2 because the patient in Example 3 was stopped and started on DM/Q several times, establishing causality (id. at 12:26-48; Tr. at 869), allowing one to rule out placebo effect, which is very common in CNS drugs (Tr. at 698-99, 858). Similarly, the Smith Abstract disclosed a double-blind, placebo-controlled, crossover trial reporting that 12 patients' PBA episodes were safely and effectively treated using 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)
By contrast, Example 2, which involved only a single patient, is insufficiently reliable. Example 2 contains no report on how many blood samples were drawn, whether the patient had reached a steady state of DM, and whether his blood concentrations were measured at C
When the prior art evidence discussed at trial is viewed as a whole, Example 3, the Smith Abstract, the Yakatan Abstract, and the Zhang reference disclosed a total of 29 individuals treated for PBA, all of whom had blood concentrations of between 100 and 200 ng/mL, in contrast to the one patient reported in Example 2. (PTX-100; DTX-6 at 12:26-48; DTX-60 ("Zhang reference") at AVAN-0207767 (Fig. 3 reporting DM concentrations for "patients receiving 150 mg quinidine per day"); DTX-499 at Abstract 61; Tr. at 624-25, 868-70) The Court is unpersuaded that a person of ordinary skill, lacking the guidance provided by the patents-in-suit, would have taken Example 2, discarded the 150 mg/day dose of Q it used, focused instead on the DM blood concentration in isolation and despite the weight of the prior art, and then looked to the PK data from the Yakatan Abstract/Poster to recalculate the dose of Q to reach the claimed invention.
Finally, the PK data Defendants rely on provides no teaching on effective treatment of PBA. The Yakatan references, along with the Boobis, Desmeules, and Nielsen references, all teach PK data alone. (DTX-135; DTX-4; DTX-8; DTX-21) The cited PK data only show that low doses of Q could cause partial inhibition of CYP2D6; not one of these PK
Defendants next contend that the claimed invention would have been obvious to a person of ordinary skill in the art in July 2002 in light of the '053 application, which teaches the claimed dose range of DM, and suggests that dosages below 150 mg/day of Q would be effective in treating PBA. Defendants once more conflate the difference between PK data and dose-efficacy results for treating PBA. Both sides' experts agreed the disclosed DM dose ranges (20-400 mg/day) in the '053 application were not directed to the treatment of PBA. (DTX-32 at AVAN-0403512-13, AVAN-0403517-18; Tr. at 517-18, 872)
Additionally, the disclosed range of Q in the '053 application falls outside the claimed range. Only 150 mg/day of Q—or a speculated low-end Q dose "such as 50 mg/day Q"—is disclosed. (DTX-32 at AVAN-0403512-13) Moreover, regardless of whether the '053 application could be read to disclose even lower doses of Q, these Q ranges do not concern the treatment of PBA. The portion of the '053 application on which Defendants rely states that "dosages of only 150 mg/day are
In sum, a person of ordinary skill would not have found it obvious to arrive at the claimed invention based on the PK data disclosed in the '053 application.
Defendants contend that the claims are obvious over the '927 patent because the claimed doses are merely a modification of the '927 patent's 20-200 mg/day dose of DM and 300 mg/day or less dose of Q. As with the '053 application,. Defendants' cited disclosures only concern effectiveness in changing DM blood concentration, not effectiveness in treating PBA. The '927 patent's disclosure of "50 mg/day to 150 mg/day" of Q did not relate to PBA treatment. (DTX-20 at 4:14-17) ("The dosage of quinidine which was found to provide a major
Defendants presented several theories as to why one of ordinary skill in the art would have been motivated to lower the maximally inhibiting doses of Q taught by the prior art to the sub-maximally inhibiting 10-30 mg/day claimed doses, and then combine that lower amount of Q with certain doses of DM, all for the treatment of PBA. Defendants' arguments relate to (i) safety concerns and (ii) industry practice.
Defendants contend that Q was known to have harmful side effects, such as cardiotoxicity associated with an excessive prolongation of the QTc interval, as well as dizziness and other conditions. Defendants additionally argue that drug-to-drug interactions ("DDIs") and DM accumulation would have served as independent bases motivating a person of ordinary skill
At the time of the invention, maximal inhibition of the CYP2D6 enzyme was known to occur at a 50-150 mg/day dose of Q; and a 150 mg/day dose of Q was specifically known to effectively treat PBA when combined with a 60 mg/day dose of DM. (DTX-8; DTX-6) Plaintiffs introduced substantial evidence that, prior to July 17, 2002, there were few safety concerns associated with the 150 mg/day dose of Q. (PTX-3 at 4:30-32; Tr. at 97, 423-27, 476-77, 515-16, 580, 596-97, 877, 879-80, 1047)
Defendants contend there were safety concerns with Q regarding cardiotoxicity due to prolongation of the QTc interval. However, cardiotoxicity was not present at the 150 mg/day dose level of Q known in the prior art; such concerns related only to the much higher
Defendants' evidence related to side effects of sub-antiarrhythmic doses of Q also does not support a motivation to pursue a sub-maximally inhibiting dose of Q. In relation to "cumulative side effects" observed
As for side effects involving dizziness, disorientation, a "drugged" feeling, and nausea, the evidence overwhelmingly pointed to the fact a person of ordinary skill would have known such side effects are attributable to DM, not to Q. (DTX-60 at AVAN-0207767; PTX-131 at AVAN-0287082; PTX-134 at AVAN-0043732-733; PTX-138 at AVAN-0289350; PTX-145 at AVAN-0291082-083; PTX-158 at AVAN-0296881; DTX-20 at 13:54-55 ('927 patent reduced dose from 75 to 25 mg/day of Q, but "patient reported continued headache side effects even when on a reduced dosage"); Tr. at 372-73, 1205) Accordingly, the motivation would not have been to lower the Q dose, but rather to reduce the DM dose, as Dr. Smith was prompted to do in response to "severe phencyclidine-like reactions" at 60/150 mg/day of DM/Q, which led him to drop the DM dose to 30 mg/day while keeping the Q dose constant. (DTX-60 at AVAN-0207763-764; DTX-10 at 9:55-62) Patients on such adjusted DM dosages did not experience similar side effects. (DTX-60 at AVAN-0207766) The dangers of DM are further evidenced by another confidential study conducted by Dr. Smith involving a high dose of DM (120 mg/day), along with 150 mg/day Q, in which "[s]evere side effects were experienced in 3/17 patients" and "[t]he majority of these side effects were due to reactions to dextromethorphan." (DTX-121 at CNS-0002366) As Defendants' expert, Dr. Poulsen, admitted, "[i]f you were absolutely certain that the side effects relate[ ] to dextromethorphan, it would be very natural to decrease that dose." (Tr. at 621)
Finally, Defendants point to an NIH application in which Drs. Smith and Yakatan discussed the side effects from the combination of DM and Q. However, their response was
Defendants also argue that DDIs would have provided an independent motivation
Based on the evidence as a whole, therefore, the Court finds that the prior art taught away from dropping the dose of Q down to levels that would compromise maximal inhibition of the CYP2D6 enzyme when formulating a combined dosage of DM and Q for treating PBA.
Defendants argue that routine industry practice would have motivated a person of ordinary skill to start at the lowest dose of both DM and Q possible and "titrate up" until efficacy was achieved, thus leading to sub-maximally inhibiting doses of Q. However, Defendants' only expert to opine on the standard course of drug development, Dr. Boobis, admitted the "start low and go slow" approach is directed toward new chemical entities, at the point at which the drug is first being administered to a human after animal testing. (Tr. at 349-50) This was hardly the situation applicable to DM/Q dosing as of July 2002, as DM and Q were not new chemical entities but instead had progressed to a much later stage of development, both individually and in combination, and had long been safely administered to humans.
Thus, the Court concludes that a person of ordinary skill in July 2002 would not have been motivated to go backwards and repeat the drug development process for DM and Q to arrive at sub-maximally inhibiting doses of Q combined with DM to treat PBA. To find otherwise would impermissibly rely on hindsight.
Defendants contend "a person of ordinary skill in the art could determine an effective DM/Q combination based on the empirical data concerning the amount of Q that produced a given DM blood level in a `straightforward' manner," leading to a reasonable expectation of success. (D.I. 444 at 9) (citing Tr. at 594) Plaintiffs respond that there is no evidence a person of ordinary skill would have reasonably expected the cited DM blood concentrations to be achieved by dropping the dose of Q; in turn, even if such DM blood concentrations could be achieved, there is no evidence therapeutic efficacy could be maintained for the treatment of PBA. The Court agrees with Plaintiffs.
As a general matter, CNS drug development is challenging and unpredictable, especially in relation to treatment of PBA, a disease for which the mechanism for treatment remains unknown. (Tr. at 593-94, 857-61) Since the etiology of PBA is not known, the development of a treatment cannot be driven by an understanding of the disease mechanism; rather, as Dr. Sellers testified, actual studies must be conducted. (Id. at 857; PTX-105 at AVAN-0207649)
Defendants contend that effective blood levels for the treatment of PBA were shown in the prior art, and would have led to a reasonable expectation of success. Defendants do not dispute, however, that
Even if it was believed that these DM blood levels could be achieved at sub-maximally inhibiting levels of Q, there is no indication in the record that, prior to July 2002, a person of ordinary skill would have reasonably believed that the 43-55 ng/mL DM blood levels effective in the single patient in Example 2 would prove effective in other patients with PBA. It is undisputed that the relationship between DM blood concentration and therapeutic efficacy in treating PBA in the majority of patients was not known. (PTX-108; Tr. at 479, 578-79) Other than the single patient in Example 2, the evidence Defendants cite concerns
Therefore, the Court finds that a person of ordinary skill in July 2002 would not have had a "reasonable expectation of success" that PBA could be effectively treated by DM combined with Q at a sub-maximally inhibiting dosage.
Repackaging its earlier arguments, Defendants contend: (1) the knowledge that "the co-administration of DM and Q successfully treated PBA with DM blood concentrations of 43-55 ng/mL" in the single patient from Example 2, and (2) "the correlation between Q dose and DM blood levels" from PK data would have made the claimed invention "obvious to try" under KSR. (D.I. 444 at 4)
Under KSR, when there is "a design need" or "market pressure" to solve a problem and "there are a finite number of identified, predictable solutions," a person of ordinary skill has "good reason to pursue the known options" and, if this leads to the anticipated success, "the fact that a combination was obvious to try might show that it was obvious under § 103." 550 U.S. at 421, 127 S.Ct. 1727. Beyond mere conclusory statements in its post-trial briefing, Defendants present no evidence that the "design need" they identify—the need to "use a lower dose of Q because of its powerful ability to inhibit the enzymatic activity of CYP2D6" (D.I. 444 at 4)—was indeed a problem in the prior art, especially given that a maximally inhibiting dose of 150 mg/day of Q combined with DM was known to safely and effectively treat PBA.
Defendants assert that a "finite number of identified, predicable solutions" for solving this problem existed. But Plaintiffs presented evidence that several alternative CYP2D6 inhibitors were available to solve the Q-related problem by avoiding the use of Q altogether, leading to a vast number of possible solutions. (DTX-10 at 10:16-26) ("A number of drugs have been identified as being effective in inhibiting debrisoquin hydroxylase . . . nortriptyline, cblorpromazine, domperidone, haloperidol, pipamperone, labetalol, metaprolol, oxprenolol, propranolol, timolol, mexlletine, quinine,
Defendants also fail to show a reasonable expectation of success for the reasons already articulated above. Therefore, based on the evidence, Defendants have not prevailed on their "obvious to try" theory. See Leo Pharin. Products, Ltd. v. Rea, 726 F.3d 1346, 1356-57 (Fed.Cir.2013) ("The problem was not known, the possible approaches to solving the problem were not known or finite, and the solution was not predictable. Therefore, the claimed invention would not have been obvious to try to one of ordinary skill in the art.").
In evaluating obviousness, courts must consider objective evidence of nonobviousness in the form of secondary considerations, as that "may often be the most probative and cogent evidence in the record" related to obviousness. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538 (Fed.Cir.1983). Here, Plaintiffs point to unexpected results, satisfaction of a long-felt but unmet need, failure of others, and commercial success as objective evidence of nonobviousness. (D.I. 432 at 11-16)
Plaintiffs contend that prior to July 17, 2002, "a person of ordinary skill in the art would not have expected that the claimed uses of low-dose DM/Q could provide comparable efficacy in treating PBA and a better safety profile compared to the use of higher DM/Q." (Id. at 12) While Defendants insist that the issue is really limited to unexpected results from a lower dosage of Q, Defendants do not challenge the evidence that nothing in the prior art taught using less than a maximally inhibiting dose of 150 mg/day Q with DM to treat PBA. (PTX-3 at 4:30-32; Tr. at 579-80, 864-65, 871, 877-78, 880, 882-83, 885-86, 935-36, 1045-47)
Plaintiffs presented evidence that, as of the date of invention, partially-inhibiting doses of Q were expected 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 to DX, consequently increasing unwanted DX plasma levels. (Tr. at 882-83, 885-86, 935-36, 1045-47) It is undisputed that when a dose of DM is introduced to a patient, DM is rapidly metabolized by CYP2D6 into DX; in turn, DX was known to cause side effects, such as depression. (Id. at 883, 1045-46) In contrast, maximally inhibiting doses of Q (such as 150 mg/day) ameliorated DX build-up, yet presented no serious safety concerns, as they were much lower than antiarrhythmic doses of Q, as discussed above.
In addition to unexpected safety benefits, sub-maximally inhibiting doses of Q also presented unexpected efficacy in the treatment of PBA. As Defendants' own cited reference, Example 2 of the '248 patent, makes clear, as of July 2002 the maximally inhibiting dose of Q at 150 mg/day was known to effectively treat PBA when combined with DM. Defendants' experts,
The Court finds a person of ordinary skill would not have expected that significantly decreasing Q could maintain the efficacy profile of a combined DM/Q dosage for treating PBA while improving the safety profile compared to the prior art.
Plaintiffs contend that as of July 2002, "there was a long-felt, but unmet need for a safe and effective treatment for PBA because none of the off-label drugs that had been previously used to treat PBA showed significant efficacy and the offlabel drugs had substantial side-effects." (D.I. 432 at 16) Defendants respond that "the claimed invention did not meet a long-felt but unmet need for a safe and effective PBA treatment because, prior to the '282 and '484 patents, several drugs were considered by the medical community to be safe and effective in treating PBA." (D.I. 444 at 13) The Court agrees with Defendants.
Plaintiffs argue that off-label use of drugs prior to the '282 and '484 patents, such as dopaminergic drugs (e.g., levodopa), tricyclic antidepressants ("TCAs"), and selective serotonin reuptake inhibitors ("SSRIs"), among others, were not considered effective treatments for PBA. (DTX-49; DTX-129; DTX-185; DTX-191; DTX-192; DTX-193; DTX-194; Tr. at 269, 287, 293-301) However, Defendants offered several published sources in the peer-reviewed medical literature that reported successes with TCAs, SSRIs, and medications such as levodopa, reboxetine, venlafaxine, mirtazapine, lamotrigine, methylphenidate, dexamfetamine, and amantadine in treating PBA. (DTX-50; DTX 53; DTX 185; DTX 191; DTX 192; DTX 194; DTX 195; DTX 419; PTX 1; PTX 2; Tr. at 729-44) 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) The available off-label treatments demonstrated noticeable efficacy, though some exhibited side effects.
To the extent there was a long-felt, unmet need for a treatment for PBA with fewer such side effects, Plaintiffs have failed to prove how the claimed inventions satisfy such a need by treating PBA without those particular side effects. The Court also finds that Plaintiffs have not proven a failure of others.
Commercial success is an indication of nonobviousness "because the law presumes an idea would successfully have been brought to market sooner, in response to market forces, had the idea been obvious to persons skilled in the art." Merck & Co., Inc. v. Teva Pharm. USA, Inc., 395 F.3d 1364, 1376 (Fed.Cir.2005). Plaintiffs contend Nuedexta® is commercially successful, as demonstrated by the sales totals, sales growth, profits, profit margins, sales forecasts, prescription totals, prescription growth, and the number of generic ANDA filers. (D.I. 432 at 14-15)
Based on the evidence as a whole, the Court finds Plaintiffs have proven "commercial success." Plaintiffs began marketing and selling Nuedexta® in February 2011 and, through June 2013, Nuedexta® had reached net sales of $93.6 million; its net sales have increased in every quarter, including 265% growth from year one to year two. (PTX-305; Tr. at 672, 777) Nuedexta®'s prescription totals were over 240,000 through early August 2013 and the
Defendants contend Plaintiffs have failed to prove a nexus between Nuedextae's commercial success and the claimed invention. It is undisputed that 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) Defendants' expert, Dr. Rausser, opined "the evidence from NDTI data suggests that Nuedexta is actually being prescribed off-label" and such sales have no nexus to the patents-in-suit because the patent claims only go to treatment of PBA. (Tr. at 821-23) However, Nuedexta® is promoted only as a treatment for PBA and Dr. Rainey opined, persuasively, that Nuedexta® is primarily used to treat PBA. (Id. at 787, 789, 791-92; see also PTX-167; PTX-150)
Thus, the Court concludes based on the evidence as a whole that a nexus exists between Nuedexta®'s commercial success and the claimed inventions, providing further objective evidence of nonobviousness.
Defendants contend that the '282 and '484 patents lack sufficient written description under 35 U.S.C. § 112, ¶ 1 because the application from which the '282 and '484 patents issued was missing the "10-30 mg/day dose range of Q," demonstrating the patentees did not have possession of the invention. (D.I. 429 at 19) Plaintiffs respond that Defendants' argument must be rejected because it improperly requires working examples to satisfy written description; more precisely, the underlying premise of Defendants' argument is "the
"The written description requirement does not demand either examples or an actual reduction to practice; a constructive reduction to practice that in a definite way identifies the claimed invention can satisfy the written description requirement." Ariad, 598 F.3d at 1352. Here, the specifications of both the '282 and '484 patents expressly disclose the claimed 10-30 mg/day Q dosage range, along with the 20-30 mg/day and 20 mg/day Q dosages as "particularly preferred" for treating PBA. (DTX-1 at 16:26-7; DTX-2 at 16:26-7; see also Ariad, 598 F.3d at 1352 ("[I]t is the specification itself that must demonstrate possession.")) Accordingly, Defendants' argument fails.
The Court finds that Defendants have not shown, by clear and convincing evidence, that any claim of the '282 or '484 patents is obvious over the prior art references. Further, secondary considerations of unexpected results and commercial success support a conclusion of nonobviousness. For these reasons, the Court concludes that the '282 and '484 patents are valid.
Defendants assert that if the Court determines the asserted claims of the '115 patent do not include a "therapeutically effective in substantially reducing chronic or intractable pain" limitation, then the patent is invalid as obvious over the '888 patent in combination with the Zhang Abstract or '207 patent. (D.I. 429 at 20) The parties and the Court agree, however, that the asserted claims of the '115 patent do contain such a limitation. (D.I. 446 at 39, 39 n.24; D.I. 257 at ¶ 5) (term given its plain and ordinary meaning)
Since Defendants have failed to proffer any evidence that a person of ordinary skill would have found the claimed invention of the '115 patent obvious in light of the "therapeutically effective" limitation, the Court concludes that Defendants have not shown, by clear and convincing evidence, that claims 18, 19, 20, and 21 of the '115 patent are obvious over the prior art references.
Plaintiffs have proven by a preponderance of the evidence that asserted claims 1-9 of the '282 patent and claims 1-9, 12, 13, 15, and 17 of the '484 patent are infringed. Defendants have failed to prove by clear and convincing evidence that claims 1-9 of the '282 patent and claims 1-9, 12, 13, 15, and 17 of the '484 patent are invalid. With respect to the '115 patent, Plaintiffs have failed to prove by a preponderance of the evidence that asserted claims 18-21 are infringed while Defendants have failed to prove by clear and convincing evidence that these same claims are invalid.
An appropriate Order will be entered.
At Wilmington this
For the reasons set forth in the Memorandum Opinion issued this date,
IT IS HEREBY ORDERED that:
1. The parties shall meet and confer and submit, no later than
2. Plaintiffs' objection to portions of Dr. Boobis's testimony (D.I. 446 at 21) is OVERRULED.
3. Defendants' motion to exclude portions of Dr. Wynn's testimony (D.I. 450 at 22-24) is DENIED.
5. Defendants' motion to strike references to Plaintiffs' demonstrative exhibits included in Plaintiffs' Proposed Findings of Fact (D.I. 444 at 2 n.2) is GRANTED.
6. The parties shall submit briefs, not to exceed five (5) pages, addressing whether, in light of the Court's finding that Nuedexta® does not meet the "therapeutically effective" limitation of the '115 patent, the Court should grant Defendants' request to "delist" the '115 patent from the "Orange Book" entry for Nuedexta®, pursuant to 21 U.S.C. § 355(b)(1)(G), no later than May 5, 2014. The parties shall file responsive briefs not to exceed three (3) pages no later than May 8, 2014.
7. The parties shall submit a proposed redacted version of the Memorandum Opinion no later than May 1, 2014.
