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Acorda Therapeutics, Inc. v. Roxane Laboratories, Inc.

United States District Court, D. Delaware

March 31, 2017

ACORDA THERAPEUTICS, INC., et al., Plaintiffs,
v.
ROXANE LABORATORIES, INC., et al., Defendants.

          Jack B. Blumenfeld, Maryellen Noreika, MORRIS, NICHOLS, ARSHT & TUNNELL LLP, Wilmington, DE Aaron Stiefel, Daniel P. Di Napoli, Jeffrey Martin, David Harris, Philip Smithback, Stephanie M. Piper, ARNOLD & PORTER KAYE SCHOLER LLP, New York, NY Sylvia M. Becker, ARNOLD & PORTER KA YE SCHOLER LLP, Washington, DC Soumitra Deka, ARNOLD & PORTER KA YE SCHOLER LLP, Palo Alto, CA Jane Wasman, Anthony Michael, ACORDA THERAPEUTICS, INC., Ardsley, NY. Attorneys for Plaintiffs.

          John C. Phillips, Jr., Megan C. Haney, PHILLIPS, GOLDMAN, MCLAUGHLIN, & HALL, P.A., Wilmington, DE Charles B. Klein, WINSTON & STRAWN LLP, Washington, DC George C. Lombardi, Samuel S. Park, Bryce A. Cooper, Reid Smith, WINSTON & STRAWN LLP, Chicago, IL Attorneys for Defendants Apotex Corp., Apotex, Inc., Teva Pharmaceuticals USA Inc., and Roxane Laboratories, Inc.

          Richard K. Herrmann, Mary B. Matterer, MORRIS JAMES LLP, Wilmington, DE Robert L. Florence, Karen L. Carroll, Michael L. Binns, PARKER POE ADAMS & BERNSTEIN LLP, Atlanta, GA Melanie Black Dubis, Catherine R.L. Lawson, Christopher M. Thomas, PARKER POE ADAMS & BERNSTEIN LLP, Raleigh, NC Attorneys for Defendant Mylan Pharmaceuticals Inc.

          MEMORANDUM OPINION

          STARK, U.S. DISTRICT JUDGE

         Acorda Therapeutics, Inc. and Alkermes Pharma Ireland Limited ("Plaintiffs") allege that Apotex Corp., Apotex Inc., Mylan Pharmaceuticals Inc., Roxane Laboratories, Inc., and Teva Pharmaceuticals, USA, Inc. ("Defendants") infringe several United States Patents. Patent No. 5, 540, 938 (the '"938 patent" or the "Elan Patent") relates to the use of a sustained-release formulation of 4-AP, administered once or twice daily, to treat neurological diseases including multiple sclerosis ("MS"). Patent Nos. 8, 007, 826 (the '"826 patent"), 8, 663, 685 (the '"685 patent"), 8, 354, 437 (the '"437 patent"), and 8, 440, 703 (the '"703 patent") (collectively, the "Acorda Patents") relate to the use of 10 mg sustained-release formulations of 4-AP to treat walking impairments in individuals with MS.

         The Court adopted stipulated constructions for certain claim terms in the patents-in-suit. (D.I. 187, 193) With respect to disputed claim terms, the Court held a claim construction hearing on March 7, 2016 and issued an opinion and order on March 16, 2016. (D.I. 195, 196) In September 2016, the Court held a four-day bench trial. (See D.I. 266-69) ("Tr.") The parties have submitted a Statement of Uncontested Facts ("SUF") (D.I. 252-1 Ex. 1) and their competing versions of proposed findings of fact (D.I. 262, 263). They have also submitted extensive post-trial briefing, which concluded with supplemental letter briefs filed on March 6, 2017. (D.I. 265, 272, 273, 274, 278, 279)[1]

         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 the asserted claims of the patents-in-suit; (2) Defendants have failed to prove by clear and convincing evidence that the asserted claims of the Elan Patent are invalid for obviousness; and (3) Defendants have proven by clear and convincing evidence that the asserted claims of the Acorda Patents are invalid for obviousness. The Court's findings of fact and conclusions of law are set forth in detail below.

         FINDINGS OF FACT

         This section contains the Court's findings of fact ("FF") on disputes raised by the parties during trial, as well as facts to which the parties have stipulated. Certain findings of fact are also provided in connection with the Court's conclusions of law.

         A. The Parties

         i. Plaintiffs

         1. Plaintiff Acorda Therapeutics, Inc. ("Acorda") is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 420 Saw Mill River Road, Ardsley, New York 10502. (SUF ¶ 1)

         2. Plaintiff Alkermes Pharma Ireland Limited ("Alkermes") is an Irish corporation having a principal place of business at Connaught House, 1 Burlington Road, Dublin 4, Ireland. (SUF¶2)

         3. Plaintiffs have standing with respect to each of Plaintiffs' claims asserted against Defendants. (D.I. 254 ¶ 9)

         ii. Defendants

         4. Defendant Apotex Corp. (together with Apotex, Inc., "Apotex") is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 2400 North Commerce Parkway, Suite 400, Weston, Florida 33326. (SUF ¶ 3)

         5. Defendant Apotex Inc. is a corporation organized and existing under the laws of Canada, having its principal place of business at 150 Signet Drive, Toronto, Ontario M9L 1T9, Canada. (SUF¶4)[2]

         6. Defendant Mylan Pharmaceuticals Inc. ("Mylan") is a corporation organized and existing under the laws of the State of West Virginia, having a principal place of business at 781 Chestnut Ridge Road, Morgantown, West Virginia 26505. (SUF ¶ 5)

         7. Defendant Roxane Laboratories, Inc. ("Roxane") is a corporation organized and existing under the laws of the State of Nevada, having a principal place of business at 1809 Wilson Road, Columbus, Ohio 43228. (SUF ¶ 6)

         8. Defendant Teva Pharmaceuticals USA, Inc. ("Teva") is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 1090 Horsham Road, North Wales, Pennsylvania 19454. (SUF ¶ 7)

         B. Multiple Sclerosis

         9. Multiple Sclerosis ("MS") is a chronic disease of the neuroimmunological system. (Peroutka Tr. at 52-53)[3] MS causes a loss of myelin, the fatty material that insulates many of the nerves in the central nervous system. (Peroutka Tr. at 53-54; see also Lublin Tr. at 392) This loss of myelin is called demyelination. (Peroutka Tr. at 52-53; Lublin Tr. at 392)

         10. Demyelination slows or blocks the movement of nerve impulses along the nerve, resulting in diminished coordination of nervous system signals. (Lublin Tr. at 392; Goodman Tr. at 432-33) This disruption results in a wide variety of symptoms affecting a range of body parts and systems. (Lublin Tr. at 392) The symptoms of MS may include walking impairment, visual difficulty, fatigue, bladder dysfunction, tingling or pain, sexual dysfunctions, balance problems, and cognitive changes. (Id.; Peroutka Tr. at 55; Goodman Tr. at 433)

         11. Weakness in the legs and/or alterations in walking are among the most common symptoms of MS. (Peroutka Tr. at 55; Goodman Tr. at 432) Roughly 50-75% of MS patients experience difficulty walking. (Peroutka Tr. at 55)

         12. MS may also cause brain scarring, which can lead to permanent symptoms and make MS patients susceptible to seizures or convulsions. (Goodman Tr. at 430-31, 442)

         13. There is substantial variability in how MS manifests itself both among different patients and within a single patient over time. (Goodman Tr. at 431-32, 434-36; Peroutka Tr. at 121) Any particular patient's symptoms may vary on a day-to-day, or even hour-to-hour, basis. (Goodman Tr. at 435-36; Peroutka Tr. at 121-22)

         C. Treating MS

         14. There is presently no known cure for MS. (Peroutka Tr. at 53-54)

         15. Current treatments for MS fall into two categories: (1) the use of disease-modifying agents, which alter the course of the disease and lessen the chance that a patient's condition deteriorates; and (2) therapies that attempt to alleviate the individual symptoms of MS, to improve a patient's quality of life. (Lublin Tr. at 393-94)

         16. Designing and interpreting the results of clinical trials for MS therapies is complex because the wide variety of MS symptoms makes it difficult to select clinical endpoints (i.e., measures of efficacy) and leads to mixed results. (Goodman Tr. at 436-37) In particular, it can be difficult to determine whether changes in symptoms result from the treatment being tested, from independent changes in the course of the disease, or from day-to-day variability in symptoms. (Id. at 436-38)

         17. Placebo effect is also a problem in analyzing results of MS trials. (Lublin Tr. at 401-05) Placebo effect is an improvement in symptoms among test subjects who do not receive a drug. (See Id. at 412; Goodman Tr. at 468-69)

         18. There are a number of methods for assessing the disease state of a patient with MS. Some measures consist of numerical scales designed to interpret patients' subjective assessment of particular symptoms - such as fatigue or walking - or their condition in general. (Goodman Tr. at 455, 481, 518-19) Other measures, such as timed walking tests, provide objective, quantitative indications of results. (Lublin Tr. at 394)

         19. In addition to tests that measure clinically manifested symptoms, other tests directly assess nerve impulse transmission. For example, researchers and clinicians can measure subclinical visually evoked potentials ("VEP") to detect the speed of nerve impulse transmissions. (JTX-0065;[4] Lublin Tr. at 394-96) Research established in the 1970s that VEP could serve as a valuable test in the early diagnosis of MS. (JTX-0065; Lublin Tr. at 395-97) By the 1980s and 1990s, VEP was also being used in conjunction with clinical metrics as a measure of therapeutic efficacy in clinical trials. (JTX-0025) VEP is an especially useful tool because it is not susceptible to placebo effect. (Lublin Tr. at 401-05)

         D. Ampyra®

         20. Acorda holds an FDA-approved New Drug Application ("NDA"), No. 022250, for the use of 10 mg dalfampridine extended release tablets to improve walking in patients with MS. (D.I. 1 ¶ 30; SUF ¶ 8) Acorda markets the approved drug product under the registered name Ampyra®. (D.I. 1 ¶ 30; SUF ¶ 8)

         21. Dalfampridine, also known as fampridine, 4-Aminopyridine, or "4-AP, " is the active ingredient in Ampyra®. Ampyra® was the first FDA-approved use of 4-AP. (SUF ¶ 9, 68)

         22. The FDA approved Ampyra® on January 22, 2010. (SUF ¶ 67) Acorda has been marketing and selling Ampyra® in the United States since March 2010. (Id. ¶ 69)

         i. Active Ingredient (4-Aminopyridine)

         23. The 4-AP molecule improves nerve conduction by blocking potassium channels and is sometimes referred to as a "potassium channel blocker." (Peroutka Tr. at 122)

         24. Adverse effects such as seizures have been related to 4-AP's potassium channel blocking mechanism of action. (Goodman Tr. at 438-39, 482; Peroutka Tr. at 122) The concern about seizures is heightened in MS patients because brain scarring associated with the disease can increase seizure risk. (Goodman Tr. at 441-42)

         ii. Ampyra® Label

         25. The "INDICATIONS AND USAGE" portion of Ampyra®'s label states that "AMPYRA (dalfampridine) is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed . . . ." (JTX-0076 at AMPDELO170808; SUF ¶ 73) Improvement of walking in MS patients is Ampyra®'s only approved use. (SUF ¶ 9)

         26. The "DOSAGE AND ADMINISTRATION" portion of Ampyra®'s label states:

The maximum recommended dose of AMPYRA is one 10 mg tablet twice daily, taken with or without food, and should not be exceeded. Doses should be taken 12 hours apart. Tablets should only be taken whole; do not divide, crush, chew, or dissolve. Patients should not take double or extra doses if a dose is missed .... No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse reactions and discontinuations because of adverse reactions were more frequent at higher doses.

(JTX-0076 at AMPDEL0170808; SUF ¶ 74)

         27. The "DESCRIPTION" portion of Ampyra®'s label states that "AMPYRA (dalfampridine) is a potassium channel blocker, available in a 10 mg tablet strength. Each tablet contains 10 mg dalfampridine, formulated as an extended release tablet for twice-daily oral administration." (JTX-0076 at AMPDELO 170811; SUF ¶ 75)

         E. The Elan Patent

         28. The FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations" ("Orange Book") lists the Elan Patent with respect to Ampyra®. (SUF ¶ 12)

         i. Development

         29. In the 1980s, Dusan Stefoski and Floyd A. Davis of the Rush Medical School began to develop immediate release formulations of 4-AP to treat MS. (JTX-0112; JTX-0043)

         30. By 1990, Elan Corporation PLC ("Elan") entered into an agreement with Rush to allow Elan to use Rush's research on 4-AP to develop pharmaceutical formulations of the drug. (Fogarty Tr. at 158-59) At the time, Elan was at the forefront of the development of sustained-release formulations. (Id. at 159-60; Myers Tr. at 151; Fassihi Tr. at 325)

         31. Sustained-release formulations release a drug continuously over a long period of time, such that, compared to an immediate release formulation, the body absorbs drug more slowly, the drug's concentration in the body peaks later, and the drug dissipates from the body more slowly. (Kibbe Tr. at 186) As a result, a sustained-release formulation of a drug is effective for longer than an immediate release formulation of the same drug. (Id.)

         32. The inventors of the Elan Patent required about three or four weeks to design three or four sustained-release 4-AP formulations "on paper, " and about a day thereafter to actually prepare a sustained-release formulation of 4-AP. (Myers Tr. at 154-55) In preparing formulations, one of the inventors, Dr. Michael Myers, used sustained-release platforms with which he already had experience, then substituted 4-AP for the active ingredients he had previously used, and "adjusted the platforms with routine testing" until he obtained the desired dissolution pattern. (Id. at 211)

         ii. Patent and Claims

         33. The United States Patent and Trademark Office ("USPTO") issued the Elan Patent, entitled "Formulations and Their Use in the Treatment of Neurological Diseases, " on July 30, 1996. (JTX-0001; SUF ¶ 10) The inventors listed on the face of the Elan Patent are Joseph G. Masterson and Michael Myers. (JTX-0001; SUF ¶ 13)

         34. The Elan Patent is a divisional of U.S. Application No. 73, 651 ("Application No. 73, 651"), filed June 7, 1993, which issued as U.S. Patent No. 5, 370, 879 on December 6, 1994. (JTX-0001) Application No. 73, 651 was a continuation of U.S. Application No. 786, 400, filed November 1, 1991, which was subsequently abandoned by the applicant. (Id.; SUF ¶ ll)[5] The Elan Patent also claims priority to an Irish patent application filed November 2, 1990. (SUF ¶ 11) The Elan Patent expires on July 30, 2018. (Id.)

         35. Elan is named on the face of the Elan Patent as the assignee on the patent. (JTX-0001) Acorda has an exclusive license to the Elan Patent. (SUF ¶ 15) Alkermes, which acquired Elan, is the successor-in-interest to the Elan Patent. (Goodman Tr. at 535)

         36. Plaintiffs assert that Defendants infringe claims 3 and 8 of the Elan Patent. (SUF ¶16)

         37. Claims 3 and 8 both depend from claim 1. Claim 1 recites:

A method for the treatment of a neurological disease where the disease is characterised by a slowing of nerve impulse • transmission, which comprises administering to a patient in need thereof a medicament containing a mono- or di-aminopyridine active agent, said medicament being effective to permit sustained release of said mono- or di-aminopyridine active agent at a rate allowing controlled absorption thereof which achieves therapeutically effective blood levels over a 12-24 hour period when administered on a once- or twice-daily basis.

(JTX-0001 at 22:16-25)

         38. Claim 3 also depends from claim 2. Claim 2 recites: "[a] method according to claim 1, wherein the neurological disease is characterised by demyelination of the central nervous system." (JTX-0001 at 22:26-28) Claim 3 recites: "[a] method according to claim 1 or 2, wherein the neurological disease is multiple sclerosis." (Id. at 22:29-30)

         39. Claim 8 recites: "[a] method according to claim 1, wherein the active agent is 4- aminopyridine." (JTX-0001 at 22:50-51)

         iii. 4-AP: Scope and Content of the Prior Art

         40. A German paper first identified 4-AP in 1902. (Peroutka Tr. at 73) The drug was subsequently used as a bird toxin and as an agent to induce seizures in animals. (Fassihi Tr. at 361)

         41. 4-AP was first used in humans in studies conducted in the 1970s, when a Swedish group tested the drug in connection with neurological diseases that resulted in muscle weakness associated with an impasse in nerve transmission. (Peroutka Tr. at 73)

         42. A 1980 British study examined the effect of 4-AP on rats with demyelinated nerves and suggested that the drug could be used to improve their condition. (Peroutka Tr. at 73-74)

         43. In 1981, Drs. Nicholas M.F. Murray and John Newsom-Davis disclosed the use of 4-AP in pharmaceutical preparations, to evaluate the safety and efficacy of the drug. (Peroutka Tr. at 74; JTX-0089)

         a. Stefoski

         44. In 1987, Stefoski and Davis, researchers at Rush Medical School, conducted a study and published a paper entitled "4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis, " Annal. Neurol, 21:11-11 (1987) ("Stefoski"). (JTX-0112) Stefoski is a printed publication in the United States and available to persons of ordinary skill in the art in 1987. (SUF ¶ 62)

         45. Stefoski studied the effect of 4-AP on VEP, ocular motor function, and motor function (defined by the researchers as power, coordination, and gait). (JTX-0112 at 71) The researchers monitored 12 MS patients and five men without MS before, during, and after IV injection of seven to 35 mg of 4-AP. (Id.) Stefoski found that ten of the 12 MS patients showed mild to marked improvement, with vision improving in seven patients, ocular motor function improving in five patients, and motor function improving in five patients. (Id.) Some of the improvements developed within minutes and at doses as low as two mg. (Id.) Stefoski concluded that 4-AP might be useful in treating MS patients, adding that studies were "currently in progress to determine the clinical usefulness of 4-AP as a symptomatic treatment." (Id. at 75)

         46. A later article by Christopher T. Bever et al, "The Effects of 4-Aminopyridine in Multiple Sclerosis Patients, " Neurology, 44:1054-59 (1994), stated that the conclusions to be drawn from the results reported in Stefoski were "limited by questions about blinding, failure to randomize treatment, and failure to either use prospectively-defined neurologic deficits or adjust significance levels to compensate for multiple comparisons." (JTX-0028 at 1058) A later article by Bever also noted several limitations with Stefoski, including that it was small in size, did not use a randomized treatment design, was not double-blind, involved only short-term use of 4-AP, and relied on outcome measures that were not widely accepted. (JTX-0027 at ¶ 19)

         b. Davis

         47. In February 1990, Stefoski and Davis published a paper entitled "Orally Administered 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis, " Annal. Neurol., 27:186-92 (1990) ("Davis"). (JTX-0043) Davis is a printed publication published in the United States and available to persons of ordinary skill in the art in 1990. (SUF ¶ 47)

         48. Davis examined the effect of 4-AP at doses of 10-25 mg versus a placebo. (JTX-0043 at 186) Fifteen patients received immediate-release capsules of 4-AP and five received placebo. (Id.) Davis found that all patients experienced mild to marked improvements, with motor function (defined by the researchers as power, coordination, and gait) improving in nine of 13 subjects. (Id.) Davis further found that improvements were observed with use of doses as low as 10 mg. (Id.) No serious adverse events, such as seizures, occurred in patients taking 10-25 mg doses of the drug. (Id. at 191) Although the study became unblinded, several patients demonstrated reversible improvements in VEP that could not be explained by placebo effect. (Id.) Davis concluded that orally-administered 4-AP produces clinically important improvements in multiple chronic deficits resulting from MS. (Id.)

         49. A later article by Christopher T. Bever et al, "The Effects of 4-Aminopyridine in Multiple Sclerosis Patients, " Neurology, 44:1054-59 (1994), described the conclusions that could be drawn from the results reported in Davis were "limited by questions about-blinding, failure to randomize treatment, and failure to either use prospectively-defined neurologic deficits or adjust significance levels to compensate for multiple comparisons." (JTX-0028 at 1059) A still later article by Bever also noted that Davis had several limitations, including that it was small in size, did not use a randomized treatment design, was not double-blind, involved only short-term use of 4-AP, and relied on outcome measures that were not widely accepted. (JTX-0027 at ¶ 19)

         c. Murray 50. In 1981, Nicholas M.F. Murray et al. published a paper entitled "Treatment with Oral 4-Aminopyridine in Disorders of Neuromuscular Transmission, " Neurology, 31:265-81 (1981) ("Murray"). Murray is a printed publication published in the United States and available to persons of ordinary skill in the art in 1991. (JTX-0089)

         51. Murray reports on a study evaluating 4-AP as an immediate release oral preparation in nine patients: four with Eaton-Lambert syndrome, four with congenital myasthenia, and one with myasthenia gravis.[6] (JTX-0089 at 265) The patients in Murray received a starting dose of 10 mg/twice daily, which was gradually increased, depending on response, to up to 200 mg daily. (Id. at 266)

         52. Of the nine patients in the study, one had an "acute confusional episode" and three others experienced seizures. (JTX-0089 at 270) Murray concluded that "[t]he central effects of 4-AP, especially seizures, limit its use." (Id.)

         iv. Sustained-Release Technology: Scope and Content of the Prior Art

         53. Every active pharmaceutical ingredient (e.g., 4-AP) is unique, with its own physical-chemical properties and pharmacokinetics. (See Fassihi Tr. at 340) There was (and is) no sustained-release formulation that works for all drugs. (Id.)

         54. In 1990-91, the FDA had not developed guidelines to aid pharmaceutical companies in developing sustained-release formulations. (JTX-0108)

         55. Once a product has been widely-consumed in immediate release form, information about the safety, efficacy, and pharmacokinetics of the drug becomes available. (Fassihi Tr. at 336-38) In 1990-91, all of the drugs that were commercially available in sustained-release dosage forms had previously been approved by the FDA in immediate release forms. (Id. at 335-36, 366)

         a. Remington's (1985 and 1990)

         56. "Sustained-Release Drug Delivery Systems, " Remington's Pharmaceutical Sciences, Alfonso R. Gennaro ed., 18th ed., pp. 1676-93 (1990) ("Remington's") is a printed publication published in the United States and available to persons of ordinary skill in the art in 1990. (JTX-0081; SUF ¶ 59) Remington's is an authoritative treatise on the subject of pharmaceutical formulations. (See Peroutka Tr. at 81 (describing Remington's as "the Bible of pharmaceuticals sciences"))

         57. The 1985 edition of Remington's highlights that, prior to 1990, there were numerous sustained-release drugs on the market. (JTX-0082 at 1644) ("1985 Remington's") The 1990 edition of Remington's lists five types of sustained-release formulation "platforms" (e.g., encapsulated dissolution) and 39 FDA-approved, commercially-available sustained-release products. (JTX-0081 at 1683-86) The 1990 edition of Remington's also explains how to make a sustained-release drug using each of the disclosed platforms, listing excipients appropriate for each. (Id.)

         58. The 1985 edition of Remington's includes a table setting forth various known advantages of sustained-release formulations. (JTX-0082 at 1646) One recognized advantage of sustained release is improved patient compliance, as the less frequently a patient has to take a dose the more likely a patient will be to take the required doses. (Id.)

         59. The 1985 edition of Remington's also lists several characteristics of a drug that are compatible with a sustained-release formulation. First, a drug with a relatively short-half-life is a good candidate for sustained release because sustained release eliminates the need for frequent dosing.[7] (JTX-0082 at 1647-50) Second, a drug with efficient absorption is a good candidate for sustained release. (Id.) Third, a drug requiring a relatively small dose is a good candidate for sustained-release dosing because the resulting sustained-release product will not be too large to swallow. (Id.) Finally, because sustained-release dosage forms are often used to treat chronic conditions that require consistent concentration of drug in the blood stream for a long period, drugs used to treat chronic conditions are good candidates for sustained-release formulations. (Id.)

         b. Robinson & Lee

         60. Robinson & Lee, whose full title is Methods to Achieve Sustained Drug Delivery and is authored by Joseph R. Robinson and Vincent Hon-Leung Lee, is a printed publication in the United States and available to persons of ordinary skill in the art in 1978. (JTX-0079) Robinson & Lee is an authoritative treatise on the subject of pharmaceutical formulations. (See Kibbe Tr. at 236-37 (describing Robinson as "a real authority on sustained release"))

         61. The 1990 edition of the Robinson & Lee treatise stated that the design of a sustained-release product was "normally a very difficult task." (PTX-0095 at 201) It further explained that the "[s]uccessful fabrication of sustained-release products . . . involves consideration of the physical-chemical properties of the drug, pharmacokinetic behavior of the drug, route of administration, disease state to be treated and, most importantly, placement of the drug in a dosage form that will provide the desired temporal and spatial delivery pattern for the drug." (Id. at 199; see also Fassihi Tr. at 326-27, 329-30)

         c. Uges

         62. In 1982, Donald R.A. Uges et. al. published a paper entitled "4-Aminopyridine Kinetics, " Clin. Pharmacol. Ther. 31(5):587-593 (1982) ("Uges"). Uges is a printed publication published in the United States and available to persons of ordinary skill in the art in 1990. (JTX-0137)

         63. Uges examined the pharmacokinetics of 4-AP in nine healthy subjects. (JTX-0137) The subjects received three different administrations of 20 mg of 4-AP: intravenous administration ("IV"), administration via an uncoated (immediate release) tablet, and administration via an enteric (delayed release) dose. (Id.) Uges reported that the half-life of 4-AP is about four hours. (Id.) Uges also reported that the bioavailability (percent absorption) of enteric-coated tablets was 95% ± 29%, suggesting that the drug was highly bioavailable even when release was delayed. (Id.) Finally, Uges taught that almost 100% of the drug was excreted unchanged in the urine, regardless of how the drug was administered. (Id.)

         F. The Acorda Patents

         i. Development

         64. Dr. Ron Cohen founded Acorda in 1993. (Cohen Tr. at 277) Dr. Cohen learned of 4-AP through Dr. Andrew Blight, one of Acorda's first employees, who had previously done some exploratory work with 4-AP and spinal cord injury. (Id. at 278-79) Acorda initially focused on developing immediate-release formulations of 4-AP. (Id. at 280)

         65. In 1997, Elan licensed the Elan Patent to Acorda, allowing Acorda to use Elan's sustained-release 4-AP formulations for clinical trials in spinal cord injury patients. (Cohen Tr. at 280-81; JTX-0020) In 1998, Elan and Acorda expanded the license to give Acorda exclusive rights over the use of the 4-AP formulations, including for use in the treatment of MS. (Cohen Tr. at 303-04; JTX-0021) Acorda did not do any independent development or formulation work on any sustained-release formulation of 4-AP but, instead, used Elan's formulation in its trials. (Cohen Tr. at 304; Blight Tr. at 163)

         66. Prior to licensing its sustained-release formulations to Acorda, Elan conducted a double-blind, randomized, placebo-controlled, 161-patient study of the safety and efficacy of twice-daily sustained-release formulations of 4-AP in MS patients. (PTX-0360) (the "Elan Study") Patients in the 4-AP group initially received 12.5 mg doses/twice daily, a dose that was increased by 5 mg every two weeks until the patients either experienced intolerable side effects or reached the maximum dose of 22.5 mg/twice daily. (Id. at 8-9) The primary endpoint of the study was the Expanded Disability Status Scale (EDSS), a composite measure of functioning that was widely accepted in the MS community. (Id. at 1; JTX-0104 at 817; Goodman Tr. at 284, 467) The only outcome measure with a statistically significant difference compared to placebo was the secondary outcome measure of lower extremity muscle strength; all other secondary outcome measures, including ambulation, showed no statistically-significant difference from placebo. (PTX-0360 at 101-02)

         67. In 2000 and 2001, Acorda conducted a 36-patient study on the use of sustained-release formulations of 4-AP to treat MS (the "MS-F201 Study"). (See PTX-0466A; Cohen Tr. at 287-88) The 25 patients in the 4-AP group received initial doses of 10 mg/twice daily for the first week of the study, with dosages increasing by 5 mg per week to a maximum of 40 mg/twice daily. (Cohen Tr. at 288) The outcome measures of the study included fatigue, a lower extremity manual muscle test, the multiple sclerosis functional composite (including a timed 25-foot walk), and subjective measures. (Id. at 289) The study failed as to all of the prospectively-defined outcome measures other than the lower-extremity manual muscle test. (Id. at 289-90) The results of the timed 25-foot walking test were not statistically significant, as members of the placebo group showed greater improvement than the 4-AP group in multiple weeks. (PTX-0466A; Cohen Tr. at 290-92) In three of the seven weeks, the placebo group demonstrated greater improvement than the members of the 4-AP group had exhibited during the 10 mg/twice-daily week. (PTX-0466A at 63) However, a post-hoc analysis of the data analyzing walking speed (rather than time) indicated a statistically-significant difference between the 4-AP and placebo groups when the 4-AP results were aggregated across all of the various doses combined together. (Cohen Tr. at 292; Goodman Tr. at 478-79)

         68. In 2003, Acorda conducted a 206-patient, "Phase II" study regarding the use of sustained-release 4-AP to improve walking speed in patients with MS. (PTX-0168A ("the MS-F202 Study")) The study explored sustained-release doses of 10 mg, 15 mg, and 20 mg 4-AP administered twice daily. (Cohen Tr. at 293) The study included a two-week up-titration period to limit side effects, followed by a twelve-week period of stable dosing. (Id. at 295) None of the 4-AP groups demonstrated a statistically significant difference in walking speed compared to placebo. (Id. at 296-98) However, a post-hoc, unblinded "responder" analysis indicated that the responders were, overwhelmingly, members of the 4-AP group (p < 0.0001). (Id.) The responder analysis also indicated that there was no meaningful difference in efficacy among the 10 mg, 15 mg, and 20 mg 4-AP groups. (Id. at 298-99)

         69. Following the Phase II study, Acorda conducted two Phase III studies of 4-AP, using 10 mg/twice-daily dosing and the walking improvement responder analysis as a prospectively-defmed primary outcome measure. (Cohen Tr. at 299-300) Both studies were successful (p O.0001). (Id.)

         ii. Patents and Claims

         70. The inventors listed on the face of the Acorda Patents are Andrew R. Blight and Ron Cohen. (See JTX-0002; JTX-0003; JTX-0004; JTX-0005; SUF ¶¶ 21, 27, 33, 39)

         71. Acorda is listed as the assignee of each of the Acorda Patents. (See JTX-0002; JTX-0003; JTX-0004; JTX-0005; SUF ¶¶ 22, 28, 34, 40)[8]

         a. The'826 Patent

         72. The USPTO issued the '826 patent, entitled "Sustained Release Aminopyridine Composition, " on August 30, 2011. (SUF ¶ 18)

         73. The '826 patent issued from U.S. Patent Application No. 11/010, 828, which was filed on December 13, 2004, and claims priority to U.S. Provisional Application No. 60/560, 894, filed on April 9, 2004. (See JTX-0002; SUF ¶ 19) The patent expires on May 26, 2027. (SUF ¶19)

         74. Plaintiffs assert that Defendants infringe claims 1, 7, 38, and 39. (SUF ¶ 23)

         75. Claim 1 recites:

A method for maintaining a therapeutically effective concentration of 4-aminopyridine in order to improve walking in a human with multiple sclerosis in need thereof, said method comprising:
orally administering to the human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a day; and thereafter, maintaining administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of at least two weeks, whereby an in vivo 4-aminopyridine CmaxSS:CminSS of 1.0 to 3.5 and a CavSS of 15 ng/ml to 35 ng/ml are obtained in the human.

(JTX-0002 at 27:17-30)

         76. Claim 7 depends from claim 6. Claim 6 recites:

A dosing regimen method for providing a 4-aminopyridine at a therapeutically effective concentration in order to improve walking in a human with multiple sclerosis in need thereof, said method comprising:
initiating administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a day without a prior period of 4-aminopyridine titration, and then, maintaining administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily;
without a subsequent period of 4-aminopyridine titration, whereby an in vivo 4-aminopyridine CmaxSS:CminSS of 1.0 to 3.5 and a CavSS of 15 ng/ml to 35 ng/ml are maintained in the human.

(JTX-0002 at 27:41-57) Claim 7 recites: "[t]he method of claim 6, whereby an increase in walking speed is obtained in said human." (Id. at 27:58-59)

         77. Claims 38 and 39 depend from claim 37. Claim 37 recites:

A method of increasing walking speed in a human multiple sclerosis patient in need thereof comprising orally administering to said patient a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of greater than two weeks, wherein said sustained release composition provides a mean Tmax in a range of about 2 to about 5.2 hours after administration of the sustained release composition to the patient.

(JTX-0002 at 30:14-21)

         78. Claim 38 recites: "[t]he method of claim 37 wherein the sustained release composition elicits a CmaxSS:CminSS ratio of 1.0 to 3.5 when administered b.i.d. [i.e., twice daily] or administered at 12-hour intervals to a human." (JTX-0002 at 30:22-25)

         79. Claim 39 recites: "[t]he method of claim 37 wherein said time period is twelve weeks." (JTX-0002 at 30:26-27)

         80. The parties have stipulated that if the two-week limitations (of, for example, claim 37) is obvious, then the 12-week limitations (of, for example, claim 39) are also obvious. (D.I. 254 ¶ 5) This ...


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