Allergan, Inc. v. Watson Laboratories, Inc. (869 F. Supp. 2d 456, 2012)

MEMORANDUM

GREGORY M. SLEET, Chief Judge.

I. INTRODUCTION

In this consolidated patent infringement action, plaintiffs Allergan, Inc., Allergan USA, Inc., Allergan Sales, LLC, Endo Pharmaceuticals Solutions Inc., and Super-nus Pharmaceuticals, Inc. (collectively, “the plaintiffs”) allege that pharmaceutical products proposed by defendants Watson Laboratories, Inc.—Florida, Sandoz, Inc., and Paddock Laboratories, Inc. (collectively, “the defendants”) infringe the asserted claims of the patents-in-suit. (D.I. 1.) The court held a seven-day bench trial in this matter on May 2 through May 10, 2011. (D.I. 204-210.) Presently before the court are the parties’ post-trial proposed findings of fact and conclusions of law concerning the validity of the patents-in-suit and whether the defendants’ proposed products infringe the patents-in-suit. (D.I. 201-203.)

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) all asserted claims of the patents-in-suit are invalid due to obviousness; (2) the asserted claims of the patents-in-suit are not invalid due to anticipation; (3) claim 1 of the '978 Patent and claim 1 of the '449 Patent are not invalid due to indefiniteness; (4) claim 1 of the '359 Patent is not invalid due to written description; (5) the defendants’ proposed products infringe the asserted claims of the patents-in-suit; and (6) each of the parties’ Rule 52(c) motions are granted in part and denied in part. These findings of fact and conclusions of law are set forth in further detail below.

II. FINDINGS OF FACT

A. The Parties

1. Plaintiffs Allergan, Inc., Allergan USA, Inc., and Allergan Sales, LLC (collectively, “Allergan”) are corporations organized and existing under the laws of the State of Delaware, with their principal place of business at 2525 Dupont Drive, Irvine, California 92612.

2. Plaintiff Endo Pharmaceutical Solutions, Inc. (“Endo”) is a corporation organized and existing under the laws of the State of Delaware and has its headquarters at 100 Endo Boulevard, Chadds Ford, Pennsylvania 19317.

3. Plaintiff Supernus Pharmaceuticals, Inc. (“Supernus”) is a Delaware corporation having its principal place of business at 1550 East Gude Drive, Rockville, Maryland 20850.

4. Allergan, Endo, and Supernus will be collectively referred to as “Allergan” or “plaintiffs.”

5. Defendant Watson Laboratories, Inc.Florida (“Watson”) is a Florida corporation with its principal place of business at 4955 Orange Drive, Davie, Florida 33314.

6. Defendant Sandoz, Inc. (“Sandoz”) is a corporation organized and existing under the laws of the State of Colorado, having its principal place of business at 506 Carnegie Center, Suite 400, Princeton, New Jersey 08540.

7. Defendant Paddock Laboratories, Inc. (“Paddock”) is a corporation organized and existing under the laws of the State of Minnesota, with headquarters at 3940 Quebec Avenue North, Minneapolis, Minnesota 55427.

8. Watson, Sandoz, and Paddock will be collectively referred to as “defendants.”

9. The court has subject matter jurisdiction, as well as personal jurisdiction over all parties.

B. Background

10. Trospium chloride (a quaternary ammonium compound with the chemical name of spiro [8-azoniabicyclo[3,2,l]octane^8,1"-pyrrolidinium]-3-[ (hydrozydiphenyl-acetyl)-oxy] chloride (lo’,3(3,5ct)-(9Cl)) is an antagonist at muscarinic cholinergic receptors.

11. In the 1990s, trospium chloride (hereafter, “trospium”), oxybutynin, and tolterodine were the three main pharmaceutical treatments for overactive bladder (“OAB”), a condition which affects approximately thirty-three million people in the United States.

12. In 2002, Ditropan (oxybutynin) and Detrol (tolterodine) were the two mainstay OAB treatments and were once-a-day formulations approved by the Food and Drug Administration (the “FDA”).

13. Unlike oxybutynin and tolterodine, trospium is a quaternary ammonium compound, rendering it permanently positively charged.

14. Though trospium had been used in the immediate release formulation of OAB pharmaceutical products for years, SANC-TURA XR® is the only product that uses a quaternary ammonium compound in its once-a-day formulation.

C. The Patents-in-Suit

15. United States Patent Number 7,410,-978 (“the '978 Patent”), entitled “Once Daily Dosage Forms Of Trospium,” naming Argaw Kidane, Henry H. Flanner, Padmanabh Bhatt, and Arash Raoufinia as inventors, was issued on August 12, 2008.

16. United States Patent Number 7,759,-359 (“the '359 Patent”), entitled “Method Of Treating Bladder Dysfunction With Once-a-Day Trospium Salt Formulation,” naming Argaw Kidane, Henry H. Flanner, Padmanabh Bhatt, and Arash Raoufínia as inventors, was issued on July 20, 2010.

17. United States Patent Number 7,781,-448 (“the '448 Patent”), entitled “Once Daily Dosage Forms Of Trospium,” naming Argaw Kidane, Henry H. Flanner, Padmanabh Bhatt, and Arash Raoufínia as inventors, was issued on August 24, 2010.

18. United States Patent Number 7,763,-635 (“the '635 Patent”), entitled “Once Daily Dosage Forms of Trospium,” naming Argaw Kidane, Henry H. Flanner, Padmanabh Bhatt, and Arash Raoufínia as inventors, was issued on July 27, 2010.

19. The applications that matured into the '359, '448, '449, and '635 Patents are continuations of Application Number 10/980,818, which matured into the '978 Patent.

20. Supernus is the assignee of the '978, '359, '448, '449, and '635 Patents (“the patents-in-suit”). Allergan and Endo hold licensing, development, and commercialization rights to the patents-in-suit.

21. The patents-in-suit are listed in the Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”) at the FDA in connection with SANCTURA XR®.

22. SANCTURA XR® is a commercial version of trospium and is available in the United States.

23. Allergan markets SANCTURA XR®, which is covered by at least one asserted claim of each of the patents-in-suit.

24. SANCTURA XR® is a 60 mg once-daily trospium extended-release formulation capsule for the treatment of OAB, and is comprised of both extended release (“XR1”) and delayed release (“DR2”) pellets.

25. The XR1 pellets are coated with release controlling ethyleellulose polymer to provide for a slow and steady release and the DR2 pellets are coated with Eudragit FS30D, enteric polymer designed to release at a pH 7.0, such that it will release in the colon and the lower gastrointestinal (“GI”) tract.

26. Dissolution data in SANCTURA XR®’s New Drug Application (“NDA”) and blood level data from clinical trials reported in the patents-in-suit are consistent with release in the lower GI tract.

27. The SANCTURA XR® label contains single dose pharmacokinetic data obtained from NDA study IP631-020 and the corresponding steady state Cmin blood level is 418.6 pg/ml and steady state Cm3X blood level is 1873 pg/ml, which occurs at a Tmax of 4.796 hours. These blood levels are within the range of approximately 0.5 ng/ml to about 6.0 ng/ml, with a C,^ above about 0.5 ng/ml and a Cmax below about 6.0 ng/ml, and a Cmax below 24000 ng/ml.

28. SANCTURA XR® has comparable efficacy to SANCTURA®, the twice-aLday immediate release 20 mg trospium product, but has a better “safety profile,” including a reduction in “dry mouth.” The incidence of dry mouth reported on the SANCTURA XR® label is 10.7%, which is about half that of the immediate release trospium product SANCTURA®.

i. The Asserted Claims

29. The plaintiffs are asserting claims 1, 2, 4, 18, 19, and 20 of the '978 Patent against all defendants.

30. The plaintiffs are asserting claims 1, 10, and 16 of the '448 Patent against all defendants.

31. The plaintiffs are asserting claims 1, 10, and 18 of the '449 Patent against all defendants.

32. The plaintiffs are asserting claim 1 of the '359 Patent against all defendants.

33. The plaintiffs assert that the claims of the '978 and '448 Patents are directed to pharmaceutical compositions, which the defendants directly infringe.

34. The plaintiffs assert that the claims of the '359 and '449 Patents are method claims, which the defendants infringe by inducement.

ii. '978 Patent, Claim 1

35. Claim 1 of the '978 Patent reads:

A pharmaceutical composition suitable for once-a-day administration of trospium chloride comprising controlled release solid, trospium chloride-bearing particulates, at least a portion of which releases trospium chloride in the lower gastrointestinal (GI) tract, such that once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium that are comparable to steady state blood levels of trospium achieved with twice daily administration of 20 mg immediate release trospium chloride tablets, said particulates comprising at least one polymer selected from enteric polymers, release controlling polymers, or combinations thereof.

iii. '978 Patent, Claim 2

36. Claim 2 of the '978 Patent reads: The composition of claim 1, in which once-a-day administration of said controlled release pharmaceutical composition provides steady state blood levels of trospium in the range of about 0.5 ng/ml to about 6.0 ng/ ml.

iv. '978 Patent, Claim 4

37. Claim 3 of the '978 Patent reads: The composition of claim 2, in which once-a-day administration of said controlled release pharmaceutical composition provides steady state blood Cmax levels of trospium in the range of about 2.5 ng/ml to about 4:5 ng/ml and Cmin levels of trospium in the range of aout 0.5 ng/ml to about 1.5 ng/ml.

v. '978 Patent, Claim 18

38. Claim 18 of the '978 Patent reads: A pharmaceutical composition comprising trospium chloride as at least one active pharmaceutical ingredient in which at least a portion of said trospium chloride is contained in a delayed release formulation, which releases trospium chloride in the lower GI tract, said delayed release formulation comprising at least one enteric polymer.

vi. '978 Patent, Claim 19

39. Claim 19 of the '978 Patent reads: The composition of claim 1 or claim 18, wherein said lower GI tract is the colon.

vii. '978 Patent, Claim 20

40. Claim 20 of the '978 Patent reads:

A pharmaceutical composition suitable for a once-a-day administration of trospium chloride comprising controlled release solid, trospium chloride-bearing particulates, at least a portion of which releases trospium chloride in the ileum, colon or both, such that once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium in the range of about 0.5 ng/ml to about 6.0 ng/ml, said particulates comprising at least one polymer selected from enteric polymers, release controlling polymers, or combinations thereof.

viii. '448 Patent, Claim 1

41. Claim 1 of the '448 Patent reads:

An oral pharmaceutical composition suitable for once-a-day administration of trospium, comprising first trospium containing component comprising at least one component selected from the group consisting of an extended release (XR) component and a delayed release (DR) component and a second trospium containing component comprising at least one component selected from the group consisting of an extended release (XR) component, a delayed release (DR) component, and an immediate release component, wherein the first and second trospium containing components are different from each other, and wherein said composition at once-a-day administration provides steady state blood levels of trospium of a minimum of about 0.5 ng/ml and a maximum of about 6.0 ng/ ml; comprises from 25 to 80 mg of trospium chloride and at least one polymer selected from the enteric polymers, release controlling polymers, or combinations thereof, and wherein at least a portion of which releases trospium in the lower gastrointestinal (GI) tract.

ix. '448 Patent, Claim 10

42. Claim 10 of the '448 Patent reads: The composition of claim 1, which is a combination of an XR trospium component and a DR trospium component.

x. '448 Patent, Claim 16

43. Claim 16 of the '448 Patent reads: The composition of claim 1, wherein said DR component releases trospium at a pH of about 7.0.

xi. '449 Patent, Claim 1

44. Claim 1 of the '449 Patent reads:

A method of treating a bladder dysfunction in a mammal comprising an oral administration to said mammal of a once-a-day dose of a pharmaceutical composition comprising 25 to 80 mg of trospium chloride for at least a time sufficient to ameliorate said dysfunction, wherein at least part of the trospium chloride is contained in an extended release (XR) component or in a delayed release (DR) component, wherein said composition comprises at least one polymer selected from enteric polymers, release controlling polymers, or combinations thereof, wherein at least a portion of said composition releases trospium chloride in the lower gastrointestinal (GI) tract, wherein said administration provides steady state blood levels of trospium of a minimum of about 0.5 ng/ml and a maximum of about 6.0 ng/ ml, and results in minimizing the occurrence of side effects as compared to twice daily administration of 20 mg of immediate release trospium chloride tablets; and wherein said bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturia, and urge-incontinence due to detrusor instability, urge syndrome, and detrusor hyperreflexia. xii.

xii. '449 Patent, Claim 10

45. Claim -10 of the '449 Patent reads: The method of claim 1, wherein said composition is a combination of an XR trospium chloride component and a DR trospium chloride component.

xiii. '449 Patent, Claim 18

46. Claim 18 of the '449 Patent reads: The method of claim 1, wherein said side effects are selected from a group consisting of dry mouth, headache, constipation, dyspepsia, abdominal pain, and a combination thereof.

xiv. '359 Patent, Claim 1

47. Claim 1 of the '359 Patent reads:

A method for treating a bladder dysfunction in a patient comprising orally administering to a patient suffering from a bladder dysfunction a once-a-day dosage formulation of a pharmaceutically acceptable salt of trospium (Tr +) comprising at least one component selected from the group consisting of an extended release (XR) and a delayed release (DR) component;

wherein at least a portion of said formulation releases trospium chloride in the lower gastrointestinal (GI) tract;

which formulation provides an average Cmax at steady state of less than 2400 pg/ml of Tr + at a Tmax of less than 6 hours; and

wherein the bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturina, urge-in-continence associated with detrusor instability, urge syndrome, and detrusor hyperreflexia.

2. The Accused Products

i. ANDA No. 91-289 Submitted by Watson

48. Watson submitted an Abbreviated Drug Application (“ANDA”) No. 91-289 to the FDA under § 505Q) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 355(j), seeking approval to engage in the commercial manufacture, use, or sale of trospium extended-release capsules, 60 mg (“the Watson Product”), prior to the expiration of the '978 Patent.

49. The Watson Product is an extended release capsule that contains two populations of extended release pellets, with each capsule containing 60 mg of trospium. Trospium is the active pharmaceutical ingredient in the Watson Product. The first population of pellets in the Watson Product (“Pellets-1”) has an ethylcellulose coating that modifies release of the active ingredient. The second population of pellets in the Watson Product (“Pellets-2”) has an Eudragit FS30D coating designed to modify release of the active ingredient.

50. Pellets-1 are trospium-bearing pellets coated with a release controlling polymer and Pellets-2 are trospium-bearing pellets coated with three different coating suspensions. The first is a polymeric film including Eudragit FS30D, the second is a talc suspension, and the third is a talc-Opadry II clear coating suspension.

51. Watson submitted the results from two in vivo bioavailability studies to the FDA to demonstrate bioequivalence between the Watson Product and SANCTURA XR®. Based on the results of its bioequivalence studies, Watson concluded that its proposed generic capsules are bioequivalent to SANCTURA XR® under both fasted and fed conditions.

52. The proposed product label for the Watson Product states that the capsules are indicated for “the treatment of [OAB] with symptoms of urge urinary incontinence, urgency, and urinary frequency.” The proposed label for the Watson Product also states that the recommended dosage is one 60 mg capsule daily in the morning. The proposed label further states that it should be dosed with water on an empty stomach, at least one hour before a meal.

53. In sum, ANDA No. 91-289 seeks approval to market trospium extended release capsules for the treatment of overactive bladder with symptoms of urge incontinence, urgency, and urinary frequency.

54. On June 1, 2009, Watson sent the plaintiffs a letter, as a paragraph IV notice, stating that it had submitted its ANDA No. 910289 to the FDA seeking approval to engage in the commercial manufacture, use, or sale of the Watson Product prior to the expiration of the '978 Patent. Watson’s letter also stated that the '978 Patent is invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the Watson Product.

55. The plaintiffs brought suit against Watson alleging infringement of the '978 Patent under 35 U.S.C. § 100 et seq, including §§ 271(e)(2) and 271(b), and 28 U.S.C. §§ 2201 and 2202 on July 13, 2009, within forty-five days of receipt of Watson’s paragraph TV letter.

56. On August 24, 2009, Watson filed counterclaims for declaratory judgment of noninfringement and invalidity of the '978 Patent. On July 23, 2010, Watson asserted an additional counterclaim for declaratory judgment of unenforceability of the '978 Patent.

57. Watson sent the plaintiffs a letter dated August 17, 2010, stating that Watson had submitted an amendment to ANDA No. 91-289 to the FDA seeking approval to engage in the commercial manufacture, use, or sale of the Watson product prior to the expiration of the '359 and '635 Patents. This letter also stated that the '659 and '635 Patents are invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the Watson Product.

58. Watson sent the plaintiffs another letter on September 10, 2010, stating that it had submitted an amendment to its ANDA to the FDA seeking approval to engage in the commercial manufacture, use, or sale of the Watson Product prior to the expiration of the '448 and '449 Patents, and that these patents were invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the Watson Product.

59. The plaintiffs brought suit against Watson alleging infringement of the '448 and '449 Patents under 35 U.S.C. § 100 et seq, including §§ 271(e)(2) and 271(a), and 28 U.S.C. §§ 2201 and 2202 on October 5, 2010, within forty-five days of receipt of Watson’s paragraph IV letter.

60. On October 27, 2010, Watson filed counterclaims for declaratory judgment of noninfringement and invalidity of the '359, '448, '449, and '635 Patents.

61. On December 27, 2010, the plaintiffs filed counterclaims for declaratory judgment of infringement of the '359 Patent under 35 U.S.C. § 100 et seq, including §§ 271(e)(2) and 271(a), and 28 U.S.C. §§ 2201 and 2202.

ii. ANDA No. 91-635 Submitted by Sandoz

62. Sandoz submitted an ANDA to the FDA under § 505(j) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 355(j). The ANDA seeks FDA approval for the commercial manufacture, use, and sale of generic trospium extended-release capsules, containing 60 mg of trospium (“the Sandoz Product”). ANDA No. 91-635 specifically seeks FDA approval to market the Sandoz Product before the expiration of the '978 Patent.

63. According to its ANDA, the Sandoz Product is a trospium extended release capsule containing two types of extended release pellets (“ER pellets”) and two types of delayed release pellets (“DR. pellets”). The active pharmaceutical ingredient is Sandoz’s proposed trospium extended release capsules is trospium.

64. Sandoz’s ANDA states that its generic “Trospium Chloride ER Capsules 60 mg have been designed as a combination of two delayed release pellets and two extended release pellets mixed in a specific ratio to produce a release profile that mimics the RLD [SANCTURA XR®] product.”

65. - In Sandoz’s Product, both of the ER pellets are trospium-bearing pellets coated with a Surelease E7-19010 coating. Sure-lease E7-19010 is an aqueous dispersion of ethylcellulose. One of the ER pellets (“ER1”) has a 15% Surelease E7-19010 coating and the other ER pellet (“ER2”) has a 24% Surelease E7-19010 coating. According to Sandoz’s ANDA, the extended release pellets are designed to create a pH independent drug release covering the extent of the GI tract.

66. The DR pellets are trospium-bearing pellets that both contain Eudragit FS30D in their enteric coating. One of the two types of DR pellets (“DR2”) is coated only with Eudragit FS30D enteric coating, at a coating level of about 26%. The other type of DR pellet (“DR1”) is coated with an enteric composition of Eudragit L30D55 and Eudragit FS30D, at a coating level of about 1.2% and 24%, respectively.

67. Sandoz’s ANDA states that “[t]he Sandoz product was designed with components to obtain similar release rates compared to the RLD. Dissolution testing of the RLD demonstrated that the product released at different rates in different media and the chosen ratio of pellets in the Sandoz product matched the RLD.” The ANDA further states that “[t]he Enteric 1 pellets have virtually no release in the stomach (pH 1-5) and target a slow drug release throughout the small intestine (pH 5.5 to < 7) pulsing the remaining drug substance at the beginning of the large intestine (pH > 7). The Enteric 2 Pellets have virtually no release of the drug substance in the stomach, a slight release throughout the small intestine and immediate release of drug substance at the beginning of the large intestine.”

68. Sandoz’s ANDA states that “[e]aeh ER pellet formulation is very similar exception one has a 15% Surelease E7-19010 (aqueous ethylcellulose) coating whereas the other ER pellet has a 25% coating. The combination of ER pellets produces a specific pH independent drug release throughout the [GI] tract.”

69. Sandoz’s ANDA states that “[w]hen used alone (Enteric 2), Eudragit FS30D has little to no permeability of the coating up to about pH of 7.0 and then the coating dissolves rapidly releasing the drug substance.”

70. Sandoz submitted the results from two in vivo bioavailability studies to the FDA to prove that its proposed generic capsules are bioequivalent to SANCTURA XR®. Based on the results of its bioequivalence studies, Sandoz concluded that its proposed generic capsules are bioequivalent to SANCTURA XR® under both fasted and fed conditions.

71. Sandoz’s proposed label states that its capsules are indicated for “the treatment of [OAB] with symptoms of urge urinary incontinence, urgency, and urinary frequency.” Sandoz’s proposed label states that the recommended adult dose for most patients is one 60 mg capsule once a day, dosed with water on an empty stomach.

72. The Sandoz Product has the same dosage form, route of administration, dosing regimen, and indication as SANCTURA XR®.

73. ANDA No. 91-635 seeks approval to market trospium extended release capsules for the treatment of OAB with symptoms of urge incontinence, urgency, and urinary frequency.

74. On or about November 4, 2009, the plaintiffs received a letter stating that San-doz had submitted its ANDA No. 91-635 to the FDA under § 505(j) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(j), seeking to market the Sandoz Product prior to the expiration of the '978 Patent. Sandoz’s paragraph TV letter stated that the '978 Patent is invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the drug product described in its ANDA.

75. Plaintiffs brought suit against Sandoz alleging infringement of the '978 Patent under 35 U.S.C. § 100 et seq., including §§ 271(e)(2) and 271(a), and 28 U.S.C. §§ 2201 and 2202 on November 19, 2009, within forty-five days of receipt of San-doz’s paragraph IV letter.

76. On or about November 24, 2010, the plaintiffs received a letter, dated November 23, 2010, stating that Sandoz had submitted an amendment to its ANDA to the FDA with a paragraph IV certification seeking FDA approval for the commercial manufacture, use, and sale of the Sandoz product prior to the expiration of the '359, '448, and '449 Patents. Sandoz’s paragraph IV letter stated that these additional patents were invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the Sandoz Product.

77. The plaintiffs brought suit against Sandoz alleging infringement of the '359, '448, and '449 Patents under 35 U.S.C. § 100 et seq, including §§ 271(e)(2) and 271(a), and 28 U.S.C. §§ 2201 and 2202 on January 22, 2011, within forty-five days of receipt of Sandoz’s paragraph IV letter.

iii. ANDA No. 20-1291 Submitted by Paddock

78. Paddock submitted ANDA No. 20-1291 to the FDA under § 505(j) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 355(j), seeking FDA approval for the commercial manufacture, use, or sale in the United States of generic trospium extended release capsules, containing 60 mg of trospium (“the Paddock Product”) prior to the expiration of the '978 Patent.

79. ANDA No. 20-1291 states that the Paddock Product is a trospium extended-release capsule that contains three small tablets, with each capsule containing 60 mg strength of trospium and that trospium is the active pharmaceutical ingredient.

80. According to Paddock’s ANDA, trospium and excipient, including magnesium aluminum silicate, stearic acid, and talc, are formed into granules using a binding solution of povidone and sodium chloride in purified water. The granules are dried, blended and sifted with talc, stearic acid, colloidal silicon dioxide, and magnesium stearate, and then compressed into tablets. Two-thirds of the tablets are coated with Eudragit L30D55.

81. Paddock submitted the results from two in vivo bioequivalence studies to the FDA to prove that its proposed generic capsules are bioequivalent to SANCTURA XR®. Based on the results of its bioequivalence studies, Paddock concluded that its proposed generic capsules are bioequivalent to SANCTURA XR® under both fasted and fed conditions.

82. Paddock’s proposed label states that its capsules are indicated for “the treatment of [OAB] with symptoms of urge urinary incontinence, urgency, and urinary frequency,” and that the recommended dose for most patients is one 60 mg capsule once a day, dosed with water on an empty stomach, at least one hour before a meal.

83. In sum, ANDA No. 20-1291 seeks approval to market trospium extended-release capsules in the United States for treatment of OAB with symptoms of urge incontinence, urgency, and urinary frequency.

84. On or about April 27, 2010, the plaintiffs received a letter dated April 26, 2010, stating that Paddock submitted ANDA No. 20-1291 to the FDA seeking approval for the commercial manufacture, use, or sale of a generic trospium extended release product prior to the expiration of the '978 Patent. Paddocks’ paragraph IV letter stated that the '978 Patent was invalid and/or will not be infringed by the commercial manufacture, use, or sale of the Paddock Product.

85. The plaintiffs brought suit against Paddock alleging infringement of the '978 Patent under 35 U.S.C. § 100 et seq, including §§ 271(e)(2) and 271(b), and 28 U.S.C. §§ 2201 and 2202 on June 9, 2010, within forty-five days of receipt of Paddocks’ paragraph IV letter.

86. On July 7, 2010, Paddock filed counterclaims for declaratory judgment of non-infringement and invalidity on the '978 Patents.

87. On or about August 19, 2010, the plaintiffs received a letter, dated August 18, 2010, stating that Paddock submitted an amendment to its ANDA to the FDA with a paragraph IV certification seeking FDA approval for the commercial manufacture, use, or sale of the Paddock Product prior to the expiration of the '359 and '635 Patents. Paddock’s paragraph IV letter also stated that the '359 and '635 Patents were invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the Paddock Product.

88. On or about September 14, 2010, the plaintiffs received another letter, dated September 13, 2010, stating that Paddock had submitted an amendment to its ANDA to the FDA with a paragraph IV certification seeking FDA approval for the commercial manufacture, use, or sale of its Paddock Product in the United States pri- or to the expiration of the '448 and '449 Patents. Paddock’s paragraph IV letter also stated that the '448 and '449 Patents were invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the Paddock Product.

89. The plaintiffs brought suit against Paddock alleging infringement of the '448 and '449 Patents under 35 U.S.C. § 100 et seq, including §§ 271(e)(2) and 271(b), and 28 U.S.C. §§ 2201 and 2202 on October 5, 2010, within forty-five days of receipt of Paddocks’ paragraph IV letter.

90. On October 28, 2010, Paddock filed counterclaims for declaratory judgment of noninfringement and invalidity on the '978, '359, '635, '448, and '449 Patents, and on November 2, 2010, filed counterclaims for declaratory judgment of non-infringement and invalidity on the '359, '635, '448, and '449 Patents.

91. The plaintiffs filed counterclaims against Paddock alleging infringement of the '359 Patent under 35 U.S.C. § 271(a), (b), (e)(2), and (g), and 28 U.S.C. §§ 2201 and 2202 on December 27, 2010.

92. The plaintiffs do not assert that Paddock infringes any claim of the '635 Patent.

D. Procedural History

93. The plaintiffs filed their Complaint for patent infringement against Watson Pharmaceuticals Inc., Watson Laboratories Inc.—Florida, and Watson Pharma, Inc. (collectively, “Watson”) on July 13, 2009, in what was labeled the 09-cv-511 action.

94. In separately-captioned actions, the plaintiffs filed complaints for patent infringement against Sandoz, 09-cv-882, and Paddock, 10-cv-501, on November 19, 2009 and June 9, 2010, respectively.

95. The plaintiffs’ action against Watson was consolidated with the Sandoz action on March 22, 2010 and consolidated with the Paddock action on September 21, 2010.

96. The plaintiffs filed an Amended Complaint for patent infringement against Paddock in the consolidated action on October 14,2010. (D.I. 75.)

97. The court held a seven-day bench trial in this matter on May 2 through May 10, 2011 (D.I. 204-210).

III. DISCUSSION AND CONCLUSIONS OF LAW

The court has subject matter jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331, 1338, and 2201. Venue is proper in this court under 28 U.S.C. §§ 1391 and 1400(b). After having considered the entire record in this case, the substantial evidence in the record, the parties’ post-trial submissions, and the applicable law, the court concludes that: (1) all asserted claims of the patents-in-suit are invalid due to obviousness; (2) the asserted claims of the patents-in-suit are not invalid due to anticipation; (3) claim 1 of the '978 Patent and claim 1 of the '449 Patent are not invalid due to indefiniteness; (4) claim 1 of the '359 Patent is not invalid due to written description; (5) the defendants’ proposed products infringe the asserted claims of the patents-in-suit; and (6) each of the parties’ Rule 52(c) motions are granted in part and denied in part. The court’s reasoning follows.

A. Obviousness

The defendants challenge the validity of each of the asserted claims as obvious in light of the prior art. The court finds, for the reasons that follow, that the defendants have established by clear and convincing evidence that the patents-in-suit are, in fact, obvious.

1. The Legal Standard

35 U.S.C. § 103(a) provides that a patent may not be obtained “if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious to a person having ordinary skill in the art.” 35 U.S.C. § 103(a). Obviousness is a question of law that is predicated on several factual inquires. See Richardson-Vicks v. Upjohn Co., 122 F.3d 1476, 1479 (Fed.Cir.1997). Specifically, the trier of fact is directed to assess four considerations: (1) the scope and content of the prior art; (2) the level of ordinary skill in the art; (3) the differences between the claimed subject matter and the prior art; and (4) secondary considerations of non-obviousness, such as commercial success, long felt but unsolved need, failure of others, acquiescence of others in the industry that the patent is valid, and unexpected results. See Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966).

A party seeking to challenge the validity of a patent based on obviousness must demonstrate by “clear and convincing evidence” that the invention described in the patent would have been obvious to a person of ordinary skill in the art at the time the invention was made. Importantly, in determining what would have been obvious to one of ordinary skill in the art, the use of hindsight is not permitted. See KSR Intern. Co. v. Teleflex, Inc., 550 U.S. 398, 421, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (cautioning the trier of fact against “the distortion caused by hindsight bias” and “arguments reliant upon ex post reasoning” in determining obviousness). In KSR, the Supreme Court rejected the rigid application of the principle that there should be an explicit “teaching, suggestion, or motivation” in the prior art, the nature of the problem, or the knowledge of a person having ordinary skill in the art, in order to find obviousness. See KSR, 550 U.S. at 415, 127 S.Ct. 1727. The KSR Court acknowledged, however, the importance of identifying “ ‘a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does’ in an obviousness determination.” Takeda Chem. Indus. v. Alphapharm Pty. Ltd., 492 F.3d 1350, 1356-57 (Fed.Cir.2007) (quoting KSR, 550 U.S. at 418, 127 S.Ct. 1727).

“Obviousness does not require absolute predictability of success,” but rather, requires “a reasonable expectation of success.” See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed.Cir.2006) (quoting In re O’Farrell, 853 F.2d 894, 903-04 (Fed.Cir.1988)). To this end, obviousness “cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed.Cir.2007). Moreover, while the Federal Circuit has noted that pharmaceuticals can be an “unpredictable art” to the extent that results may be unexpected, it also recognizes that, per KSR, evidence of a “finite number of identified, predictable solutions” or alternatives “might support an inference of obviousness.” See Eisai Co. Ltd. v. Dr. Reddy’s Labs. Ltd., 533 F.3d 1353, 1359 (Fed.Cir.2008). .

2. The Level of Ordinary Skill in the Art

A person of ordinary skill in the art with respect to the patents-in-suit would have: (1) a Ph.D. in pharmaceutics, pharmacy, chemistry, or a related field, several years of experience formulating and evaluating dosage forms, and would have participated as a member of a development team, though “[e]xtensive practical experience could be substituted for the relevant degrees”; or (2) a B.S. in pharmacy or a similar field with several years of formulation experience or a Ph.D. with a few years of experience and, at least one year of experience working with controlled release dosage forms. The court concludes that the parties’ definitions of a person of ordinary skill in the art do not differ in a meaningful way.

3. The Scope and Content of the Prior Art and Differences Between the Claimed Subject Matter and the Prior Art

As an outset consideration, it is important to identify what the asserted claims of the patents-in-suit cover and what they do not. The court notes that the claims do not cover a new drug, a new method of treatment, or novel ways of formulating trospium. In fact, Madaus, a German company, had been selling trospium in an immediate release form in Europe since 1967. Interneuron, now called Indevus, acquired the U.S. rights to trospium in 1999 and began selling an immediate release, twice-daily dosage trospium in the United States under the name SANCTURA®. Here, the claims cover an invention that “is directed to pharmaceutical compositions that allow for once daily dosage forms of trospium.” See generally '978 Patent. The patent states that a once-a-day administration of trospium is “advantageous over the twice-a-day administration in terms of both patient compliance and reduced adverse events, thus providing better treatment” of OAB. Id. at col. 1:66-2:2.

Both at trial and in their post-trial briefings, the plaintiffs focus their non-obviousness arguments on the fact that trospium is a quaternary ammonium, which renders the compound positively charged and, as a result, leads to negligible colonic absorption. Specifically, the plaintiffs assert that, for the defendants to meet their burden of demonstrating, by clear and convincing evidence, that the patents-in-suit are obvious, they must show that “each of the limitations can be found in the prior art and that there was a reason to combine the prior art to make the claimed inventions with a reasonable expectation of success.” (D.I. 203 at 26.) The plaintiffs contend that the defendants cannot make this showing because trospium’s lack of colonic absorption and challenging attributes made use of the molecule in a once-a-day formulation non-obvious to a person of ordinary skill in the art. This issue dominated the parties’ invalidity arguments at trial. Consequently, although the court concludes that the prior art renders every element of the asserted claims obvious, it will focus its discussion on how trospium was viewed as a potential candidate for once-a-day formulation by a person of ordinary skill in the art in 2002 based on its quaternary ammonium properties.

As noted, unlike Ditropan and Detrol, the two mainstay OAB drugs available in 2002, SANCTURA XR® utilized trospium, a quaternary ammonium. The plaintiffs assert that the following trospium attributes make it a challenging molecule to use in a once-a-day formulation: (1) permanent positive charge; (2) negligible colonic absorption, particularly in view of the thirty-percent colonic absorption “threshold” required for a successful once-a-day formulation; (3) paracellular absorption; (4) wide range of variable half-life values; and (5) binding to mucus and feces. (D.I. 203 at 28.) During the years preceding the filing of these applications, however, a number of prior art references appeared disclosing, among other things: multiparticulate formulations using extended, delayed, and immediate release pellets; multiparticulate formulations designed to target the lower GI tract; properties of trospium that made it a good candidate for once-a-day formulation, such as its relatively long half-life; and the market drive to formulate once-daily formulations. A number of these references suggested that trospium could be used in a once-a-day formulation. The court discusses each of the prior art references presented at trial below,

a. Prior Art Addressing Multiparticulate Formulations to Target Drug Delivery Along the GI Tract & Prolong Release

Multiparticulate formulations designed to target release in the lower GI tract were standard technology in the prior art in 2002. As explained by Dr. Kibbe, Watson’s expert, multiparticulate formulation refers to a type of dosage form in which there can be different kinds of release within the same capsule. Tr. at 870:4-18 (Kibbe). For instance, a formulator can have “an immediate release segment, an extended release segment, a delayed release segment, and extended release with a delayed release coating.” Id. Dr. Kibbe testified that, as of 2002, those of ordinary skill in the art: (1) were familiar with the materials and methods used to make multiparticulate formulations, including excipients to control release; (2) could examine numerous prior art publications that described particulates with active ingredients coated with enteric polymers, release controlling polymers, or combinations thereof; and (3) would be aware that the prior art taught methods to target the lower GI tract by utilizing release controlling polymers. Id. at 871:9-872:2; 1034:9-1035:7. Notably, even the plaintiffs’ expert, Dr. Davis, stated that formulations using extended and delayed release pellets were “well-known systems that had been described in the literature and in patents,” and that a person of skill in the art could effectively select and combine polymers to target drug release in the GI tract. See id. at 1472:7-11, 1475:12-1476:14, 1520:8-14 (Davis).

One such prior art reference is the 1975 edition of Remington’s Science and Practice of Pharmacy, which lists more than thirty long-acting multiparticulate dosage forms. Dr; Kibbe testified that multiparticulate dosages have been used since the 1950s and that the long-acting products listed in Remington are “long-acting because they contain coated or slow release beads.” Id. at 867:9-21 (Kibbe). Dr. Kibbe also identified two FDA-approved prior art products having multiparticulate dosage forms, Shire’s Carbatrol® and Adderall XR®. (D.I. 202 at 3.) Both products employed Shire’s “Microtol platform,” which is the same platform Shire used in developing once-a-day trospium. Tr. at 375:13-376:3 (Kidane); see also id. at 1349:25-1350:16 (Bhatt).

Specifically, Carbatrol®, developed by Shire in 1997, combines immediate, extended, and delayed release pellets in a single capsule and, per its Orange Book U.S. Patent No. 5,326,570 (the “ '570 Patent”) specification, the extended release pellets can be coated with ethyleellulose and hydroxypropyl methylcellulose. See DTX-2075 at 3; '570 Patent at col. 6:21-27, 6:34-40; Tr. at 872:3-13, 875:8-21 (Kibbe). The '570 Patent also reveals that the delayed release pellets can be coated with polymers such as methyl methacrylate, which is often referred to as Eudragit. See '570 Patent at col. 7:16-25, 7:30-36; see also Tr. at 876:2-9 (Kibbe). Dr. Kibbe testified that a person of ordinary skill in the art would have known that this polymer blend can be adjusted to control the release of the drug. Tr. at 875:22-876:1 (Kibbe). Finally, the '570 Patent also teaches that a combination of immediate, extended, and delayed release pellets releases carbamazepine for approximately twelve hours, which allows it to be administered twice-a-day rather than four times a day. See DTX-1014 at Fig. 1. In light of Dr. Davis’ testimony regarding transit times of pellets through the GI tract in the fasted state, a person of ordinary skill in the art could conclude that Carbatrol® would be expected to release the drug in the ileum and the colon.

In response to this reference, the plaintiffs assert that Carbatrol® and the '570 Patent do not teach that a once-a-day trospium product could prove successful because Cabatrol® is a tertiary amine that is only available in a twice-daily extended release dosage form and Shire was not able to make a once-daily formulation. DTX-1158; DTX-2075; Tr. at 872:14-17, 1071:23-1072:3, 869:16-17, 1072:4-1073:8 (Kibbe). The plaintiffs also note that Dr. Kibbe acknowledged on cross-examination that Carbatrol® “wouldn’t meet a lot of the claims” of the patents-in-suit “for a lot of reasons, one of which is that it’s a completely different drug ... [and that] you have to take into account the nature of the drug before you can make a decision that you can move it to a once daily.” (D.I. 203 at 33 (quoting Tr. at 1073:15-24 (Kibbe)).)

The plaintiffs did not, however, establish that the difference in chemical structure between Cabatrol® and trospium would preclude use of multiparticulate dosage forms in developing a once-a-daily formulation, or challenge that substituting trospium for carbamazepinein in this formulation resulted in the claimed invention at issue here. Thus, while the court agrees with the plaintiffs that Carbatrol® would not meet several of the claims of the patents-in-suit because it is not a once-a-day drug, the court does not agree with the plaintiffs’ conclusion that the “Carbatrol® art teaches nothing about once-daily trospium.” (Id.) Instead, the court concludes that, despite the patents-in-suit and Cabratrol® being different formulations, the Carbatrol® art, including the '570 Patent, does teach that multiparticulate formulations can be employed to target release in the lower GI tract by adjusting the polymer blend used to control release of the drug.

Other references that disclosed the use of multiparticulate dosage formulations include two Canadian patent applications, the 2,035,155 application (“the CA '155”) and the 2,403,670 application (“the CA '670”). The CA '155 discloses that using extended release and delayed release pellets in a multiparticulate formulation can target the ileum and the colon. See DTX-1021 at Abstract, page 8:3-25; Tr. at 878:15-880:11 (Kibbe). Specifically, the Abstract to CA '155 states:

The invention provides pharmaceutical compositions with the property of targeted controlled release of active principles which act pharmacologically within the intestine and in particular within the colon and the terminal portion of the ileum. To attain this object the active principle is prepared in multiparticle multidose form and is covered with at least two membranes, one of pH-dependent solubility and the other insoluble but permeable to the intestinal fluids.

While the covered active principle remains in the stomach and in the initial intestinal portion, ie while the pH is less than 5.5, it is not released.

Only when it reaches an environment of higher pH (small intestine or colon) does the pH-dependent membrane dissolve to commence release of the active principle.

From this moment the second membrane, which is pH-independent but impermeable to the intestinal fluids, acts to slow down and control the dissolution of the medicament within the small intestine-colon tract.

DTX-1021 at Abstract. The CA '670 also discloses the use of two different polymer-coated pellets to target release along the GI tract, including the lower intestine, and combining pellets with enteric coatings of different pH sensitivities to target different regions, including the colon. DTX-2029 at Abstract, page 10:1-18; see also Tr. at 880:12-882:12 (Kibbe).

The court rejects the plaintiffs’ assertion that CA '155 does not teach that multiparticulate formulations can be used to target the lower GI tract simply because that application “describes delivery of drug to the lower GI for local, topical action” rather than delivery for absorption. (D.I. 203 at 33.) Specifically, and as the defendants make clear, while CA '155 does not teach absorption in the lower GI tract, it does teach that multiparticulate dosage forms can be used, in combination with coating selections, to target when a drug is released in the lower GI tract. Moreover, the court finds unavailing the plaintiffs’ argument that CA '670 “teaches that [its inventors] did not consider trospium to be one of the many molecules that would lend to once a day extended release formulation” because it was not included in a four page list of possible active ingredients. (Id. at 33-34.)

Similar to the court’s finding with respect to CA '155, the court concludes that a person of ordinary skill in the art would find CA '670 highly relevant to the subject matter of the patents-in-suit because it teaches that polymer-coated pellets can be used to target release in the lower GI tract. Contrary to the plaintiffs’ arguments in connection with these Canadian applications, the court notes that each prior art reference is not required to teach each claim of the patents-in-suit for those patents to be deemed obvious. Consequently, because these applications are relevant in revealing how a skill artisan can target pellet release, the court concludes that these references teach to the multiparticulate claims of the patents-in-suit.

Similarly, another prior art reference, U.S. Patent No. 6,322,819 (“the '819 Patent”), also describes a multiparticulate system for pulsed delivery of a drug throughout the GI tract. See DTX-1016 at Abstract; see also Tr. at 1215:8-1216:15 (Mayersohn). This patent, which is assigned to Shire Laboratories, describes the same “Microtrol platform” that was ultimately employed in the once-a-day trospium formulation. Tr. at 1216:9-15 (Mayersohn); id. at 367:8-11 (Kidane). Moreover, it discloses enteric polymers, including Eudragit, for targeting delivery to the colon by delayed release for a period of time or until the pellets reached a particular pH level. See '819 Patent at col. 2:5-14, 3:57-4:4. Here, again, the court rejects the plaintiffs’ argument that, because the '819 Patent covers amphetamine salts, it “does not teach that there is a reasonable likelihood of success of developing once-daily trospium product as it does not disclose trospium, quaternary ammonium compounds, or any blood levels.” (D.I. 203 at 34.) For the reasons stated above, the court finds that a person of ordinary skill in the art would find this reference relevant to the claimed invention because it discloses targeting the release of multiparticulate formulations in the lower GI tract through the use of enteric polymers.

Finally, the defendants also introduced European Patent Application Nos. 1101490 and 1125586 (collectively, “the Ishibashi Patents”), which were published in 2001. (D.I. 202 at 4; D.I. 203 at 33.) The Ishibashi Patents describe a multiparticulate system for targeting drug release throughout the ileum and the colon, residence time in the GI tract, and disclose how release can be targeted through the use of pH enteric polymers. DTX-1022 at 7:15-17, 2:16-31, 4:35-39; DTX-1023 at 4:21-25; Tr. at 876:10-878:14 (Kibbe); id. at 1215:18-1216:8 (Mayersohn). In addition, the Ishibashi Patents include a list of various possible active ingredients for controlled release formulas and includes trospium among them. Tr. at 877:2-878:14, 1077:20-1078:19 (Kibbe); id. at 1265:1-14 (Mayersohn).

In response, the plaintiffs argue that the Ishibashi Patents are not relevant to the obviousness analysis because they do not discuss “trospium’s unique characteristics, challenges, or any blood levels” and none of the other quaternary ammonium molecules included on the list have been “made into an extended release form.” (D.I. 203 at 33.) With respect to the plaintiffs’ former argument, again, the court finds this reference relevant because it discloses multiparticulate formulation targeted release in the lower GI tract. Regarding the plaintiffs’ latter argument, the court does not find this assertion persuasive because the fact that the other quaternary ammonium molecules listed were not developed into extended release formulations is irrelevant to how a person of skill in the art in 2002 would view the Ishibashi Patents’ disclosures and teachings.

In light of the references examined above, the court finds that the use of multiparticulate dosage forms, including enteric-coated polymers, to target the lower GI tract was obvious in 2002. Notably, even the plaintiffs’ expert Dr. Davis agreed on cross-examination that a person of ordinary skill in the art in 2002 would have an “extensive toolkit” of technologies available for formulating controlled release dosage forms. Tr. at 1470:14-1471:2 (Davis). Dr. Davis also acknowledged that one of skill in the art would be able to use this toolkit to develop dosage forms designed to release a drug in the lower GI tract, specifically the ileum and the colon, and that this artisan would know that a once-a-day formulation would need to be delivered throughout the GI tract. Id. at 1472:7-11, 1520:8-14, 1384:18-1386:8. The court agrees.

In view of the foregoing, the court concludes that: (1) the asserted claims of the patents-in-suit are obvious as they relate to the administration of trospium through a controlled release solid, trospium-bearing particulates; (2) the asserted claims of the patents-in-suit are obvious as they relate to using multiparticulate formulations to target the lower GI tract; (3) claims 1 and 20 of the '978 Patent, claims 1,10, and 16 of the '448 Patent, claims 1 and 10 of the '449 Patent, and claim 1 of the '359 Patent, are obvious as they relate to multiparticulate formulations ; and (4) claims 1, 18, and 20 of the '978 Patent, claim 1 of the '448 Patent, and claim 1 of the '449 Patent, as they relate to using a delayed release formulation comprising at least one enteric polymer to target the lower GI tract, are obvious in light of the references discussed.

b. Prior Art Addressing Trospium’s Attributes That Rendered It a Viable Candidate for Once-a-Day Formulation

In addition to the foregoing, the prior art in 2002 also taught that trospium was a candidate for once-a-day formulation. The testimony of both sides’ experts makes clear that a person of ordinary skill in the art would weigh and consider all known attributes of a molecule before determining whether it is a candidate for a once-a-day formula. See, e.g., Tr. at 1026:21-1027:22, 1073:13-24, 1074:3-13 (Kibbe); id. at 1400:4-24 (Davis). As Dr. Davis explained:

The first thing they would want to do is find out about the drug molecule. What are the properties of the molecule? I referred to this in the past as understand the personality of the molecule. What is its stability? What is its solubility, its partition coefficient? Then what do we know about its pharmacokinetic properties?

So the person that is going to start formulation really start looking at the literature, try to find out as much as possible about the molecule and any deficiencies or any concerns. Is this going to be easy, mediocre, or difficult? To start thinking about the challenge you are going to face.

Id. at 1400:9-24. In light of this testimony, the court concludes that prior art references related to trospium’s characteristics, aside from what the plaintiffs argue is its negligible colonic absorption, are relevant in determining whether trospium would be perceived by one of skill in the art as a once-a-day formulation candidate in 2002. The court further concludes that these references, discussed below, not only showed trospium to be a candidate for once-a-day formulation, but also suggested how formulators could identify steady state blood levels, develop a formulation utilizing known half-life data, and address trospium’s low colonic absorption.

By 2002, there were three references available that identified trospium’s pharmacokinetic parameters, as observed from its long use as an immediate release product: G. Frohlich (DTX-1031), Fusgen (DTX-1033), and Zerres (DTX-1169). Specifically, Frohlich and Fusgen disclosed that trospium is known to have a Cmax of 3-5 ng/ml with a Tmax of about five hours. DTX 1031 at 295; DTX-1031 at 225; see also Tr. at 1010:3-11 (Kibbe). Zerres also disclosed that trospium had a steady state Cmin of about 0.6 ng/ml, steady state Cmax of about 1.9 ng/ml, and an area under the curve (an “AUC”) of 30 ng/ml per hour. Tr. at 1206:25-1207:18 (Mayersohn); id. at 1469:4-16 (Davis). Drs. Kibbe, Mayersohn, and Kidane all testified that a person of ordinary skill in the art would have used these pharmacokinetic parameters, known from immediate release trospium, to establish target blood levels for a once-a-day formulation. Id. at 1038:22-1039:21 (Kibbe); id. at 1207:19-1208:2 (Mayersohn); id. at 296:3-9, 302:5-13 (Kidane).

Specifically, Dr. Kibbe testified that a person of skill in the art seeking to develop a controlled release dosage form would start with the “goal of having a lower Cmax and slightly higher 0^„” than the immediate release formulation and would “establish [concentration] ranges based on the immediate release drug.” Id. at 1035:21-1036:12, 1038:22-1039:21 (Kibbe). Namely, the objective in controlled release formulations, as Dr. Kibbe explained, is to slow absorption such that the “peak shifts to the right,” i.e., the Tmax occurs later and the minimum effective concentration is maintained. Id. at 860:5-18. Dr. Kibbe testified that, because trospium has a “relatively long Tmax, five hours, and a relatively long half-life, 12 to 14 hours,” shifting the peak requires:

only ... a little bit.... We don’t have to move it to where the Cmax comes in at 12 hours or 14 hours, because we know that the half-life is 14 hours. So if we could just move it some, and perhaps move it six hours, we would get levels in the body that would then, because of the long half-life, still stay above the minimum concentrations as we moved it out.

Id. at 1014:4-1016:5. The Fusgen and Zerres references each teach that trospium has a half-life of five to seventeen hours, which is a range considered favorable for a once-a-day formulation because only a small increase in the effective half-life is needed to provide twenty-four hour therapeutic effect. DTX-1033 at 225; DTX-1169; see also Tr. at 1206:25-1208:9, 1215:3-7, 1281:19-1283:15, 1294:11-24 (Mayersohn); id. at 1469:17-22 (Davis).

The plaintiffs maintain that the Frohlich, Fusgen, and Zerres references do not disclose “a once-daily trospium product, releasing trospium in the lower GI tract or that once-daily form of trospium could produce blood levels comparable to the twice-a-day product.” (D.I. 203 at 31.) Specifically, the plaintiffs contend that: (1) the Frohlich reference, a review paper, “noted the low bioavailability of trospium [ ] and differentiated trospium from the two tertiary amine OAB products”; (2) Zerres was “similarly discouraging” in that it reported trospium’s half-life to be in the range of 6.18 hours to 16.76 hours, “evidencing] the difficulty in formulating once daily trospium and the low expectation of success a person of skill would have had in 2003”; and (3) Fusgen reported on trospium’s “low bioavailability, differences from tertiary amines, side effects and observed maximum concentrations for twice a day administration.” (Id.) The plaintiffs also note that Dr. Davis testified that trospium’s reported half-life was a “wide range” that “could be problematic.” Tr. at 1400:25-1401:18 (Davis).

Dr. Mayersohn, however, explained that formulators routinely deal with this level of variability. Id. at 1208:3-9, 1292:25-1294:24 (Mayersohn). In response to Dr. Mayersohn’s comments that trospium’s half-life was in a “normal range,” Dr. Davis stated that he was “not sure that they’re normal, but [he had] not checked the literature.” Id. at 1401:8-18 (Davis). Notably, Dr. Kidane, a member of the Shire development team, also found the half-life of trospium encouraging, stating:

Due to its rather long elimination half-life, this drug would benefit from a slight extension on the absorption phase without significantly compromising its bioavailability. By extending its absorption phase by 4-8 hours, it is possible to achieve an extended release preparation that could be used as a once a day rather than the current twice a day treatment.

JTX-039 at Background. Based on these conclusions, the court disagrees with the plaintiffs’ argument that a person of skill in the art would have found Zerres’ findings as to trospium’s half-life discouraging.

The court notes that the plaintiffs’ argu