GREGORY M. SLEET, Chief Judge.
In this consolidated patent infringement action, plaintiffs Allergan, Inc., Allergan USA, Inc., Allergan Sales, LLC, Endo Pharmaceuticals Solutions Inc., and Supernus 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.
1. Plaintiffs Allergan, Inc., Allergan USA, Inc., and Allergan Sales, LLC (collectively,
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.
10. Trospium chloride (a quaternary ammonium compound with the chemical name of spiro [8-azoniabicyclo[3,2,1]octane-8, 1"-pyrrolidinium]-3-[ (hydrozydiphenyl-acetyl)-oxy] chloride (1α,3β,5α)-(9C1)) 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, SANCTURA XR® is the only product that uses a quaternary ammonium compound in its once-a-day formulation.
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
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 Raoufinia 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 Raoufinia 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 ethylcellulose 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 C
28. SANCTURA XR® has comparable efficacy to SANCTURA®, the twice-a-day 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®.
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.
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.
35. Claim 1 of the '978 Patent reads:
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.
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 C
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.
39. Claim 19 of the '978 Patent reads: The composition of claim 1 or claim 18, wherein said lower GI tract is the colon.
40. Claim 20 of the '978 Patent reads:
41. Claim 1 of the '448 Patent reads:
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.
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.
44. Claim 1 of the '449 Patent reads:
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.
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.
47. Claim 1 of the '359 Patent reads:
48. Watson submitted an Abbreviated Drug Application ("ANDA") No. 91-289 to the FDA under § 505(j) 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
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 IV 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.
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. Surelease
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 L30D-55 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]ach 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 Sandoz 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 IV letter stated that the '978 Patent is invalid, unenforceable, and/or will not be infringed by
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 Sandoz'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.
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
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 prior 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.
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.)
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.
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.
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"
"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).
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"
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
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,
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
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,
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 ethylcellulose
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:
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,
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,
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
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:
Id. at 1400:9-24. In light of this testimony
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
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 C
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
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:
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' arguments, in the main, focus exclusively on how trospium's "negative" attributes are disclosed in these references, rather than on the "positive" attributes and/or useful information also disclosed. For example, in arguing that the Frohlich paper would have been "discouraging" to one of skill in the art because it disclosed trospium's low bioavailability, the plaintiffs neglect to detail that the Frohlich reference also taught trospium's C
Another reference detailing trospium's pharmacokinetic parameters was the Langguth study
In response, the plaintiffs assert that Langguth discouraged development of the claimed invention because it disclosed that "permeability of trospium was low and could not be improved by microemulsion or cyclodextrin complex formulations." (D.I. 203 at 34 (citing Tr. at 1098:14-25; 1100:11-1101:2 (Kibbe)).) The plaintiffs argue that Langguth demonstrated that the absorption mechanism of trospium across the intestinal epithelum is "rather complex," "bioavailability of quaternary parasympatholytics (trospium) is low and variable, and intestinal permeability is low due to positive charge." (Id. (citing JTX-12 at 75607; Tr. at 1246:6-1248:3 (Mayersohn)).) Moreover, the plaintiffs assert that Langguth's suggestion to encourage absorption by adding excess hexamethonium bromide does not teach to the asserted claims because it suggested a compound other than trospium. (Id. at 35.) The plaintiffs cite Langguth's "Conclusion" as evidence that it taught away from the claimed invention:
JTX-012 at 75613. As noted, however, persons of skill in the art would evaluate a drug's positive and negative attributes in assessing whether it can be developed into a once-a-day formulation. To this end, a formulator would not focus exclusively on trospium's low bioavailability, but, rather, would consider this attribute in combination with its other pharmacokinetic parameters as well as references suggesting ways to remedy negative attributes. Consequently, in light of the evidence before it, the court finds the plaintiffs' argument that this study would discourage use of trospium unavailing.
The court also rejects by the plaintiffs' argument that a person of skill in the art would not find this reference or the '357 Patent relevant because they do not suggest the use of excess trospium, for three reasons. First, the Langguth reference suggests the use of a quaternary ammonium and, therefore, the fact that it does not suggest trospium itself is inconsequential. Second, the court finds that the '357 Patent's suggestion of using therapeutically inactive material to reduce mucin binding and absorption would be considered relevant, despite not mentioning the addition of trospium, as it taught a method of enhancing absorption applicable to the
DTX-2175; see also Tr. at 398:11-403:17 (Kidane); id. at 1028:17-1033:4 (Kibbe). This statement, coupled with a September 12, 2002 Shire email citing the Langguth study by name and highlighting its findings, makes clear to this court that the Langguth reference would be considered both relevant and instructive to a person of ordinary skill in the art pursuing the subject matter of the claimed inventions because it taught how to overcome trospium's low colonic absorption. See DTX-2174 at 2.
In light of these references, the court concludes that: (1) claims 1, 2, 4, and 20 of the '978 Patent, claims 1 and 16 of the '448 Patent, claim 1 of the '449 Patent, and claim 1 of the '359 Patent, as they relate to seeking steady state blood levels comparable to the immediate release formulation blood levels, are obvious based on the Frohlich, Fusgen, and Zerres references
By 2002, Distropan and Detrol had been reformulated to once-a-day dosage forms. Rover,
Dr. Kibbe testified that the Rovner reference disclosed that lowering the C
The plaintiffs' cross-examination of Dr. Kibbe was limited to establishing that Rovner reviewed oxybutynin and tolterodine, which are not quaternary ammoniums. Id. at 1063:14-1064:23, 1066:8-11. Dr. Davis' testimony regarding Rovner likewise focused on the distinction that trospium is a quaternary ammonium. Id. at 1413:19-1414:5 (Davis). The plaintiffs did not, however, counter Rovner's findings that the market was moving toward once-a-day formulations by 2002 or that having a lower C
In view of the foregoing, the court concludes that: (1) all of the asserted claims of the patents-in-suit and, in particular, claim 1 of the '978 Patent, as it relates to the development of a once-a-day trospium formulation, are obvious based on the Rovner reference; and (2) claims 1, 10, and 18 of the '449 Patent, as they relate to "minimizing the occurrence of side effects",
The plaintiffs argue that a person of skill in the art in 2002 would not have a reasonable expectation of success that a once-a-day trospium formulation could be developed. Aside from the arguments already addressed, the plaintiffs assert this proposition, in the main, in connection with their contentions that: (1) the Fuhr/Schroder Poster disclosed that trospium, because of its quaternary ammonium structure, has low colonic absorption; and (2) that this low absorption, coupled with trospium's other negative attributes, would lead those of skill in the art to believe that a once-a-day trospium formulation would prove unsuccessful. (D.I. 203 at 27.) With respect to their first argument, the plaintiffs assert that the Fuhr/Schroder Poster taught away from the claimed invention. The court, therefore, addresses the Fuhr/Schroder Poster's conclusions separately in connection with the plaintiffs' "teaching away" argument,
In support of their argument that formulators would have a low expectation of success, the plaintiffs cite to the testimony of Drs. Davis, Derendorf, Mayersohn, and Kibbe, who all noted, to varying degrees, that trospium presented challenges. This testimony included: (1) Dr. Davis' prediction that once-a-day trospium would be difficult to develop (Tr. at 1389:5-8); (2) Dr. Derendorf s assessment that trospium is a "very unusual compound" and a "very, very poorly absorbed drug" (id. at 1005:5-6); (3) Dr. Mayersohn's conclusion that, on a scale of easy to extremely difficult, development of once-a-day trospium would be characterized as "to the right of medium" (id. at 1291:5-14); and (4) Dr. Kibbe's assessment that such development, while not impossible, would be challenging and that these challenges, though not insurmountable, would be difficult (id. at 1022:15-17, 1062:7-22, 1027:18-19, 1062:23-1063:20).
The plaintiffs also state that, as of 2002, persons of skill in the art knew that low colonic absorption, specifically, absorption under the thirty-percent — which was viewed as the threshold for once-a-day formulation success — would make once-daily formulation "very difficult and probably impossible." (D.I. 203 at 28 (citing Tr. at 1428:13-1429:15 (Davis)).) The plaintiffs cite to an article edited by Dr. Park, a Watson expert who did not testify, that described molecules with low colonic absorption
The court, however, disagrees with the plaintiffs' conclusion that recognition of trospium's challenges equated to a low expectation of success. Rather, while trospium's low colonic absorption rendered its development of a once-a-day formulation more challenging than other molecules due to its quaternary ammonium structure, the prior art discussed above makes clear that persons of skill in the art had numerous references available that addressed trospium's positive attributes as well as how to remedy trospium's negative attributes.
In light of these prior art references, and accepting as credible Drs. Davis and Kibbe's testimony that a person of skill in the art would evaluate a molecule's positive and negative attributes in determining whether to attempt a once-a-day formulation, the court finds the plaintiffs' argument that a person of skill in the art would not have a reasonable expectation of success unpersuasive. This argument, which focuses primarily on trospium's low colonic absorption, fails to sufficiently weigh trospium's positive attributes that would have been known to skilled artisans or the prior art teachings that disclosed how to overcome recognized absorption challenges.
Notably, and as noted, even Dr. Davis acknowledged that a person of skill in the art in 2002 had an "extensive toolkit" of technologies available for formulating controlled release products and that these technologies could be employed to develop dosage forms to release in the lower GI tract. Id. at 1470:14-1471:2, 1472:7-11, 1520:8-14 (Davis). Dr. Davis further testified that, although he was aware that some references not included in the prior art
The court also notes that Shire's development team was not dissuaded by trospium's challenges and developed the trospium once-a-day formulation in a short period of time. Specifically, Dr. Sandage testified that, in September 2001, Indevus was "very optimistic that we could eventually make a once-a-day" formulation due, at least in part, to trospium's relatively long half-life. Id. at 149:10-151:5, 256:4-257:4 (Sandage). Indevus also told prospective partners that trospium could "easily" be converted into a once-a-day because of this long half-life.
For the reasons stated above, the court concludes that a person of skill in the art in 2002 would have a reasonable expectation of success that, by combining the teachings and disclosures known in the prior art, once-a-day trospium formulation development was possible.
The evidence in the record on several relevant secondary considerations does not weigh for or against a finding of obviousness and, consequently, does not undermine the court's finding that the patents-in-suit are obvious in light of the prior art. Under relevant law, once a prima facie case of obviousness has been established, the burden then shifts to the applicant to present evidence of secondary considerations of non-obviousness to overcome this prima facie showing. See, e.g., In re Huang, 100 F.3d 135, 139 (Fed.Cir.1996). The Supreme Court has made clear that secondary considerations can include evidence of: commercial success; long felt but unsolved needs; and/or the failure of others. See Graham, 383 U.S. at 17-18, 86 S.Ct. 684. A plaintiff may also rebut obviousness by demonstrating that there were: unexpected results created by the claimed invention; unexpected properties of the claimed invention; licenses showing industry respect for the invention; and/or skepticism of skilled artisans before the invention. See In re Rouffet, 149 F.3d 1350, 1355 (Fed.Cir.1998). However, "[e]vidence of commercial success, or other secondary
Here, the plaintiffs contend that the defendants failed to establish a prima facie case of obviousness in light of the evidence adduced at trial. The plaintiffs also argue, in the alternative, that should the court determine, as it has, that the defendants established a prima facie case on this issue, the secondary considerations of copying, teaching away, failure of others, licensing, and unexpected results/skepticism sufficiently rebut this prima facie case. (D.I. 202 at 137); see also Alza Corp. v. Mylan Labs., Inc., 391 F.3d 1365, 1373 n. 9 (Fed.Cir.2004). The court addresses each secondary condition the plaintiffs raise in turn.
The plaintiffs assert that Watson and Sandoz's proposed products are copies of the patented invention. (D.I. 202 at 137.) Specifically, the plaintiffs contend that, like SANCTURA XR®, Watson and Sandoz's proposed products are capsules containing extended release and delayed release pellets. Moreover, the plaintiffs assert that Paddock's proposed product also copies the patented invention, in that it is a capsule that contains extended release and delayed release components intended to release in the lower GI tract and, as Paddock stated to the FDA, was designed to "match" SANCTURA XR®. See PTX-131; Tr. at 644:25-645:14 (Davis). In view of relevant law, however, the court does not agree that the defendants' alleged "copying" rebuts the prima facie case of obviousness.
Specifically, and as several courts have recognized, demonstration that a defendant has copied a patented invention is not compelling evidence of non-obviousness in the Hatch-Waxman context due to the unique nature of the ANDA process. See, e.g., Purdue Pharma Products L.P. v. Par Pharmaceutical, Inc., 642 F.Supp.2d 329, 373-74 (D.Del.2009) ("[A] showing of copying, which Plaintiffs have provided here, is not compelling evidence of non-obviousness in the Hatch-Waxman context."); Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., No. IP 99-38-C H/K, 2001 WL 1397304, at *14 (S.D.Ind. Oct. 29, 2001) ("[T]he ANDA procedures established by the Hatch-Waxman Act require generic drug manufacturers to copy the approved drug. Variations undermine the FDA's ability to assume that if the patented drug is safe and effective, the generic competitor will also be safe and effective."). Consequently, even assuming that the defendants engaged in copying, such conduct is not strong objective evidence of non-obviousness in this action.
The plaintiffs cite the Fuhr/Schroder Poster as teaching away from the claimed invention because it discourages the use of once-daily trospium.
The study ultimately concluded that absorption of trospium from rectal administration, which "can be used as a model of colonic absorption," was only two-percent, far below the thirty-percent colonic absorption threshold generally recommended for successful extended release formulations. (D.I. 203 at 30 (citing JTX-0014 at Table 2).) The plaintiffs assert that these results taught away from the claimed invention because, as stated in the Poster's conclusions, there were "very low concentrations of trospium chloride found after rectal administration," "colonic absorption [was] almost negligible," and, as a result, "modified release preparations of the study drug using conventional technology are not expected to improve trospium chloride bioavailability." (Id. at 30-31 (citing JTX-0014).)
Based on the evidence presented at trial, however, the court concludes that the Fuhr/Schroder Poster does not teach away from the claimed invention. First, the reference itself and the methodology employed both indicate that the study was directed toward improving trospium bioavailability, rather than attempting to target trospium in the lower GI tract through the use of an extended release formulation.
Second, this conclusion is further supported by testimony at trial indicating that the Fuhr/Schroder findings were viewed as speculative, inconclusive, and inconsistent with the known therapeutic effectiveness of trospium suppositories. In particular, this testimony detailed that the scope and methodology of the study limited the validity of its results. The study included a small sample of eight males and placed only five milliliters, the equivalent of one teaspoon, of trospium in the rectum. Drs. Kibbe, Mayersohn, and Flanner, in testimony the court finds credible, questioned the legitimacy of implementing the methodology employed based on the conclusion reached. See Tr. at 1010:17-1011:16, 1020:10-1027:22 (Kibbe); id. at 1210:4-22, 1259:20-1260:20, 1272:9-16 (Mayersohn); id. at 1335:12-1336:9 (Flanner); id. at 1457:5-1462:2, 1462:24-1465:4 (Davis).
Notably, even the plaintiffs' expert, Dr. Davis, stated at trial that: (1) it would be "unlikely" for a five millimeter mini-enema to physically make it from the rectum to the colon (id. at 1462:7-15); (2) he had never employed an enema to evaluate colonic absorption (id. at 1463:12-20); (3) the Fuhr/Schroder Poster was not published in a peer reviewed, scientific journal (id. at 1463:12-20); and (4) the prior art did not demonstrate a correlation between rectal and colonic absorption (id. at 1458:10-1465:4). Drs. Kibbe and Mayersohn concurred with Dr. Davis' assessment that while absorption in the rectum can indicate a drug will be absorbed in the colon, poor absorption in the rectum does not allow a conclusion regarding colonic absorption. Id. at 1023:20-1024:10 (Kibbe); id. at 1259:20-1260:20 (Mayersohn). In addition, various references on trospium suppositories demonstrated that trospium was particularly effective for nocturnal enuresis in children and Dr. Mayersohn testified that this effectiveness "suggests colonic absorption following rectal administration" at least for that test group.
See JTX-038.
In view of the foregoing, the court concludes that the Fuhr/Schroder Poster did not teach away from the asserted claims. Specifically, the plaintiffs' argument that the Fuhr/Schroder study demonstrated negligible trospium absorption in the colon and, therefore, would have discouraged the invention of once-daily trospium, is not grounded in the evidence. Rather, the trial testimony made clear that the study's correlation of rectal to colon absorption, methodology, and conclusions would have been questioned by skilled artisans in 2002. Consequently, the plaintiffs' teaching away argument does not rebut the finding of obviousness.
The plaintiffs further contend that, by 2002, no other inventor or company had successfully formulated trospium into a once-daily dosage, despite the fact that trospium had been marketed in Europe for several decades and there was a motivation to do so. (D.I. 203 at 37.) In support of this argument, the plaintiffs state that: (1) Dr. Kibbe, recognized that there had always been a motivation to develop a once-a-day extended release formulation; (2) Madaus unsuccessfully attempted to develop a modified release trospium formulation; (3) Paddock failed "both pilot and pivotal biostudies before its third formulation attempt," which was the basis for its ANDA; and (4) Mr. Bhalani, a member of Paddock's development team, acknowledged that the project took approximately twenty months longer than expected and was his "most challenging in [his] 30 years of product development experience." (Id.) Based on the evidence presented at trial, however, the court concludes that the plaintiffs' assertions do not undermine its obviousness finding.
First, the plaintiffs have failed to demonstrate that the development of the patents-in-suit met a long felt but unmet need. The plaintiffs cite to the testimony of the defendants' expert, Dr. Kibbe, who stated that the "motivation" to turn the twice-daily dosage to a once-daily formulation "ha[d] been with us for a long time
Second, the plaintiffs' argument that others had attempted to create a once-daily trospium formulation and failed does not rebut the prima facie case of obviousness. In support of this argument, the plaintiffs state that: (1) "Madaus unsuccessfully attempted to develop a modified release trospium chloride formulation"; (2) Paddock twice failed in their pilot and pivotal biostudies before creating the ANDA at issue here; and (3) Mr. Bhalani noted that the project took much longer than expected and was his "most challenging." Tr. at 1140:9-10, 1141:5-14 (Bhalani). With respect the plaintiffs' first contention that Madaus attempted to develop a once-a-day formulation, this evidence, as stated, is not sufficiently established in the record. Specifically, Dr. Sandage's testimony regarding Madaus' work with trospium related not to its attempt to develop a once-daily formulation, but instead to its effort to reduce trospium dosing by doubling the immediate release dosage in a single 80 mg tablet. Id. at 152:11-15 (Sandage). Notably, Madaus' effort to simply double the immediate release dosage is not the claimed invention and does not demonstrate "failure of others" to develop a once-a-day extended release trospium formulation.
Further, and with respect to Paddock's failures during its development of its ANDA, the plaintiffs cite to Mr. Bhalani's testimony that "[o]n the first formulation we did not meet the bioequivalent set out by the FDA," and that, on the second attempt, Paddock "failed again ... although we got fairly close." See id. at 1140:9-10, 1141:5-14 (Bhalani). The plaintiffs join these statements with Mr. Bhalani's testimony that development of the Paddock product was difficult and took longer than anticipated. While Mr. Bhalani did testify that the project was lengthy and difficult, the plaintiffs do not reference his explanation that the difficulty and length of the project did not rest exclusively trospium's challenges, but also on the fact that: creating a "bioequivalent product is difficult" and the "unusual formulation [of the drug] required [him] to modify [the] equipment design." See id. at 1196:13-1198:15. Consequently, though Mr. Bhalani did testify that the development of Paddock's ANDA was difficult, took longer than expected, and proved successful on the development team's third try, the court does not agree that this evidence demonstrate "failure of others" sufficient to undermine the prima facie case of obviousness.
The plaintiffs assert, without developed argument, that Indevus' granting of licenses to Allergan and Madaus to market its once-a-day technology, constitutes a relevant secondary consideration. Id. at 190:1-17; 208:12-209:7 (Sandage); see also PTX-239; JTX0024A. The Federal Circuit has directed that licensing can be taken into account in evaluating secondary considerations, particularly with respect to whether the patentee has received substantial industry recognition or acceptance. See, e.g., EWP Corp. v. Reliance Universal, 755 F.2d 898, 907-08 (Fed.Cir.1985); see also Santarus, Inc. v. Par Pharm., Inc., 720 F.Supp.2d 427, 436 (D.Del.2010). The plaintiffs, however, did not introduce evidence at trial as to revenue generated from the licenses or that Allergan and Madaus licenses were granted because these entities were interested in competing in the patented area and could not do so without infringing the patents-in-suit. Rather, the plaintiffs demonstrated that the licenses were granted so that the licensees could market trospium in their respective territories. Consequently, because there is no evidence that any license was granted by the patent owner to a potential infringer who wanted to compete in the market but was impeded from doing so, and the plaintiffs have not otherwise established evidence of substantial industry recognition, the court concludes that the licensing in this case does not undermine the prima facie case of obviousness.
The plaintiffs maintain that a person of "skill [in the art] would not have expected to be able to make a successful once-daily modified release trospium dosage form." (D.I. 203 at 38.) The plaintiffs cite the following as evidence supporting this contention: (1) the skepticism of leading pharmaceutical companies, Bayer and Madaus; (2) "the conventional wisdom taught by the Fuhr/Schroder Poster and others that trospium absorption in the colon was negligible"; and (3) Drs. Kibbe, Derendorf, and Mayersohn's "admissions that trospium is a challenging, complex drug." (Id.) Because the court has already addressed the plaintiffs' arguments with respect to the Fuhr/Schroder Poster and testimony that trospium presented formulation challenges, it does not reexamine these arguments here. In light of the evidence before it, the court finds Bayer and Madaus' alleged skepticism similarly unavailing in rebutting obviousness.
In support of their skepticism argument, the plaintiffs presented testimony of Drs. Sandage and Bhatt that Bayer decided not to partner with Indevus due to a "high degree of skepticism as to the likelihood of success in developing a once per day XR dosage form." See PTX-398; see also Tr. at 187:1-5, 189:1-9 (Sandage). The plaintiffs also entered into evidence an email from Dr. Woody Bryan, Shire's Vice President of Business Development in 2003, wherein he stated that Bayer was not interested in partnering with Shire and explained that, "[a]pparently the limited absorption in the colon [was] the main reason for their skepticism." See PTX-398. Drs. Sandage and Bhatt also recalled "a general sense of skepticism from [Bayer] regarding the chances of success in developing a once-a-day controlled release product of trospium." Tr. at 187:1-5, 189:1-9 (Sandage); id. at 1347:21-25 (Bhatt). However, this testimony refers only to out-of-court statements of unnamed Bayer employees, no Bayer employees testified at trial, and no written or published statements of skepticism from Bayer were introduced into evidence to support Bayer's alleged rationale. Thus, though Drs. Sandage, Bhatt, and Bryan may have accurately relayed their impressions as to
With regard to Madaus' decision not to partner with Indevus, Dr. Sandage testified that Madaus was skeptical as to whether trospium could be developed into a once-a-day formulation based on Dr. Fuhr's findings reported in the Fuhr/Schroder Poster. Id. at 157:2-21, 158:17-162:4 (Sandage); see also PTX287; JTX-31. Dr. Sandage testified that he personally met with Dr. Fuhr in Germany and that Dr. Fuhr told him that "he [Fuhr] didn't think there was a chance to make a once-a-day," that "since you don't have colonic absorption, we are never going to be able to do that," and that Indevus "should abandon the program because we weren't able to do it." Tr. at 164:6-166:5 (Sandage). As discussed above in connection with the plaintiffs' "teaching away" argument, however, the court does not find the Fuhr/Schroder Poster's conclusions to be reflective of how persons of ordinary skill in the art viewed trospium or the correlation between rectal and colonic absorption in 2002. Consequently, the court concludes that Dr. Fuhr and/or Madaus' skepticism, based on the Fuhr/Schroder findings, fails to establish that those of skill in the art were generally skeptical as to whether a once-a-day trospium formulation was possible. Moreover, the court notes that Dr. Fuhr did not testify at trial and the plaintiffs did not depose Dr. Fuhr in connection with this litigation, despite Dr. Fuhr current position as a Madaus' consultant.
The court also concludes, for the reasons outlined in the obviousness analysis above, that the development of once-a-day trospium did not yield unexpected results. While some persons of ordinary skill in the art believed it would be challenging to develop a once-a-day trospium formulation, the plaintiffs have not demonstrated that there was a widespread belief that the claimed invention was impossible or that the challenges of trospium were insurmountable, such that development of the claimed invention was unexpected. In light of this finding, the court concludes that these arguments do not rebut the defendants' prima facie case of obviousness.
"[I]nvalidity by anticipation requires that the four corners of a single[] prior art document describe every element of the claimed invention, either expressly or inherently, such that a person of ordinary skill in the art could practice the invention without undue experimentation." Advanced Display Sys., Inc. v. Kent State Univ., 212 F.3d 1272, 1282 (Fed.Cir.2000). The Federal Circuit recently discussed the standards for inherent disclosure in Verizon Services Corp. v. Cox Fibernet Virginia, Inc., 602 F.3d 1325 (Fed.Cir.2010):
The plaintiffs argue that the Fuhr/Schroder Poster does not anticipate the asserted claims of the patents-in-suit because all elements of these claims are not included within the four corners of the Poster. (D.I. 203 at 25.) Specifically, the plaintiffs note that the Poster does not disclose: (1) a formulation suitable for once-daily administration of trospium; (2) steady state blood levels; (3) any ingredients of the formation; and (4) a formulation designed to release in the lower GI tract. (Id. (citing JTX-0014; Tr. at 1407:1-6; 1407:11-18 (Davis)).)
In light of the evidence presented and in consideration of the relevant law, the court agrees with the plaintiffs that the Fuhr/Schroder Poster does not anticipate the asserted claims. As noted, the law governing anticipation narrowly confines the court's analysis to the "four corners" of the specific prior art reference in question. See Adv. Display Sys., 212 F.3d at 1282. Here, the Fuhr/Schroder Poster summarizes a study that measured tropsium concentration in eight subjects after administration of: (1) an immediate release tablet; (2) an enteric-coated delayed release tablet; and (3) a mini-enemato put trospium into the rectum. See JTX-0014. Based on the findings of this experiment, the authors concluded that trospium evidenced poor colonic absorption. While the court examines the implications of this Poster and its findings in connection with the obviousness discussion separately, relevant here is whether a person of ordinary skill in the art would consider every element of the claimed invention expressly or inherently described in this reference.
Review of the Fuhr/Schroder Poster makes clear that it does not disclose a formulation suitable for once-a-day trospium administration or a formulation designed for release in the lower GI tract. To the contrary, the Poster describes how an Eudragit coated immediate release tablet dissolves at pH 6.0 for "local administration to the small intestine." (Id.) Conversely, the asserted claims in the patents-in-suit at issue here: disclose a once-a-day trospium formulation designed to release in the lower GI; employ multiparticulate formulations to target the lower GI tract; and seek to establish steady state blood levels comparable to those of the twice-daily dosage trospium formulation. Thus, while the Fuhr/Schroder study showed that trospium could be released and absorbed lower in the small intestine and in the lower GI tract
At trial, Watson
Importantly, however, a claim term is not necessarily rendered indefinite because the term's construction defines it without reference to precise measurements. See Enzo Biochem v. Applera, 599 F.3d 1325, 1335 (Fed.Cir.2010) (citing In re Marosi, 710 F.2d 799, 803 (Fed.Cir.1983)). To determine whether those skilled in the art "would understand what is claimed," courts are instructed to apply general principles of claim construction, considering such intrinsic evidence as the claim language, the specification, and the prosecution history. See id. at 1332 (citing Young v. Lumenis, Inc., 492 F.3d 1336, 1346 (Fed.Cir.2007)). Thus, where a court finds that the intrinsic evidence provides "a general guideline and examples sufficient to enable a person of ordinary skill in the art to determine [the scope of the claims]," the claim is not indefinite. See id. at 1335 (citing Young, 492 F.3d at 1346); see also Seattle Box Co., Inc. v. Indus. Crating & Packing, Inc., 731 F.2d 818, 826 (Fed.Cir.1984) (noting that when a "word of degree" is used, the court must determine whether the patent provides "some standard of measuring that degree").
Watson first asserts that claim 1 of the '978 Patent is indefinite because the specification does not define "comparable to" or provide guidance as to the term's scope. (D.I. 202 at 22.) Watson supports this contention with the fact that Dr. Weiner, plaintiffs' expert who testified that a person of ordinary skill in the art would understand the meaning of "comparable to" as recited, nevertheless defined the meaning of this term differently in his March 2011 deposition. (Id. (citing Tr. at 597:23-599:22 (Weiner)).) This inconsistent testimony, Watson argues, is consistent with Dr. Davis' testimony that the claims reciting this term do not "define what it means by those blood levels or how they are actually measured." (Id. (citing Tr. at 724:5-21 (Weiner)).) In addition, Watson notes that "comparable to" is recited in an independent claim in the '978 Patent, "and a dependent claim adds the 0.5-.60 ng/ml limitation", while "the '448 and '449 [P]atents recite the 0.5-6.0 ng/ml limitation in an independent claim, and a dependent claims adds the `comparable to' limitation." (Id. at 22-23.) Based on the placement of this term, Watson contends that a person of ordinary skill in the art would not know "from the language of the claims, specification, and prosecution history how the steady state blood levels obtained with a once-a-day formulation should be compared [to] meet the claim limitation" because there is no explanation as to how this term could be both broad and narrow, how the comparison should be made, or what is required to satisfy it. (Id. at 23.)
In response, the plaintiffs assert that the specification provides general guidelines
Moreover, the plaintiffs note that the patent itself provides numerous guidelines and examples to define this term's scope. Specifically, the plaintiffs note that the '978 Patent identifies the following as acceptable metrics of comparability: a steady state blood level range of 0.5 to 6.0 ng/ml; average C
The court finds Dr. Davis' testimony credible and agrees with the plaintiffs that the intrinsic evidence — namely, the '978 Patent's claims and specification — provides general guidelines and examples sufficient for a person of ordinary skill in the art to understand the meaning of "comparable to." Specifically, and as the plaintiffs correctly note, the '978 Patent's specification recites the acceptable ranges of comparability and serves as a general guideline informing construction of the term. See '978 Patent at col. 4:24-34. The fact that "comparable to" is included in an independent claim in the '978 Patent and in dependent claims in the '448 and '449 Patents, does not undermine this conclusion in light of the court's findings. Moreover, the court is not persuaded by the defendants' argument that: (1) Dr. Weiner's inconsistent testimony as to the meaning of "comparable to" demonstrates the indefiniteness of this term; or (2) Dr. Davis' statement that claim 1 of the '978 Patent does not define "what it means by those blood levels or how they are actually measured" renders the term indefinite.
With respect to Dr. Weiner's statements, Dr. Weiner clarified in his trial testimony that his initial deposition testimony was incorrect because he "was confused by the hypotheticals" Watson presented, due at least in part to his belief that the product described in the hypothetical could not be created.
In view of the foregoing, the court finds that the defendants have not established by clear and convincing evidence that the "comparable to" limitation is indefinite. See Enzo Biochem, Inc., 599 F.3d at 1335. Consequently, the court concludes that the claims reciting the term "comparable to" are not invalid under Section 112.
The court is not persuaded by the defendants' remaining indefiniteness arguments. (D.I. 202 at 23-24.) The defendants assert that the term "minimizing the occurrence," included in claim 1 of the '449 Patent, is indefinite. (Id.) The court disagrees, and finds that this term can he construed to have a definite meaning that would be readily understood by a person of ordinary skill in the art. Specifically, the court agrees with the plaintiffs that Dr. Davis' testimony is credible and negates the defendants' argument that the term is indefinite because it does not disclose "how high trospium blood levels or spikes in those levels must be to cause side effects" or "how low they must be to reduce side effects." (Id. at 23-24; D.I. 203 at 39-40.)
Dr. Davis testified that one of ordinary skill in the art would have "no problem in understanding what the patentees meant" in using the term "minimizing the occurrence of side effects." Tr. at 683:4-8 (Davis). Specifically, Dr. Davis testified that this term is informed by the '978 Patent's specification, which details in at least three places that the purpose of the invention is to reduce the side effects associated with the spikes that typically occur in plasma concentration.
In addition to these arguments, the defendants also maintain that "minimizing the occurrence" is indefinite because the '449 Patent does not disclose which side effect(s) must be minimized to meet the "minimizing the occurrence of side effects" limitation in claim 1 of the '449 Patent. (D.I. 202 at 23.) The defendants assert that Dr. Davis' only response to Dr. Kibbe's conclusion that "minimizing" is indefinite was that "minimizing" means "reducing incidences of dry mouth" only. (Id. at 24 (quoting Tr. at 840:8-14 (Davis)).) The court disagrees with this assertion. Dr. Davis clarified in his testimony that one of ordinary skill in the art would understand the side effects to which the applicants were referring. Specifically, Dr. Davis noted that, for instance, column 1 of the '978 Patent states that the side effects associated with the "use of twice daily trospium chloride regimen" includes "dry mouth, headache, constipation, dyspepsia" and result from "high blood concentration of trospium chloride." '978 Patent, col. 1:57-62. The applicants also state in the '978 Patent that a once-daily administration of trospium is advantageous over twice-a-day because it lends to increased patient compliance and reduction in adverse side effects. Id. at col. 1:58-2:3.
Finally, the court notes that the '449 Patent itself describes the goal of "minimiz[ing]" or "reduc[ing]" the side effects associated with twice-daily trospium and the general way in which the patented formulation does so. Specifically, the '449 Patent states:
'449 Patent, col. 2:9-18. In view of the foregoing, the court finds that the defendants have not established by clear and convincing evidence that the "minimizing
Paddock argues that the C
Here, Paddock asserts that the "average C
Conversely, the plaintiffs maintain that claim 1 of the '359 Patent is not invalid because Formulations C and D in Table 6 demonstrate that the C
The plaintiffs argue that the disclosure here provides the necessary guidance. In particular, the plaintiffs note that the patent emphasizes the importance of lowering C
In light of Drs. Kidane and Davis' testimony and the evidence before it, the court concludes that claim 1 of the '359 Patent is not invalid for lack of written description. As the plaintiffs correctly note, to challenge the sufficiency of a patent's written description the defendants must prove by clear and convincing evidence that the claim is invalid or not entitled to an asserted filing date. See Tech. Licensing Corp., 545 F.3d at 1329-30. Here, the defendants have failed to do so. While Dr. Derendorf's testimony was limited primarily to identifying that the specification mentions ranges other than that required by claim 1, Drs. Kidane and Davis, discussed the meaning of claim 1's C
As noted, the plaintiffs contend that the defendants directly infringe the asserted claims of the '978 and '448 Patents, which are directed to pharmaceutical compositions. (D.I. 203 at 7.) In addition, the plaintiffs allege that the defendants infringe the asserted claims of the '359 and '449 Patents, which are directed to method claims, by inducement. (Id.) Defendants Sandoz and Watson focus their infringement defenses on the assertion that the plaintiffs have failed to show that their proposed products meet the "release" element of the asserted claims because the plaintiffs offered in vitro as opposed to in vivo data at trial. (D.I. 202 at 25-27.) Because each of the asserted claims require that the defendants' ANDA products "release" a portion of trospium in the lower GI tract, Watson and Sandoz argue that the plaintiffs cannot meet their burden of proving infringement. In addition, Watson and Sandoz also maintain that the plaintiffs failed to establish: (1) infringement of claim 1 of the '359 Patent based on Dr. Weiner's assessment that their proposed products, as well as Paddock's product, do not possess the C
Notably, defendant Paddock presents two other infringement defenses, asserting that the plaintiffs failed to prove that its proposed product: (1) meets the steady state blood level and AUC limitations of the patents-in-suit; and (2) contains particulates comprising an enteric and/or release controlling polymer. (D.I. 201.) Because Paddock presents its own infringement defenses on these issues, the court will consider the defenses separately in its infringement analysis.
For the reasons that follow the court concludes that each of the defendants' proposed products infringe the asserted claims of the patents-in-suit.
The application of a patent claim to an accused product is a fact-specific
Under Section 271(b), "[w]hoever actively induces infringement of a patent shall be liable as an infringer." 35 U.S.C. § 271(b). To establish liability under this Section, a patent holder must prove that once the defendant knew of the patent, it "actively and knowingly aid[ed] and abett[ed] another's direct infringement." DSU Med. Corp. v. JMS Co., Ltd., 471 F.3d 1293, 1305 (Fed.Cir.2006) (citation omitted) (emphasis in original). The "mere knowledge of possible infringement by others does not amount to inducement; specific intent and action to induce infringement must be proven." Id. (citing Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1364 (Fed.Cir.2003)).
As noted, each of the asserted claims require that the defendants' proposed products "release" trospium in the lower GI tract, which the court construed to mean the ileum and colon,
In light of the evidence before it, the court concludes that the plaintiffs have met their burden of proving, by a preponderance of the evidence, that each of the defendants' proposed products meet the "release" element and, therefore, infringe the asserted claims of the patents-in-suit. The court examines Dr. Davis' findings and addresses each of the defendants' noninfringement arguments in turn below.
The defendants argue, in the main, that the plaintiffs have failed to show their products meet the "release" element of the asserted claims because Dr. Davis' in vitro data does not sufficiently model in vivo release. The defendants cite a number of propositions in support of this contention. First, all defendants assert that Dr. Davis' in vitro testing did not adequately reflect or take into account the actual in vivo conditions of the GI tract. Specifically, the defendants note that while the GI tract "contains many millions of charged particles in both the fasted and fed states," the in vitro dissolution data Dr. Davis used contained "relatively few charged particles — only those necessary to adjust the pH," and did not account for the fact that trospium slows pellet release. (Id. at 3) (citing Tr. at 899:21-900:4, 905:10-13, 906:17-24) (Derendorf); id. at 1150:7-13 (Bhalani); id. (citing Tr. at 795:7-21 (Davis); id. at 899:15-900:22 (Derendorf).) Second, the defendants assert that this argument is confirmed by the fact that the in vivo dissolution rates for SANCTURA XR®'s XR1 and the Shojaei applications do not tract Dr. Davis' in vitro dissolution data method. (Id. at 3-4.) In consideration of the totality of evidence presented, however, the court disagrees with the defendants' contention that the plaintiffs, via Dr. Davis' testimony, have failed to show that it is more likely than not that the defendants' proposed products release in the lower GI tract.
As noted, Dr. Davis' evaluation of the defendants' proposed products encompassed consideration of a number of factors, including: (1) the defendants' ANDA data; (2) in vitro dissolution data; (3) known data about GI transit times of dosage forms; and (4) in vivo data from SANCTURA XR®. (D.I. 203 at 7-8.) With regard to Dr. Davis' in vitro data assessment, Dr. Davis testified that, based on his decades of experience in transit times of dosage forms, known transit times for pellets to travel through the GI tract can be considered in combination with in
In conducting his analysis of the defendants' proposed products, Dr. Davis stated that he compared the dissolution data contained in their ANDAs to the known transit times outlined above. Id. at 621:15-622:3. In particular, Dr. Davis tracked the GI tract transit times on the x-axis of each dissolution profile to correspond roughly to where materials would be in the GI tract. Id. Dr. Davis concluded, based on this comparison, that each of the defendants' proposed products releases trospium in the lower GI tract because, per their dissolution data, each product continues to release trospium after two and a half hours (i.e., the ileum) and after three and a half hours (i.e., the colon). In particular: Watson's dissolution data in its ANDA shows trospium release after five hours, and transit times to the ileum and colon are about two and three and a half to five hours, respectively; Sandoz's dissolution profiles show that only twenty percent of the trospium is released at around two hours, when pellets would be arriving in the lower GI tract and ileum; and Paddock's dissolution data showed that after two hours, more than eighty percent of trospium was not yet released and, further, that more than fifty percent of trospium was not yet released after four hours. Id. at 635:1-18, 621:11-622:3, 613:17-617:16, 653:17-658:13.
In addition, Dr. Davis further explained that the in vivo data on SANCTURA XR® confirms that the defendants' in vitro dissolution data establishes this release. Specifically, Figure 10 of the '978 Patent charts the in vivo blood levels for various formulations. Id. at 1530:13-1531:4. Formulation B presents a delayed release formulation with Eudragit FS30D polymer coating that releases at around pH 7.0, which corresponds to the pH in the colon. Figure 10 shows that Formulation B did not produce measurable blood levels until about three hours later than the other formulations, which resulted in bioavailability of only five percent of the immediate release formulation, depicted in Formulation F. Id. at 1530:7-1531:4; id. at 346:3-11 (Kidane). Dr. Davis testified
Finally, Dr. Davis also explained the pH levels present at various parts of the GI tract and compared this information to the defendants' ANDAs. Specifically, Dr. Davis testified that the pH level is approximately 7 in the ileum and the colon, in addition to defining levels in other areas. Id. at 612:7-613:4. Dr. Davis explained that formulators seeking to target drug release at a particular part of the GI tract would use these known pH values to determine an appropriate pellet coating that would release at that pH level. Id. at 613:5-16. Dr. Davis then compared these values to the information contained in the defendants' ANDAs and considered the defendants' statements to the FDA to conclude that at least some portion of the trospium in the proposed products release in the lower GI tract.
For the Watson proposed product, Dr. Davis testified that its ANDA describes a 60 mg capsule containing extended release and delayed release pellets, wherein the extended release pellets are coated with ethylcellulose polymer and the delayed release pellets are coated with Eudragit FS30D, which has a pH sensitivity of 7.0. Id. at 617:17-618:25; see also PTX-162 at 12765; PTX-156 at 12762, 12764. Watson's ANDA also states that its product uses the polymers to mimic SANCTURA XR®'s drug release profile and, more specifically, that it intended to target colonic absorption and employed the polymers selected to delay release until the lower GI tract. Tr. at 1107:12-18 (Davis). In addition, Watson told the FDA that a "key excipient" for its product is Eudragit FS30D, which "dissolves by salt formation above pH 7.0" and "allows target colon delivery." Id. at 617:22-618:11; see also PTX-162 at 12770. In consideration of Watson's selected polymers and its statements to the FDA, Dr. Davis concluded that Watson's proposed product releases in the lower GI tract. Tr. at 1107:12-18 (Davis).
With regard to the Sandoz proposed product, Sandoz's ANDA states that is product was 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 [SANCTURA XR®]." See PTX-145 at 281; Tr. at 634:6-14 (Davis). To this end, Sandoz's proposed product is a 60 mg capsule that contains two types of extended release and two types of delayed release pellets: ER1 and ER2 pellets coated with fifteen and twenty-four percent ethyl cellulose polymer, respectively; and DR1 pellets coated with Eudragit FS30D polymer, with a pH sensitivity of 7.0, such that it is designed to release at that pH level. See PTX-147 at 433-34; PTX-145 at 269; Tr. at 633:3-634:5 (Davis). Dr. Davis also noted that Sandoz told the FDA in its ANDA that it intended to release trospium throughout the "extent of the GI tract," and that its product's enteric coated pellets have a "slight release throughout the small intestine and immediate release of drug substance at the beginning of the large intestine," which is the same as the colon. See Tr. at 635:19-636-16; PTX-145 at 273-74. In consideration of the pH sensitivity coating Sandoz selected as well as its representations to the FDA that it intended to release trospium in the lower GI tract, Dr. Davis concluded that Sandoz's proposed product meets the "release" limitation of the asserted claims. Tr. at 637:22-24.
Regarding Paddock's proposed product, Dr. Davis noted that Paddock's ANDA states that it is designed as a "multi minitablets system to match the pellets of
The court finds Dr. Davis' testimony and methodology for assessing the defendants' proposed products credible. This conclusion is not undermined by the defendants' noninfringement arguments outlined above. First, the court finds the defendants' assertion that Dr. Davis' consideration of in vitro dissolution data was improper to be unpersuasive in light of the evidence adduced at trial. Specifically, while Dr. Davis agreed with Paddock on cross-examination that "GI tract fluid is more complicated than what is in a standard in vitro dissolution system," he also testified that the absence of such fluid components as bile acids, bile salts, and electrolytes, among others, is inconsequential because such components are "not going to be in the gastrointestinal tract in the fasted state." Id. at 772:15-774:11. Similarly, Dr. Davis stated that the presence of mucous in the GI tract in its fasted state would not impact the release from a pharmaceutical dosage form such that it would need to be included in an in vitro dissolution test. Id. at 775:6-10. Thus, while the inclusion of varying pH levels was needed-and was, in fact, included — in the in vitro dissolution test because pH sensitivity along the GI tract is relevant, Dr. Davis concluded, in what the court finds credible testimony, that the absence of other GI tract fluid components in the dissolution test does not impact the validity of his analysis.
Defendant Paddock also asserts that Dr. Davis acknowledged that trospium "significantly" slows transit time from the duodenum to the lower GI tract, but "did not account for this slowed transit at all, much less try to quantitatively apply it to his analysis as would be required to establish a reliable correlation between the in vitro dissolution data and in vivo release times." (D.I. 201 at 3.) The court notes, however, that Paddock did not develop the argument it presents in its cross-examination of Dr. Davis at trial. Notably, while Dr. Davis did agree that he has not conducted studies assessing pellet release of trospium, Paddock did not adduce testimony from Dr. Davis that he did not consider this fact
The defendants also argue that the in vitro dissolution data does not adequately predict in vivo release because "it is undisputed that there is no `in vitro/in vivo correlation,' or `IVIVC for trospium.'" (D.I. 201 at 2) (citing Tr. at 496:19-23 (Raoufinia); 770:18-25, 1404:19-24 (Davis); 911:5-7 (Derendorf). Aside from expert testimony, the defendants support this contention with Indevus' statement to the FDA that:
DTX-1055. The defendants argue that without IVIVC, "one cannot draw any conclusions regarding the in vivo performance of Paddock's product from the in vitro dissolution tests." (D.I. 201 at 3) (citing Tr. at 910:7-16 (Derendorf).) However, while the experts agree that there is no IVIVC for trospium, such correlation is not required here. Namely, IVIVC relates in vitro dissolution data and in vivo pharmacokinetic parameters, not in vivo release. Tr. at 769:16-19 (Davis); see also DTX-1148. As noted, pharmacokinetic parameters are factors such as C
Finally, the defendants argue that Dr. Davis' correlation of dissolution data and GI tract transit times cannot be used to demonstrate release because his release projections are unreliable. In support of this assertion the defendants note that: (1) while the XR1 portion of SANCTURA XR® is designed to release in vivo in the upper GI tract in two and a half hours, this formulation took ten to twelve hours to dissolve in an in vitro dissolution test; and (2) the patent applicants represented to the PTO that all of the Shojaei applications release their trospium in the upper duodenum, although the formulations were not fully dissolved for six to twelve hours in vitro. (D.I. 201 at 4 (citing Tr. at 497:5-9 (Raoufinia); id. at 817:25-819:2 (Davis); id. at 1351:13-1352:4 (Bhatt); id. at 419:22-25 (Kidane); DTX-1093 at 1; PTX-210 at SANCXRAGN00000359-60).) In consideration of the testimony presented regarding these two examples, the court concludes that they do not undermine Dr. Davis' methodology and findings.
With regard to the SANCTURA XR® XR1 dissolution time, Dr. Bhatt, a member of the Shire development team, testified that, based on the model developed, XR1 would release in the stomach and continue to release in the upper part of the GI tract at two and a half hours. Tr. at 1351:19-25 (Bhatt). Dr. Bhatt qualified in his testimony, however, that this in vivo release prediction was part of an initial model and that that model was changed throughout the development process. Id. at 1352:15-1353:9. In particular, Dr. Bhatt noted that models are built on "assumptions that have to be made because you don't know everything that you are trying to achieve" and or the "exact performance." Id. at 1351:5-12. To this end, Dr. Bhatt described the use and development of models as an "iterative exercise where you build something with assumptions, you project the next phase, you bring that actual data ... back into the model" and then "you predict into the unknown again for the next phase." Id. at 1353:1-6.
In light of this testimony, the court finds the defendants' argument unpersuasive in undermining the use of in vitro dissolution data. Specifically, it is clear from Dr. Bhatt's testimony that while the XR1 was designed to release in the stomach and continue releasing in the upper GI tract at two and a half hours, this timeframe was a projection made in a model, rather than a figure based on in vivo data. Thus, while a difference in in vivo versus in vitro dissolution times may be probative as evidence that a correlation does not exist between the two, the court finds that the difference between actual in vitro dissolution and predicted in vivo release of XR1 does not alter its conclusion in this case. Moreover, the court notes that its findings regarding the "release" element of the asserted claims do not rest exclusively on Dr. Davis' comparison of in vitro dissolution to GI transit times, but also includes consideration of other factors such as the defendants' ANDA statements and SANCTURA XR®'s in vivo data.
With respect to the defendants' second example, Dr. Kidane testified that the dissolution time of the Shojaei applications cannot be used to discredit the use of in
In view of the foregoing, the court finds Dr. Davis' testimony and conclusions — including his comparison of in vitro dissolution data to known GI tract transit times, analysis of SANCTURA XR®'s in vivo data, and the defendants' ANDA representations — to be credible and well supported. Thus, in the court's view, the plaintiffs have shown, by a preponderance of the evidence, that the defendants' proposed products meet the "release" element of all the asserted claims.
As noted, Paddock presents a separate non-infringement argument that the plaintiffs cannot show that "at least a portion of the formulation `releases trospium [] in the lower GI tract'" because its formulation actually releases all trospium rapidly in the upper GI. For the reasons noted above and those that follow, the court finds this argument unavailing.
In support of its argument, Paddock explains that its formulation utilizes a Eudragit L30D55 coating polymer on two of its three mini-tablets that dissolves as the pH level corresponding to release in the upper GI tract. Id. at 1142:7-21, 1162:9-19 (Bhalani). Paddock states that its third mini-tablet does not have a coating to delay release. Id. at 893:14-894:17 (Derendorf). Paddock also describes that its mini-tablets are contained in a clay matrix, such that when the capsule is ingested, the trospium and clay interact with the charged particles in the GI tract by an ion exchange mechanism wherein trospium is rapidly released from the clay matrix. Id. at 903:20-906:11; DTX-4068 at 2-4.
The evidence presented at trial, however, does not support this conclusion. First, Mr. Bhalani, the lead developer of the Paddock proposed product testified that his goal was to have a formulation with "[a]n extended release and an enteric release component" and agreed that he "decided to design [his] formulation to have no immediate release." Tr. at 1159:23-1160:8 (Bhalani). Mr. Bhalani also stated that he studied SANCTURA XR® and determined that it released trospium in the lower GI tract. Id. at 1135:5-12, 1136:10-15, 1136:20-1137:14. Moreover, and in addition to Paddock's ANDA statements referenced in the preceding section, the plaintiffs presented a Paddock development document stating that the uncoated extended release mini-tablet "releases drug in a pH independent manner
The court also finds persuasive Dr. Davis' testimony that: (1) Paddock asserts that the gastric transit and dissolution profile of its formulation is essentially the same as SANCTURA XR® and gives no indication that the GI transits are different (Tr. at 644:25-655:14 (Davis); PTX-131 at 135); (2) if Paddock's proposed product released all of its trospium in stomach and duodenum there would be a "huge peak" in the blood plasma levels due to a "serious problem of dose dumping" (id. at 652:24-654:2); and (3) Paddock's ANDA describes its matrix as "hydrophobic," or "water-hating," which slows dissolution.
All of the asserted claims, except claims 18 and 19 of the '978 Patent, require one or more steady-state pharmacokinetic parameters. These parameters include: steady state blood levels (claims 1, 2, and 20 of the '978 Patent); steady state C
As noted, Paddock presents separate defenses with respect to the steady state pharmacokinetic parameters. Specifically, Paddock maintains that the plaintiffs failed to show infringement based on the steady state claims because: (1) Paddock's proposed product does not include information related to steady state blood levels or AUC on its label and the plaintiffs did not test what the steady state levels would be "following administration of [the Paddock] product according to the proposed label"; and (2) the plaintiffs' use of Paddock's bioequivalence study to extrapolate single dose data was improper and, thus, was not probative, because (a) the bioequivalence study was designed to assess the relative differences between the two products, not actual values, and (b) the study was not administered amongst the U.S. population and was instead conducted in India.
In addition, Paddock also presented "affirmative evidence" via Dr. Derendorf, who testified that he conducted a study wherein, using Paddock's bioequivalence data, he assessed the relative difference between steady state blood levels and AUC for SANCTURA XR® and the Paddock product, and then applied the difference to the actual steady state blood levels for SANCTURA XR® in the applicants' 020 study
Conversely, the plaintiffs argue that, per Dr. Weiner's testimony, the linear superposition technique it employed to calculate the defendants' mean steady state pharmacokinetic values was appropriate and demonstrates infringement. (D.I. 203 at 10.) In support of this argument, the plaintiffs maintain that Dr. Weiner's calculation method is more credible than Dr. Derendorf's calculations because the Derendorf model seeks first to compare the steady state blood levels measured for SANCTURA XR® and for the Paddock's Indian bioequivalence study, to determine a blood level ratio between the two. (Id. at 21) (citing Tr. at 932:19-934:13 (Derendorf).) Once this ratio, estimated at roughly 1.5, is established, the Derendorf model then calculates the steady state blood levels by multiplying this ratio by the steady state blood levels determined for SANCTURA XR® in clinical trials. (Id.)
The plaintiffs contend that Dr. Derendorf's method
Tr. at 605:22-606:4 (Weiner).
Based on this assessment, Dr. Weiner engaged a different linear superposition methodology. Because the defendants'
From this analysis, Dr. Weiner calculated the mean steady state pharmacokinetic values for the defendants' proposed products as:
Mean Parameter Defendant Watson Defendant Sandoz Defendant Paddock C max (ng/ml) 3.56 3.89 5.58C min (ng/ml) 0.77 0.88 1.45AUC (ng/ml*hr) 37.05 38.41 63.66Blood Level Range (ng/ml) 0.77-3.25 0.88-3.55 1.46-4.91
Notably, Dr. Derendorf testified that he agreed with the linear superposition methodology Dr. Weiner used as well as his calculation results, and stated that linear superposition is the "standard way to" project out single dose to steady state values. Id. at 954:5-13 (Derendorf). Dr. Derendorf disagreed, however, "with the data [Dr. Weiner] used and conclusion he came up with." Id. at 954:14-20. Specifically, Dr. Derendorf stated that: "The method was fine. The math was fine. But [Dr. Weiner] used the results from the study in India to say this is what will happen, compare these numbers with the limitations of the patent, and that is not proper." Id.
The court disagrees with Dr. Derendorf's assessment. In consideration of the expert testimony presented at trial, the court finds Dr. Weiner's methodology and results credible. The court notes that in reaching this finding it rejects Paddock's arguments, enumerated above, that the plaintiffs erred in not testing Paddock's steady state levels "following administration... according to the proposed label" and in using Paddock's bioequivalence study
In light of these findings, the court concludes that Paddock infringes the asserted claims referenced above that include the steady state pharmacokinetic parameters element.
The court further concludes that Watson and Sandoz likewise infringe these asserted claims, as the values Dr. Weiner calculated for their proposed products fall within the limitations stated in the patents-in-suit. Consequently, the court concludes that all three defendants infringe claims 1, 2, and 20 of the '978 Patent, claims 1, 10, and 18 of the '448 Patent, claims 1, 10, and 18 of the '449 Patent, and claim 4 of the '978 Patent.
The court next addresses whether the defendants infringe claim 1 of the '359 Patent. As noted, the defendants assert that they do not infringe this claim because, based on Dr. Weiner's modeling which the court accepts as credible, their proposed products do not have a C
The court concludes that such comparison is appropriate in this case. Namely, and as detailed above, the defendants decided to include SANCTURA XR®'s pharmacokinetic data on their labels, rather than file a petition with the FDA to put their own single-dose data on their labels instead.
Consequently, because the defendants' label C
Claims 1, 2, 4, and 20 of the '978 Patent require that the claimed composition have trospium-bearing particulates comprising enteric polymers, release controlling polymers, or combinations thereof. See '978 Patent. Watson and Sandoz do not dispute that their proposed products infringe the asserted claims requiring these elements. Paddock, however, asserts that: (1) pursuant to the court's claim construction, the mini-tablets in its proposed product are not particulates or equivalent to particulates; and (2) its proposed product contains "granules" and that the "magnesium aluminum silicate (Veegum) and povidone in those granules are [not] `release controlling polymers.'" (D.I. 201 at 11.) For the reasons that follow, the court concludes that Paddock's proposed product infringes the asserted claims requiring these elements. For the purpose of clarity, the court will address the "polymer selected from enteric or release controlling polymers" element separately from the "controlled release" element examined below.
Paddock asserts that Veegum is not a polymer. Tr. at 941:2-19 (Derendorf). Specifically, Dr. Derendorf offered this opinion based on a manual published by the Environmental Protection Agency under the Toxic Substances and Control Act. See id.; DTX-4080. That Manual describes a polymer as a carbon-based compound that has covalent bonds. DTX-4080 at 7; Tr. at 941:2-19 (Derendorf). Because Veegum is inorganic clay that does not contain covalent bonds and controls release via ion exchange, Paddock's argues that its proposed product does not meet this limitation of the asserted claims. Tr. at 940:20-941:1, 941:20-22, 907:5-909:10 (Derendorf).
The court disagrees. As the plaintiffs correctly note and Dr. Davis testified, veegum
With respect to the "controlled release solid, tropsium-bearing particulates" element of the asserted claims, Paddock contends that the plaintiffs have failed to prove this limitation by a preponderance of the evidence because: (1) Paddock's proposed product are not "particulates" as construed by the court in its claim construction and are not equivalent to particulates because they are much larger and function in a different manner; (2) povidone, even if it is capable of controlling release when used as a coating, does not do so in the Paddock product because it acts as a binder instead of a release controlling agent; and (3) this limitation has been construed to require that povidone "actually function to control the rate of release" of tropsium, and it does not do so. (D.I. 201 at 6-8.)
Conversely, the plaintiffs assert that Paddock's proposed product meets this limitation. (D.I. 203 at 14-17.) For the reasons that follow, the court agrees. First, as is clear from Paddock's ANDA, the proposed product is made using a wet granulation process, wherein trospium, veegum, stearic acid, talc, povidone, and sodium chloride are processed together as granules and subsequently compressed to form extended release mini-tablets. PTX-131 at 150; Tr. at 646:6-647:16 (Davis). As admitted by Paddock's expert, Dr. Derendorf, these mini-tablets are, in fact, "solid, tropsium-bearing particulates" within the meaning of claim 1 of the '978 Patent.
Second, the court also finds that the Paddock proposed product meets the "controlled release" limitation of the asserted claims. Specifically, Paddock's ANDA describes veegum as a "controlled release agent" and a "hydrophobic matrix former" and identifies stearic acid and talc as "hydrophobic matrix formers." PTX-131 at 131, 132, 144, 145, 148; see also Tr. at 664:1-22 (Davis); id. at 1181:25-1182:17 (Bhalani). As noted above, Dr. Davis testified that "hydrophobic" is defined as "water-hating" and, because of this property, acts to slow the release of trospium by making it "very difficult for water to get into the matrix." Tr. at 651:10-12 (Davis). Dr. Derendorf likewise stated on cross-examination that veegum "certainly has an effect on release." In light of this testimony, the court rejects Mr. Bhalani's assertion that the matrix is not "hydrophobic" and was termed "hydrophobic" due to a "poor choice of words." Id. at 1181:9-21 (Bhalani).
This finding is further supported by Sidmark's draft quality overall summary and product development report. The report states that stearic acid and talc are hydrophobic matrix formers, a point which Mr. Bhalani conceded. See PTX-880 at 18827; PTX-888 at 20007; PTX-131; Tr. at 1185:18-22 (Bhalani). Thus, the court rejects Dr. Derendorf's opinion that talc is hydrophilic ("water-loving") and that talc and stearic acid do not form a hydrophobic matrix, as inconsistent with this report and Paddock's ANDA. See PTX-131; Tr. at 918:19-24 (Derendorf). Similarly unpersuasive is Dr. Derendorf's explanation that the terming of these components as hydrophobic was "maybe a mistake." Tr. at 918:25-919:1 (Derendorf).
Moreover, the court also finds that povidone, which is contained in Paddock's granules, acts as a "binder" that "glues" the matrix together and slows trospium's release. See id. at 669:16-670:21; PTX-604; PTX-595. In particular, while it has been established that disintegrants can override povidone's release controlling property and cause rapid dispersion, there are no disintegrants present in Paddock's proposed product. Tr. at 670:16-18 (Davis). As such, the court concludes that povidone, as used in the Paddock proposed product, is a "controlled release" agent. Id.
The development of Paddock's formulation reinforces the court's "controlled release" finding. Specifically, Mr. Bhalani testified that Paddock's first formulation attempt utilized an extended release hydrophilic matrix system. Id. at 1139:8 (Bhalani). This formulation, however, resulted in trospium being released too quickly, with high AUC and C
Finally, the court concludes that Dr. Derendorf's testimony that trospium release occurs rapidly via ion exchange is unsupported by the record generally and by Paddock's ANDA in particular. Tr. at 905:2-906:11, 896:3-14, 975:7-12 (Derendorf). On this point, the court finds Dr. Davis' testimony credible and instructive. Specifically, Dr. Davis explained that while ion exchange might occur in Paddock's formulation, its effect is limited by the rate at which water can penetrate the hydrophobic matrix. Id. at 761:14-21 (Davis). Because Paddock's matrix resists water penetration, the rate of trospium release is not controlled by ion exchange, but, instead, by a slow diffusion. Id. at 650:25-652:23; see also PTX-130, 131 at 148.
In light of these findings, the court concludes that Paddock's proposed product meets the limitations of claims 1 and 20 of the '978 Patent and, therefore, infringes these asserted claims.
As noted, claim 1 of the '449 Patent requires that the patented invention "results in minimizing the occurrence of side effects as compared to twice daily administration of 20 mg of immediate release trospium tablets." '449 Patent at col. 21:1-13. The defendants assert that the plaintiffs have failed to prove that their proposed products infringe this claim either directly or by inducement because the plaintiffs did not establish that SANCTURA XR® or the defendants' products "reduce" side effects. (D.I. 202 at 26.) In support of this argument, the defendants cite to the testimony of Dr. Oefelein, who stated that "[i]f the intent to minimize means to make as small as possible, there is no data or evidence for me to answer that question." Tr. at 125:4-23 (Oefelein). The defendants also contend that the plaintiffs cannot prove infringement by inducement because they presented "no evidence to show that each element of the method claims are part of the proposed labels of [d]efendants' products" or that "the [d]efendants possessed the requisite levels of knowledge and intent." (D.I. 202 at 27 (citing Global-Tech Appl., Inc., 131 S.Ct. at 2064-65).)
The court disagrees with the defendants' assertions with respect to this claim. First, and as the plaintiffs correctly note, the defendants' labels indicate that their products are designed for once-a-day administration for the treatment of OAB
Second, the court finds the cited portion of Dr. Oefelein's testimony irrelevant for the proposition the defendants pose. Specifically, Dr. Oefelein stated that he had no evidence to prove the "minimizing the occurrence of side effects" element in response to a question posed on cross-examination where "minimizing" was hypothetically defined as "make as small as possible." Tr. at 124:4-125:23 (Oefelein). The court, however, has not construed "minimizing the occurrence of side effects" to mean "make as small as possible." Rather, and as noted above in connection with the court's indefiniteness examination, "minimizing" as used in the patents-in-suit did not require construction
Third, and with respect to the defendants' argument related to the intent element of inducement, the court finds, based on the evidence before it, that the defendants had knowledge of the '449 Patent and intended for their products to be used in a manner consistent with the labeled conditions of use copied from the SANCTURA XR® label. See Global-Tech Appl., Inc., 131 S.Ct. at 2071-72 (concluding that the copying of a patented invention, even in the absence of knowledge of the patent, can meet the intent element). This conclusion is further supported by the defendants' own statements to the FDA that their proposed products were developed to "mimic" or "match" the claimed invention. See, e.g., Tr. at 634:6-14, 644:25-645:14, 617:17-618:11 (Davis); see also PTX-162; PTX-147; PTX-145.
In view of the foregoing, the court concludes that the defendants' proposed products meet the "minimizing" limitation and induce infringement of claim 1 of the '449 Patent. See Adams Resp. Therapeutics, 616 F.3d at 1288-89. The court further concludes, based on this finding, that the defendants infringe claim 18 of the '449 Patent requiring side effects to be selected "from a group consisting of dry mouth, constipation, dyspepsia, abdominal pain, and a combination thereof." Tr. at 686:3-10 (Davis).
For the reasons stated above, 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
At Wilmington this 31st day of March, 2012, IT IS HEREBY ORDERED THAT:
The court's findings of fact with respect to matters that were the subject of dispute between the parties are included in the Discussion and Conclusions of Law section of this opinion, preceded by the phrase "the court finds" or "the court concludes."
(D.I. 203 at 27) (quoting Tr. at 532:25-533:15 (Weiner); id. at 610:18-19 (Davis); id. at 856:23-857:3 (Kibbe).)
Tr. at 1427:21-1428:8 (Davis).
Id. at 15.
Tr. at 1491:3-17 (Davis); see also id. at 1491:18-149:4.
Tr. at 1490:5-1491:10.
Tr. at 598:1-599:18 (Weiner).
Tr. at 932:19-934:13 (Derendorf).
Id. at 577:13-578:2 (Weiner).
Tr. at 980:20-981:15 (Derendorf).
