Research Foundation of State University v. Mylan Pharmaceuticals Inc. (809 F. Supp. 2d 296, 2011)

United States District Court for the District of Delaware 2011-08-26

Citations

Full opinion text

OPINION

STARK, District Judge:

In July 2011, the Court held a four-day bench trial in this patent infringement action brought pursuant to the Hatch-Wax-man Act. The case arises from Defendant’s efforts to bring to market a generic version of Plaintiffs’ Oracea® drug product, a once-daily 40 milligram (mg) administration of doxycycline indicated for the treatment of acne rosacea. Plaintiffs assert that claims of five separate patents are infringed. Defendants contend that all five patents are invalid. As explained below, the Court concludes that the asserted claims of one patent-in-suit are infringed and valid. The preliminary injunction entered in July 2010 will remain in effect pending the Court’s receipt and review of supplemental briefing as to an appropriate permanent remedy.

FINDINGS OF FACT

1. PARTIES

1. Plaintiff The Research Foundation of State University of New York (“RF SUNY”) is a private, non-profit corporation organized and existing under the laws of the State of New York, having a principal place of business in Albany, New York. (Statement of Uncontested Facts (C.A. 09-184-LPS D.I. 257-1) (“SUF”) ¶ 1)

2. Plaintiff New York University (“NYU”) is a private, non-profit corporation organized and existing under the laws of the State of New York, having a place of business in New York, New York. (SUF ¶ 2)

3. Plaintiff Galderma Laboratories Inc. (“GLI”) is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business in Fort Worth, Texas. (SUF ¶ 3)

4. Plaintiff Galderma Laboratories, L.P. (“GLLP”) is a privately held partnership registered in the State of Texas, having a principal place of business in Fort Worth, Texas. (SUF ¶ 4)

5. Plaintiff Supernus Pharmaceuticals, Inc. (“Supernus”) is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business in Rockville, Maryland. (SUF ¶ 5)

6.Defendant Mylan Pharmaceuticals Inc. (“Mylan”) is a corporation organized and existing under the laws of the State of West Virginia, having a principal place of business in Morgantown, West Virginia. (SUF ¶ 6)

II. DOXYCYCLINE

7.The structural formula of doxycycline monohydrate is:

(SUF ¶ 41)

8. Doxycycline is a member of the tetracycline class of antibacterial drugs. (SUF ¶ 42)

9. Doxycycline is an antibiotic tetracycline compound. (SUF ¶ 44)

10. There are two general categories of antibiotics: bacteriostatic agents, which inhibit bacterial growth; and bactericidal agents, which kill bacteria. (SUF ¶ 45)

11. Generic doxycycline is commercially available in at least 50 mg, 75 mg, 100 mg, 150 mg, and 200 mg dosage forms. (SUF ¶ 46)

12. Periostat® is a 20 mg dose of doxycycline administered twice-daily to a human and is indicated for treatment of periodontal disease. (SUF ¶ 47)

13. According to its approved label, Periostat® has a steady state Cmax of 0.790 ixg/ml. (SUF ¶ 48)

III. ROSACEA AND ITS TREATMENT

14. Rosacea is a long-lasting, chronic inflammatory disorder. (Tr. 71)

15. Historically, rosacea has been treated by oral administration of antibiotics in antibiotic dosages and/or administration of topical gels and creams to treat the signs and symptoms of the disease. (PTX 209 at 1249; Tr. 75, 534-36)

16. The most common oral treatments for rosacea prior to the launch of Oracea® were antibiotic doses of tetracyclines. (PTX 209 at 1249; Tr. 534-36)

IY. Oracea®

17. Plaintiff GLLP currently holds New Drug Application (“NDA”) 50-805 on Oracea® brand doxycycline capsules (“Oracea®”), which was approved by the U.S. Food and Drug Administration (“FDA”) on May 26, 2006. (SUF ¶49)

18. GLLP is the exclusive distributor of Oracea® in the United States. (SUF ¶ 50)

19. The active ingredient in Oracea® is doxycycline monohydrate. (SUF ¶ 51)

20. Oracea® is a capsule dosage form for oral administration. (SUF ¶ 52)

21. The dosage strength of Oracea® is 40 mg. (SUF ¶ 53)

22. Oracea® is an oral pharmaceutical composition of doxycycline to be administered once-daily. (SUF ¶ 54)

23. Oracea® is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. (SUF ¶ 56)

24. Oracea® is a hard shell gelatin capsule filled with two types of doxycycline beads, 30 mg immediate-release (“IR”) beads and 10 mg delayed-release (“DR”) beads (coated with an enteric polymer). (SUF ¶¶ 57-58)

25. Oracea® does not contain a bisphosphonate compound. (SUF ¶ 59)

26. Oracea® contains one or more pharmaceutical excipients. (SUF ¶ 60)

27. Oracea® is the first and only orally administered, systemically delivered drug approved by the FDA for the treatment of rosacea. (PTX 426 at GAL 0229992; Tr. 540)

28. Oracea® treats rosacea in a human. (PTX 426 at GAL 0229992; PTX 381 at GAL 0240969-70; Tr. 73, 129-30)

29. Oracea®, when administered once-daily, is administered in an amount that reduces lesion count and an amount that is effective to treat the papules and pustules of rosacea. (PTX 426 at GAL 0229996-97; PTX 381 at GAL 0240969-70; Tr. 73, 287-88, 727)

30. Oracea® is administered long-term, i.e., over a period of time longer than eight to ten days. (PTX 426 at GAL 0229993, -96-97; SUF ¶ 38)

31. Oracea® is administered by “sustained release,” i.e., a method of drug delivery to achieve a certain level of the drug over a particular period of time. (PTX 426 at GAL 0229993, -95,-96)

32. Oracea®, when administered once daily, is administered in an amount that results in no reduction of skin microflora during a six-month treatment. (PTX 426 at GAL 0229996; PTX 394; 459, 612-15)

33. In vivo microbiological studies utilizing a similar drug exposure to Oracea® for up to 18 months demonstrated no detectable long-term effects on bacterial flora of the oral cavity, skin, intestinal tract, and vagina. (PTX 426 at GAL 0229996; PTX 394; PTX 413; PTX 200; PTX 201)

34. Oracea® should not be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. (PTX 426 at GAL 0229996)

35. Patients should not take Oracea® to treat infections caused by bacteria germs or viruses. (PTX 426 at GAL 0229998)

V. MYLAN’S GENERIC PRODUCT

36. Defendant Mylan submitted Abbreviated New Drug Application (“ANDA”) 90-855 to the FDA under § 505(j) of the Federal Food, Drug and Cosmetic Act (“FFDCA”), seeking FDA approval for the commercial manufacture, use, and sale of a generic version of Oracea® (“Mylan’s Generic Product” or “Mylan’s ANDA Product”) before the expiration of the '267 patent, the '572 patent, the '395 patent, and the '775 patent. (SUF ¶ 61)

37. ANDA 90-855 identifies Mylan as the manufacturer of Mylan’s Generic Product. (SUF ¶ 62)

38. The FDA approved ANDA 90-855 on July 1, 2010. (SUF ¶ 63)

39. Mylan’s Generic Product will contain the package insert approved by the FDA for Mylan’s Generic Product (“Mylan’s Label,” “Mylan Label,” or “Label”). (SUF ¶ 64)

40. The active ingredient in Mylan’s Generic Product is doxycycline. (SUF ¶ 65)

41. The dosage strength of Mylan’s Generic Product is 40 mg. (SUF ¶ 66)

42. Mylan’s Generic Product is a hard shell gelatin capsule filled with two types of doxycycline beads, 30 mg IR and 10 mg DR. (SUF ¶ 67)

43. Mylan’s Generic Product does not contain a bisphosphonate compound. (SUF ¶ 68)

44. FDA has found Mylan’s Generic Product to be bioequivalent to Oracea®. (SUF ¶ 69)

45. The statements in the approved package insert for Mylan’s Generic Product are true. (Memorandum Opinion granting Preliminary Injunction (D.I. 177) at 9; see also 18 U.S.C. § 1001; 21 Ü.S.C. §§ 355b(a)(l), 355c(a); Tr. 323)

46. The doxycycline in Mylan’s Generic Product is doxycycline monohydrate. (DTX 2091 at MYL-D118692-93; DTX 2267 at MYL-D000206; Tr. 98-99)

47. Mylan’s Label instructs doctors and patients that one doxycycline capsule (40 mg) of Mylan’s Generic Product should be taken once-daily by oral administration. (DTX 2091 at MYL-D118686-87; DTX 2267 at MYL-D000220; Tr. 83, 100-01)

48. Mylan’s Generic Product is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. (DTX 2091 at MYLD118686-87; Tr. 82)

49. Mylan’s Label instructs doctors and patients to use Mylan’s Generic Product to treat rosacea in a human. (DTX 2091 at MYL-D118686-87, -97; Tr. 82)

50. Mylan’s Generic Product, when administered once-daily in accordance with Mylan’s Label, is administered in an amount that reduces lesion count and that is effective to treat the papules and pustules of rosacea. (DTX 2091 at MYLD118695-96; Tr. 82-83)

51. Mylan’s Generic Product is administered long-term, i.e., over a period of time longer than eight to ten days. (DTX 2091 at MYL-D118687, -95-96; Tr. 84)

VI. PATENTS-IN-SUIT

A. The Ashley Patents

1. Ashley '267 Patent

52. U.S. Application Number 10/117,-709, from which the '267 patent issued, was filed on April 5, 2002. (SUF ¶ 7)

53. The '267 patent issued on May 1, 2007, naming Robert A. Ashley as the sole inventor and listing CollaGenex Pharmaceuticals, Inc. as assignee. (SUF ¶ 8) The '267 patent is entitled “Methods of Treating Acne.” (PTX 1)

54. GLI is the current assignee of the '267 patent. (SUF ¶ 9)

55. The '267 patent claims priority from provisional application no. 60/325,489, filed September 26, 2001 and provisional application no. 60/281,916, filed April 5, 2001. (SUF ¶ 10)

56. The '267 patent is set to expire on April 5, 2022. (SUF ¶ 11)

2 Ashley '572 Patent

57. U.S. Application Number 11/061,-866, from which the '572 patent issued, was filed on February 18, 2005. (SUF ¶ 12)

58. The '572 patent issued on June 19, 2007, naming Robert A. Ashley as the sole inventor and listing CollaGenex Pharmaceuticals, Inc. as assignee. (SUF ¶ 13) The '572 patent is entitled, “Methods of Treating Rosacea.” (PTX 2)

59. GLI is the current assignee of the '572 patent. (SUF ¶ 14)

60. The '572 patent is a continuation of application no. 10/272,499, filed on October 15, 2002, and issued as U.S. Patent No. 7,014,858, which is a continuation of application no. 10/117,709, which issued as the '267 patent. (SUF ¶ 15)

61. The '572 patent claims priority from provisional application no. 60/281,916, filed April 5, 2001 and provisional application no. 60/325,489, filed September 26, 2001. (SUF ¶ 16)

62. The '572 patent is set to expire on April 5, 2022. (SUF ¶ 17)

3. Facts relating to infringement and validity of Ashley Patents

63. Dr. Webster, who was called at trial by Galderma, is an expert in the field of clinical dermatology and microbiology. (Tr. 70; PTX 248)

64. Dr. Chambers, who was called at trial by Mylan, is an expert in the field of infectious diseases and antimicrobial agents, including antibiotic resistance and the pharmacokinetics and pharmacodynamics of antimicrobial agents. (Tr. 552; DTX 2102)

65. Dr. Randall Stafford, who was called at trial by Mylan, is an expert in the field of clinical epidemiology, including the use prescription patterns generated by IMS Health. (Tr. 416; DTX 2208)

66. Dr. Barbara Gilchrest, who was called at trial by Mylan, is an expert in the field of clinical dermatology with a specific focus in the treatment of acne and rosacea. (Tr. 449; DTX 2135)

67. A microorganism is a single cellular life form or sub-life form, including a bacterium, a virus, a yeast, or protozoan. (Tr. 557)

68. Microorganisms live everywhere on and in our bodies. (Tr. 557)

69. Approximately 100,000,000,000,000 bacterial cells inhabit the human body. (Tr. 149-50, 557)

70. In our bodies, the number of bacterial cells is greater than the number of human cells by a factor of 10. (Tr. 557)

71. Doxyeyeline is among the most potent known antimicrobial agents. (Tr. 558)

72. Doxyeyeline is “broad spectrum,” which means that it affects a large number of organisms. (Tr. 558)

73. Doxyeyeline is a protein synthesis inhibitor that inhibits the growth of microorganisms by paralyzing their protein machinery. (Tr. 559)

74. When administered orally, doxyeyeline is absorbed into the bloodstream and travels wherever blood goes in the body. (Tr. 558-59)

75. The inhibitory effect caused by doxyeyeline can be measured in several ways, including reduction in count of an organism and the emergence of organisms resistant to doxyeyeline. (Tr. 559-60, 562-66)

76. In vivo microbiological studies utilizing a similar drug exposure to Mylan’s Generic Product for up to 18 months demonstrated no detectable long-term effects on bacterial flora of the oral cavity, skin, intestinal tract, and vagina. (DTX 2091 at MYL-D118694; PTX 394; PTX 413; PTX 200; PTX 201; Tr. 90-95, 325-26, 608-09, 612-14, 616-17, 620, 621-25)

77. Mylan’s Generic Product, when administered as 40 mg of doxycycline once a day, is administered in an amount that results in no reduction of skin microflora during a six-month treatment. (DTX 2091 at MYL-D118694; PTX 394; Tr. 88-93, 326, 459, 612-15)

78. The assessment of whether an antibiotic substance has activity against microorganisms should not be limited to examining only certain types of categories of bacteria. (Tr. 151)

79. The purpose of the Haffajee study was to examine subgingival microbiological changes in human subjects with periodontitis. (DTX 2097 at 148; Tr. 561)

80. Patients in the Haffajee study received one of four treatments: 1) scaling and root planning (“SRP”) alone; 2) SRP and doxycycline (20 mg twice-daily for 3 months); 3) SRP and metronidazole (150 mg thrice-daily for 14 days); and 4) SRP and azithromycin (500 mg once-daily for 3 days). (DTX 2097 at 149; Tr. 561-62)

81. Samples of subgingival plaque and saliva were taken at baseline, two weeks, three months, nine months and twelve months. (DTX 2097 at 150; Tr. 561)

82. Each sample was measured for the percentage of total isolates that were resistant to 4 (jig/ml of doxycycline at each time point. (DTX 2097 at 152 (Figure 3); Tr. 566-67)

83. Figure 3 in the Haffajee study is a graphic representation of the percentage of total isolates resistant to 4 |jug/ml of doxycycline at each time point in both the doxycycline group and placebo group. (DTX 2097 at 152 (Figure 3); Tr. 562-63, 566-70)

84. At time zero (i.e., prior to administration of drug), the percentage of total isolates resistant to 4 |xg/ml of doxycycline are virtually identical in both the doxycycline and placebo groups — approximately 10% of the isolates are resistant. (DTX 2097 at 152 (Figure 3); Tr. 567-68)

85. At the two week time point, the percentage of resistant isolates in the doxycycline group spiked from 10% to approximately 45%, whereas in the placebo group, the two week data indicated virtually no change in the percentage of isolates resistant to doxycycline. (DTX 2097 at 152 (Figure 3); Tr. 568)

86. The spike in percentage of resistant isolates in the doxycycline group at the two week time period is due to significant inhibition of growth caused by exposure to doxycycline. (DTX 2097 at 152 (Figure 3); Tr. 562-66, 568)

87. The significant inhibition of growth of microorganisms susceptible to doxycycline allowed microorganisms resistant to doxycycline to increase in numbers. (DTX 2097 at 152 (Figure 3); Tr. 562-66, 568)

88. The statistical analysis included in the Haffajee study confirms that there is virtually no chance that the data in Figure 3 resulted from random occurrence. (DTX 2097 at 152 (Figure 3); Tr. 568)

89. The data in Figure 3 of the Haffajee study provides conclusive evidence that Mylan’s Generic Product will significantly inhibit the growth of microorganisms in the oral cavity. (DTX 2097 at 152 (Figure 3); Tr. 568-70)

90. The Haffajee study did not detect any long-term effect of 40 mg dose of doxycycline. (DTX 2097 at 152 (Figure 3); Tr. 568-69)

91. The purpose of the Thomas study was to assess whether doxycycline changes antibiotic susceptibility of the oral micro-flora in adults with periodontitis. (DTX 2121 at 1472; Tr. 571-72)

92. Patients in the Thomas study received one of the following treatments: 20 mg doxycycline twice daily, 20 mg doxycycline once daily, 10 mg of doxycycline once daily or placebo. (DTX 2121 at 1473 (Table 1); Tr. 571-72)

93. Samples of subgingival plaque were taken at baseline, twelve months, fifteen-to-eighteen months, and twenty-one to twenty-four months. (DTX 2121 at 1473 (Table l);Tr. 571-72)

94. The Thomas study measured the doxycycline MIC50 values for Actinomyces species isolates at each sample period. (DTX 2121 at 1477 (Figure 2A); Tr. 572)

95. An increase in MIC50 values in the presence of an antibiotic indicates emergence of drug resistant cells due to inhibition of susceptible cells, (DTX 2121 at 1477 (Figure 2A); Tr. 572)

96. Figure 2A in the Thomas study is a graphic representation of the MIC50 data for Actinomyces species isolates at each sample period. (DTX 2121 at 1477 (Figure 2A); Tr. 572-73)

97. At baseline, the MIC50 values of all four groups are at or near 1. (DTX 2121 at 1477 (Figure 2A); Tr. 572-73)

98. At twelve months, the MIC50 values in the 20 mg twice daily and 20 mg once daily groups jumped to 32, while the placebo group remained relatively constant. (DTX 2121 at 1477 (Figure 2A); Tr. 572-73)

99. The difference between the baseline and twelve month data is due to the significant inhibition of growth of microorganisms susceptible to doxycycline, which facilitates growth of microorganisms resistant to doxycycline. (DTX 2121 at 1477 (Figure 2A); Tr. 573)

100. The Thomas study reflects the same results as the Haffajee study — administration of a 40 mg daily dose of doxycycline caused an increase in the number of microorganisms resistant to doxycycline. (DTX 2121 at 1477 (Figure 2A); Tr. 573-74)

101. The Thomas study did not detect any long term effect of a 40 mg dose of doxycycline. (DTX 2121 at 1477 (Figure 2A); Tr. 574)

102. The purpose of the Walker 2000 study was to determine whether treatment with a 40 mg daily dose of doxycycline exerted an antimicrobial effect on the microflora associated with adult periodontitis. (DTX 2120 at 1465; Tr. 575-76)

103. Patients in the Walker 2000 study received one of the following treatments: 20 mg doxycycline twice-daily or placebo. (DTX 2120 at 1466; Tr. 575-76)

104. Each patient also received scaling and root planning in half of their mouth; thus, there were effectively 4 treatment groups: SRP-plaeebo, SRP-doxycycline, placebo, and doxycycline. (DTX 2120 at 1466; Tr. 575-76)

105. Samples of subgingival plaque were taken at baseline, three months, six months, nine months, and twelve months. (DTX 2120 at 1466; Tr. 575-76)

106. The Walker 2000 study measured the mean percentage of spirochetes (a type of microorganism) relative to the total microscopic flora at each sampling period. (DTX 2120 at 1467-68 (Tables 1, 2 & 3); Tr. 576-77)

107. The mean percentage of spirochetes data, which appears in Tables 1-3, shows that a 40 mg daily-dose of doxycycline significantly inhibited the growth of microorganisms. (DTX 2120 at 1467-68 (Tables 1, 2 & 3); Tr. 576-77, 579)

108. Table 1 provides data regarding small spirochetes. (DTX 2120 at 1467 (Table 1); Tr. 577)

109. In Table 1, at baseline, the mean percentage of small spirochetes in the SRP-doxycycline and SRP-placebo groups is nearly identical-approximately 10.35%. (DTX 2120 at 1467 (Table 1); Tr. 577-78)

110. At three months, the number of small spirochetes was significantly reduced in the doxycycline group to 4.32%, whereas the percentage in the placebo group was relatively unchanged at 9.59%. (DTX 2120 at 1467 (Table 1); Tr. 578)

111. According to the statistical analysis in Walker 2000, that difference is statistically significant i.e., very unlikely to be the result of random chance. (DTX 2120 at 1467 (Table 1); Tr. 578)

112. The significant reduction in the mean percentage of small spirochetes was due to the exposure of doxycycline and resulting significant inhibition of growth. (DTX 2120 at 1467 (Table 1); Tr. 578)

113. Table 2 (data regarding reduction of large spirochetes) and Table 3 (data regarding reduction of intermediate spirochetes) also show significant inhibition of growth. (DTX 2120 at 1467-68 (Tables 2 & 3); Tr. 579)

114. The Walker 2000 study did not detect any long term effect of 40 mg dose of doxycycline. DTX 2120 at 1467 (Table 1); Tr. 578-79.

115. The FDA reviewed the clinical microbiology studies described in PTX 394 (“Skidmore”), PTX 413 (“Walker 2005”), PTX 200 (“Walker 2000”), and PTX 201 (“Thomas”) during the approval process for Oracea®, and Mylan’s Label relies on these studies. (Tr. 90-95, 612-13,615-16,-622-23,626)

116. Mylan is unaware of any in vivo microbiology studies of Mylan’s Generic Product or a product with similar drug exposure that demonstrate a detectable long-term effect on bacterial flora of the oral cavity, skin, intestinal tract, or vagina. (Tr. 325-26)

117. Mylan is unaware of any in vivo microbiology studies of Mylan’s Generic Product or a product with similar drug exposure that demonstrate a detectable long-term effect on the bacterial flora at any site in the human body other than the oral cavity, skin, intestinal tract, and vagina. (Tr. 326)

118. Neither Mylan nor any of its experts has tested Mylan’s Generic Product, Oracea®, or a product with a similar drug exposure to determine whether it will significantly inhibit the growth of microorganisms, e.g., bacteria. (Tr. 328, 659-60)

119. Mylan’s Generic Product should not be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. (DTX 2091 at MYLD118687, -94; Tr. 89, 324-25, 606-07, 608)

120. When administered once daily in accordance with Mylan’s Label, the plasma concentrations of doxycycline achieved with Mylan’s Generic Product during administration are less than the concentration required to treat bacterial diseases. (DTX 2091 at MYL-D118694; Tr. 89-90, 607)

121. Mylan’s Generic Product should not be used for the treatment of infections. (DTX 2091 at MYL-D1 18682, -97, Tr. 606-07)

122. Patients should not take Mylan’s Generic Product to treat infections caused by bacterial germs or viruses. (DTX 2091 at MYL-D118683, -99)

123. Exceeding the recommended dosage for Mylan’s Generic Product may result in an increased incidence of side effects including the development of resistant organisms. (DTX 2091 at MYLD1 18687)

124. Nothing in Mylan’s Label instructs doctors or patients to administer Mylaris Generic Product with a bisphosphonate compound. (DTX 2091; Tr. 84-85)

125. The doxycycline in Mylaris Generic Product is administered by “sustained release,” i.e., a method of drug delivery to achieve a certain level of the drug over a particular period of time. (DTX 2091 at MYL-D118687, -93; Tr. 100)

126. Both of the Ashley Patents identify Periostat® as “an especially preferred embodiment” of the inventions. (SUF ¶ 70; PTX1, 2; Tr. 457, 460)

127. Periostat® is an oral antibiotic tetracycline compound that provides a 40 milligram daily dose of doxycycline (20 mg BID). (PTX 1 at col. 5 lines 63-67; Tr. 143)

128. Dr. Lawrence Feldman is a physician who specializes in dermatology, including the treatment of patients with rosacea. (Tr. 333, 335-37)

129. Dr. Feldman is afflicted with rosacea, including the papules and pustules of rosacea. (Tr. 344, 408-09)

130. In October 1998 or 1999, Dr. Feldman attended a dermatology meeting in Las Vegas, Nevada. (Tr. 338^10)

131. At the convention, Dr. Feldman learned “new[ ] ideas,” including “Periostat as being a treatment for rosacea.” (Tr. 341 — 42)

132. Dr. Feldman learned that use of Periostat® to treat rosacea was a “new kind of idea in dermatology where an antibiotic could work as anti-inflammatory and not kill bacteria and it was just the dawn of that whole idea.” (Tr. 403)

133. While taking Periostat® for his gingivitis, the Periostat® improved Dr. Feldman’s rosacea. (Tr. 344-45, 408-09)

134. In January 2000, Dr. Feldman contacted CollaGenex and requested “professional courtesy samples of Periostat” to continue his use. (Tr. 366-67)

135. CollaGenex provided Dr. Feldman with 300-400 professional courtesy samples of Periostat®. (Tr. 367)

136. In late January or early February 2000, Dr. Feldman used the professional courtesy samples of Periostat® to treat his rosacea. (Tr. 409-10)

137. Periostat® reduced Dr. Feldman’s pustules. (Tr. 344^15, 409)

138. On February 19, 2000, Dr. Feldman diagnosed a patient as suffering from rosacea, including rosacea pustules. (DTX 1559; Tr. 356)

139. On February 19, 2000, Dr. Feldman gave his patient a three month prescription for Periostat®, and one three month refill. (DTX 1559; Tr. 359)

140. Dr. Feldman prescribed “Periostat 20 BID [twice daily] due to its anti-inflammatory effect with decreased risk of side effects.” (DTX 1559; Tr. 357)

141. Dr. Feldman’s personal use of Periostat® led him to anticipate that Periostat® would improve his patient’s condition. (Tr. 345, 362-63; DTX 1559)

142. Dr. Feldman did not prescribe a bisphosphonate compound to his patient. (Tr. 408; DTX 1559)

143. In 2004, Dr. Feldman saw his patient again, at which time he did not notice anything about her rosacea and the patient did not say anything about her rosacea. (Tr. 365-66)

144. Dr. Feldman was free to discuss, publicly or privately, his own personal use of Periostat® to treat rosacea, including the specific dosage regimen he used. (Tr. 408)

145. Dr. Feldman’s patient was free to discuss, publicly or privately, her use of Periostat® to treat rosacea, including the specific dosage regimen she used. (Tr. 159, 408)

146. Apart from this litigation, Dr. Feldman has never disclosed the Feldman patient record to anyone else. (Tr. 348-49, 405, 504)

147. Dr. Feldman stored the original of the Feldman patient record in a secure, locked storage facility. (Tr. 348-49, 405, 504)

148. Mylan has not identified Dr. Feldman’s patient.

149. Mylan has not produced any testimony from Dr. Feldman’s patient.

150. Mylan has not produced the prescription of Periostat® to Dr. Feldman’s patient.

151. Dr. Feldman never published, publicly presented, or in any other way made public his prescribing of Periostat® to his patient, or his own personal use of Periostat®. (Tr. 399-400, 410,500-02,505-06)

152. Dr. Feldman never (1) attempted to sell the idea of using Periostat® to treat rosacea, (2) informed CollaGenex that Periostat® could be used to treat rosacea, or (3) considered submitting a patent application for the use of Periostat® to treat rosacea. (Tr. 400, 506)

153. Prior to February 19, 2000, Dr. Feldman was not personally aware of anyone who had prescribed Periostat® for the treatment of rosacea. (Tr. 403)

154. Periostat® is FDA-approved for the treatment of periodontitis, and has off-label uses other than the treatment of rosacea. (Tr. 418, 442)

155. The IMS Health Periostat® data demonstrates that Dr. Feldman prescribed a patient Periostat®, a prescription which was actually dispensed at a pharmacy. (Tr. 432; DTX 2211)

156. The IMS Data does not provide any patient-identifying information. (Tr. 435, 440-41)

157. The IMS Data does not provide patient diagnosis information, and the word “rosacea” does not appear anywhere in the IMS Data. (Tr. 435, 441-42)

158. None of DTX 1764 (“Murphy”); DTX 1484 (“Cotterill”); DTX 1901 (“Sneddon”); DTX 2067 (“Wereide”); DTX 1703 (“Marmion”); DTX 1418 (“Bartholomew”) (collectively, “the six Gilchrest References”) discloses the administration of any antibiotic tetracycline compound in a sub-antibacterial amount or an amount that has substantially no antibiotic activity (i.e., an amount that does not significantly inhibit the growth of microorganisms, e.g., bacteria). (Tr. 518-19)

159. None of the six Gilchrest References discloses the administration of (1) doxycycline in any amount, (2) any antibiotic tetracycline compound in an amount of less than 100 mg/day, or (3) Periostat® or 20 mg doxycycline twice-daily. (Tr. 521-22)

160. Murphy, a clinical study conducted in 1962, followed 85 moderate to severe acne patients administered 125 mg oxytetracycline for 6-12 months. (Tr. 481; DTX 1764)

161. Cotterill, a study from 1971, administered 250 mg of oxytetracycline to 42 acne patients for 3 months. (DTX 1484)

162. Sneddon, a clinical study from 1966, administered a controlling dose of 100 mg tetracycline to severe rosacea patients. (Tr. 486; DTX 1901)

163. Wereide, a study from 1969, administered 250 mg oral tetracycline to reduce the papules and pustules of rosacea. (Tr. 487; DTX 2067)

164. Marmion, another study from 1969, treated ocular and cutaneous rosacea patients with 300 mg oxytetracycline. (Tr. 486; DTX 1703)

165. Bartholomew, a study from 1982, administered 500 mg oxytetracycline to treat both ocular and cutaneous rosacea. (Tr. 487; DTX 1418)

166. According to the '267 patent, 50 or 100 mg of doxycycline is an antibacterial effective amount. (PTX 1 at col. 5 lines 47-49)

167. None of the six Gilchrest references discloses the administration of doxycycline by “sustained release,” i.e., by a method of drug delivery to achieve a certain level of the drug over a particular period of time. (DTX 1764; DTX 1484; DTX 1901; DTX 2067; DTX 1703; DTX 1418)

168. Prior to the invention of the Ashley Patents, no one developed a doxycycline treatment for rosacea at any dose lower than 50 mg per day. (Tr. 523)

169. None of DTX 1640 (“Hussar”), DTX 1694 (“Maibach”), DTX 1996 (“the '836 patent”), DTX 2005 (“the '065 patent”), DTX 1840 (“Plewig & Kligman”), DTX 1838 (“Plewig & Schopf’), DTX 1436 (“Braun-Falco”), DTX 1897 (“Smith & Mortimer”), or DTX 1493 (“Cunliffe”) discloses the treatment of acne or the papules and pustules of rosacea with an antibiotic tetracycline compound administered in a sub-antibacterial amount. (Tr. 115-16, 536-40)

170. Plewig & Kligman and Plewig & Schopf were both considered by the United States Patent and Trademark Office (“PTO”) during examination of the Ashley Patents. (PTX 1 at GAL 0037676; PTX 2 at GAL 0037655-56; Tr. 536-37, 538-39)

171. The authors of Plewig & Kligman stated that “beyond doubt ... it is the antibiotic activity of antibiotics that accounts for therapeutic benefits” in treating acne. (DTX 1840 at MYL-D098330-31, Tr. 538)

172. Plewig & Schopf reported use of an antibiotic dose of tetracycline (1000-1500 mg per day) to treat inflammatory pustules induced by potassium iodide; and Braun-Falco instructed that the initial dose of tetracyclines to treat rosacea is an antibacterial dose (1000-1500 mg, divided in two to three doses a day) until there is significant clinical improvement. (DTX 1838 at MYL-D119127; DTX 1436 at MYL-D098730; Tr. 539-40)

173. Smith & Mortimer and Cunliffe report studies of 250 mg tetracycline administered once-daily or more frequently, which according to Wereide is an antibacterial amount that may alter the intestinal flora and lead to growth of yeast or emergence of resistant strains of bacteria in the intestine. (DTX 1897 at MYL-D098386; DTX 1493 at MYL-D098304; DTX 2067 at MYL-D094936-37)

174. DTX 1045 (U.S. Patent No. 6,455,-583) (“Pflugfelder”) was considered by the PTO during the prosecution of the '572 patent, and the patent examiner for the '572 patent noted that its claims were patentable over Pflugfelder. (PTX 478 at GAL 0037966; Tr. 104-05, 524)

175. Pflugfelder does not disclose (1) a method of treating acne or acne rosacea, (2) a method for treating the papules and pustules of rosacea, (3) administration of an antibiotic tetracycline compound in a sub-antibacterial amount that reduces lesion count wherein the lesions are papules and pustules, or (4) administration of an antibiotic tetracycline compound in an amount that is effective to treat the pa-pules and pustules of rosacea. (Tr. 103-04, 523-24)

176. Up to 50% of patients with cutaneous or facial rosacea also have symptoms of ocular rosacea. (Tr. 140, 492-93; DTX 2059 at MYL-D098660)

177. Facial rosacea and meibomian gland disease are distinct disease states, and patients with meibomian gland disease do not necessarily have acne, acne (facial) rosacea, or papules and pustules of rosacea. (PTX 478 at GAL 0037966; DTX 1045 at col. 1 lines 9-12; Tr. 102-03,524-25)

B. The Amin Patents

1.Amin '395 Patent

178. U.S. Application Number 08/697,-815, from which the '395 patent issued, was filed on August 30, 1996. (SUF ¶ 18)

179. The '395 patent issued on August 4, 1998, naming Ashok R. Amin, Steven B. Abramson, Lome M. Golub, Nungavaram 5. Ramamurthy, Thomas F. McNamara, Robert A. Greenwald, and Howard Trachtman as inventors, and RF SUNY and the Hospital for Joint Diseases as assignees. (SUF ¶ 19) The '395 patent is entitled, “Method of Using Tetracycline Compounds for Inhibition of Endogenous Nitric Oxide Production.” (PTX 3)

180. RF SUNY and NYU are the current assignees of the '395 patent. (SUF ¶ 20)

181. GLI is the licensee of the '395 patent. (SUF ¶ 21)

182. The '395 patent is set to expire on August 30, 2016. (SUF ¶ 22)

2.Amin '775 Patent

183. U.S. Application Number 09/061,-286, from which the '775 patent issued, was filed on April 16, 1998. (SUF ¶ 23)

184. The '775 patent issued on July 6, 1999, naming Ashok R. Amin, Steven B. Abramson, Lome M. Golub, Nungavaram S. Ramamurthy, Thomas F. McNamara, Robert A. Greenwald, and Howard Trachtman as inventors, and RF SUNY and the Hospital for Joint Diseases as assignees. (SUF ¶ 24) The '775 patent is entitled, “Method for Inhibiting Expression of Inducible Nitric Oxide Synthase with Tetracycline.” (PTX 4)

185. The '775 patent is a division of and claims priority from Application No. 08/697,815, filed August 30, 1996, which issued as the '395 patent. (SUF ¶ 25)

186. The '775 patent is set to expire on August 30, 2016. (SUF ¶ 26)

187. RF SUNY and NYU are the current assignees of the '775 patent. (SUF ¶ 27)

188. GLI is the licensee of the '775 patent. (SUF ¶ 28)

3.Facts relating to infringement and validity of Amin Patents

189. Nitric Oxide (“NO”) is a chemical compound (a free radical gas) made up of one nitrogen atom and one oxygen atom. (SUF ¶ 73)

190. The first biological functions of NO were discovered in the 1980s. (SUF ¶ 75)

191. NO research immediately received a great deal of attention. In 1992, NO was named “molecule of the year” by the U.S. journal Science. (SUF ¶ 76)

192. NO is a short-lived molecule that rapidly decomposes into nitrate and nitrite. (SUF ¶ 78)

193. In mammalian cells, endogenous NO is synthesized by a group of enzymes known as “nitric oxide synthases” (“NOS”). (SUF ¶ 79)

194. NOS are expressed in a wide variety of mammalian cells, and can generally be categorized into three different types, or “isoforms.” (SUF ¶ 80)

195. The production of large amounts of NO associated with inflammatory responses is generated by inducible nitric oxide synthase (“iNOS”). (SUF ¶ 81)

196. Expression of the gene coding for iNOS in cells and tissue involved in the inflammatory response leads to increased NO levels. (SUF ¶ 82)

197. Increased NO production has numerous downstream effects, e.g., vasodilation, increased vascular permeability, altered white blood cell function, and tissue damage. (SUF ¶ 83)

198. The expression of the iNOS gene is modulated by signaling cytokines that are activated in response to inflammatory stimuli. (SUF ¶ 84)

199. NO production can be reduced by inhibiting expression of the iNOS gene. (SUF ¶ 85)

200. Doxycycline decreases NO production from iNOS by destabilizing iNOS mRNA. (SUF ¶ 86)

201. Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as the presence of pathogens (e.g., bacteria) or compounds (e.g., bacterial endotoxin). (SUF ¶ 87)

202. Dr. Richard Robbins, who testified on behalf of Mylan with respect to the Amin Patents, has extensive education and experience in the area of NO and iNOS, as well as the inflammatory effects of antibiotics, including doxycycline, on NO and iNOS. (DTX 2168; Tr. 672-676)

203. Dr. Robbins is recognized as an expert in the area of NO and iNOS as well as the inflammatory effects of antibiotics, including doxycycline, on NO and iNOS. (Tr. 676)

204. Dr. Matthew Grisham, who testified on behalf of Galderma with respect to the Amin Patents, has extensive education and experience in the area of NO and iNOS, as well as acute and chronic inflammation and NO. Dr. Grisham is recognized as an expert in molecular and cellular physiology particularly as it relates to the biological functions of nitric oxide. (Tr. 261; PTX 245)

205. Claims 1, 2, 4, 11, 13, 14, and 16 of the '395 patent and claims 1, 2, 4, 5, and 9 of the '775 patent require administration of a tetracycline in an amount sufficient to decrease or inhibit endogenously produced NO or inhibit the expression of iNOS. (PTX 3 at col. 21 line 48-col. 24 line 9; PTX 4 at col. 21 line 47-col. 22 line 63)

206. There are no tests, studies, or other experimental data showing that a 40 mg dose of doxycycline administered daily decreases NO production or inhibits iNOS expression. (Tr. 289-90,291,687-88)

207. There is no quantitative data showing a decrease of NO production or inhibition of iNOS expression when a 40 mg dose of doxycycline is. administered daily. (Tr. 292)

208. According to the Oracea® package insert, a 40 mg daily dose of doxycycline achieves a steady state Cmax blood concentration of 0.6 |xg/ml. (PTX 426 at GAL 0229996; Tr. 293,681-82)

209. There is no evidence that the 0.6 irgdnl steady state Cmax blood concentration achieved by a 40 mg daily administration of doxycycline has an effect on endogenous NO production or iNOS expression. (Tr. 294, 680-90)

210. Examples 2 and 3 in the Amin Patents provide data regarding the effect of doxyeycline on endogenous NO production and iNOS expression observed as part of in vitro experiments. (PTX 3 at col. 11 line 22-col. 12 line 67; Tr. 682-83)

211. Figures 1A, IB, and 1C of the Amin Patents present graphical data regarding the effect of doxyeycline and minocycline on endogenous NO production and iNOS expression in the study discussed in Example 2 of the Amin Patents. (PTX 3 at FIG-1A, FIG-1B, FIG-IC; see also Tr. 683-84)

212. To determine the effect of doxycycline and minocycline on endogenous NO production and iNOS expression in the studies discussed in Examples 2 and 3 of the Amin Patents, nitrite, a stable-end product of the decomposition of NO, was measured in the mediums treated with doxyeycline and minocycline. (PTX 3 at col. 11 line 22-col. 12 line 67; Tr. 683)

213. As shown in Figures 1A, IB, and 1C of the Amin Patents, doxyeycline does not appear to have a dose-dependent inhibition of nitrite below 10 p,g/ml doxycyeline. (PTX 3 at FIG-1A, FIG-1B, FIG-IC; see also Tr. 684-85)

214. The 0.6 pg/ml Cmax steady state blood concentration achieved by the 40 mg doxyeycline in Oracea® administered daily is “far below” what one would expect to be required to decrease NO production. (Tr. 687-88)

215. As shown in Figures 2A and 2B, doxyeycline appears to have a dose-dependent inhibition of nitrite at concentrations of doxyeycline much higher than 0.6 ixghnl doxyeycline. (PTX 3 at FIG-2A, FIG-2B; Tr. 687-88)

216. The results of the experiments performed in Dr. Robbins’ laboratory regarding the in vitro effect of doxyeycline on nitrite production, NO production, and iNOS protein expression are published in Hoyt et al., “Doxyeycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells,”. J. Immun. (2006) 176:567-72. (DTX 1627; Tr. 688)

217. In experiments conducted in Dr. Robbins’ laboratory, doxyeycline showed an inhibition of iNOS expression and NO production at a concentration of 30 ¡xg/ml, but not at 10 |xg/ml and lower. (Tr. 688-690; DTX 1627)

218. The data from Dr. Robbins’ research shows that the maximal blood concentration obtained with the 40 mg per day dosage of doxyeycline is insufficient to cause inhibition of iNOS expression or NO production. (Tr. 689-90)

219. CollaGenex, the predecessor in interest to Galderma, proposed that the FDA approve the following language for the Oracea® label: “[Oracea®] has been shown in vitro to suppress pro-inflammatory processes such as neutrophil activation, inhibition of matrix metalloproteases, endogenous nitric oxide release, and expression of inducible nitric oxide synthase.” (DTX 1340 at GAL 0034431)

220. The FDA rejected CollaGenex’s proposed language, requiring the label to read instead: “The mechanism of action of Oracea® in the treatment of inflammatory lesions of rosacea is unknown,” (PTX 426 at GAL 0229996)

221. Dr. Grisham disagrees with the FDA that “[t]he mechanism of action of Oracea® in the treatment of inflammatory lesions of rosacea is unknown.” (Tr. 297-99; PTX 426 at GAL 0229996)

222. Gürer et al., “The seroprevalence of Helicobacter pylori and nitric oxide in acne rosacea,” published in Int’l J. Dermatol. (2002) 41:768-770 (“Gürer”), is cited within one of the review articles upon which Dr. Grisham relies in support of his opinion that NO and iNOS are involved in the mechanism of action of acne rosacea. (Tr. 270-71)

223. Giirer concluded that “the inflammatory species NO ... has no role in the inflammatory mechanism of acne rosacea.” (DTX 2180 at 770)

224. Another of Galderma’s experts, Dr. Webster, testified that “[w]e still don’t know convincingly what the cause of rosacea is.” (Tr. 136)

225. Robert Ashley, the named inventor on the Ashley Patents, testified that he did not “think causality has ever been proven one way or the other” with respect to acne rosacea. (Tr. 670)

226. Mylan’s expert, Dr. Robbins, testified that “there is no evidence that nitric oxide is involved in the pathogenesis of rosacea.” (Tr. 692)

227. The Amin Patents list more than thirty different chronic inflammatory conditions. (PTX 3 col. 7 line 58-col. 8 line 3; PTX 4 col. 7 line 53-col. 8 line 8)

228. The word “rosacea” does not appear anywhere in the Amin Patents. (PTX 3; PTX 4;Tr. 691-92)

229. The Amin Patents contain the first disclosure that tetracycline compounds inhibit iNOS expression and NO production. (Tr. 740^41)

230. Prior to August 1996, there were no literature reports in which tetracyclines were reported to have any effect on NO or iNOS. (Tr. 740)

231. None of the eight prior art references relied on by Mylan’s Dr. Robbins (“Robbins References”) disclose, explicitly or inherently, NO or iNOS. (DTX 2183; DTX 2181; DTX 2182; DTX 2184; DTX 2188; DTX 1603; DTX 2186; DTX 2187; see also Tr. 730-37)

232. None of the eight Robbins References disclose, explicitly or inherently, using any tetracycline compounds in methods of decreasing NO production or inhibiting iNOS expression. (DTX 2183; DTX 2181; DTX 2182; DTX 2184; DTX 2188; DTX 1603; DTX 2186; DTX 2187; see also Tr. 730-33, 735-39)

233. None of the eight Robbins References disclose, explicitly or inherently, whether the patients in those studies experienced elevated levels of NO production or iNOS expression. (DTX 2183; DTX 2181; DTX 2182; DTX 2184; DTX 2188; DTX 1603; DTX 2186; DTX 2187; see also Tr. 730-33, 735-39)

234. Dr. Robbins did not form an opinion as to whether 20 mg of doxycycline administered twice a day decreases iNOS expression or NO production in humans with periodontitis or inhibits endogenous production of NO or expression of iNOS in patients with rheumatoid arthritis. (Tr. 730, 734-35)

235. Dependent claims 2 and 14 of the '395 patent and claim 2 of the '775 patent add the limitation that the administered tetracycline compound have substantially no antimicrobial activity. (PTX 3 at col. 21 lines 54-56; id. at col. 23 lines 8-10; PTX 4 at col. 21 lines 53-55)

236. Dependent claims 2 and 14 of the '395 patent and claim 2 of the '775 patent require a dose of tetracycline sufficient to reduce endogenous NO production or inhibit iNOS expression. (PTX 3 at col. 21 lines 49-56; id. at col. 22 line 67-col. 23 line 3; id. at col. 23 lines 8-10; PTX 4 at col. 21 lines 48-55)

237. The lowest concentration of doxycycline and minocycline used in the studies that are the subject of Examples 2 and 3 of the Amin Patents is 5 [rg/ml. (PTX 3 at col. 11 line 22-col. 12 line 67, FIG-1 A, FIG-1B, FIG-1C, FIG-2A, FIG-2B; Tr. 720-21)

238. The Amin Patents do not teach that 5 |o,g/ml is a concentration that has substantially no antimicrobial activity. (PTX 3; PTX 4; Tr. 720-21)

239. The Amin Patents do not provide any teaching or description to allow one of ordinary skill in the art to make or use a dose of a tetracycline that is both sufficient to reduce endogenous NO or inhibit iNOS expression and has substantially no antimicrobial activity. (Tr. 719-21)

C. The Chang Patent

1. Chang '532 Patent

240. U.S. Application Number 10/819,-620, from which the '532 patent issued, was filed on April 7, 2004. (SUF ¶ 29)

241. The '532 patent issued on July 6, 2010, naming Rong-Kun Chang, Arash Raoufinia, and Niraj Shah as inventors, and listing Supernus Pharmaceuticals, Inc. as assignee. (SUF ¶ 30) The '532 patent is entitled, “Once Daily Formulations of Tetracyclines.” (PTX 5)

242. Supernus is the current assignee of the '532 patent. (SUF ¶ 31)

243. The '532 patent is set to expire on December 19, 2027. (SUF ¶ 32)

244. GLI is the licensee of the '532 patent. (SUF ¶ 33)

2. Facts relating to infringement and validity of Chang Patent

245. Dr. Edward Rudnic, who testified on behalf of Galderma, is an expert in the field of pharmaceutical drug development and formulation. (Tr. 174)

246. Dr. David Friend, who testified on behalf of Mylan, is an expert in the field of designing and developing controlled release drug delivery systems. (Tr. 782)

247. Dr. Werner Rubas, who testified on behalf of Mylan, is an expert in the area of phannacokinetics and pharmacokinetic modeling. (Tr. 753)

248. Mylan admits that its Generic Product infringes claims 1-3, 5, 7-9,13-17, and 19-21 of the '532 patent. (D.I. 103 (C.A. No. 10-892))

249. Mylan’s Generic Product contains an amount of doxycycline that, when administered once-daily in accordance with Mylan’s Label, will give steady state blood levels of doxycycline of a minimum of 0.1 p,g/ml and a maximum of 1.0 p,g/ml. (PTX 5, claims 1, 15, 20; PTX 464 at GAL 0004365-66; DTX 2091 at MYL-D118693; Tr. 182-83)

250. Mylan’s Generic Product contains an amount of doxycycline that, when administered once-daily in accordance with Mylan’s Label, will give steady state blood levels of doxycycline of between 0.3 |jug/ml to 0.8 |xg/ml. (PTX 5, claims 4 and 18; PTX 464 at GAL 0004365-66; DTX 2091 at MYL-D118693; Tr. 183, 640)

251. Mylan’s Generic Product is bioequivalent to Oracea® and Mylan relied on Galderma’s pivotal pharmacokinetic study of Oracea® in seeking FDA approval for Mylan’s Generic Product. (Tr. 288: SUF ¶ 69)

252. The pivotal pharmacokinetic study demonstrates that 30 of 31 subjects have steady state blood levels of doxycycline of a minimum of 0.1 |xg/ml and a maximum of 1.0 |xg/ml. (PTX 464 at GAL 0004365-66; DTX 1305; Tr. 183)

253. The pivotal pharmacokinetic study demonstrates that the majority of subjects will have steady state blood levels of doxycycline of between 0.3 |rg/ml to 0.8 |rg/ml at the majority of time points. (PTX 464 at GAL 0004365-66; Tr. 183)

254. Mylan’s expert, Dr. Friend, testified that the Ashley CR References and the Ashley Rosacea Reference are the closest prior art to the Chang patent. (Tr. 832)

255. None of the references Mylan relies on expressly discloses once-daily doses of doxycycline. (Tr. 191-96, 831-33, 844, 853)

256. None of the references Mylan relies on expressly discloses formulations with a 30 mg IR portion and a 10 mg DR portion. (Tr. 829-34, 839, 844, 849-50)

257. None of the references Mylan relies on expressly discloses formulations that result in steady state blood levels of a minimum of 0.1 ¡xg/ml to a maximum of 1.0 ¡xg/ml. (Tr. 831-34, 845-46, 850)

258. None of the references Mylan relies on expressly discloses formulations that result in steady state blood levels of between 0.3 ¡xg/ml to 0.8 ¡xg/ml. (Tr. 190-91,195-98, 200-01, 850)

259. The Ashley CR References do not disclose any examples of any formulations. (Tr. 191, 194-95, 833; DTX 1008)

260. The inventor of the Ashley CR References did not make any formulations of doxycycline. (Tr. 191, 194-95, 833, 869-70; DTX 1008)

261. The Ashley CR References do not disclose, teach, or suggest the use of an IR/DR formulation. (Tr. 192; DTX 1008)

262. The Ashley CR References do not disclose, teach, or suggest any composition that contains a 30 mg IR component or any composition that contains a 10 mg DR component. (Tr. 192, 194-95, 834, 839; DTX 1008)

263. The Ashley Rosacea Reference does not disclose any examples of any formulations. (Tr. 195, 831)

264. The Ashley Rosacea Reference does not disclose, teach, or suggest any composition that contains a 30 mg IR component or any composition that contains a 10 mg DR component. (Tr. 195-96, 829, 832)

265. The Ashley Rosacea Reference does not disclose, teach, or suggest any formulation that will give steady state blood levels of doxycycline of a minimum of 0.1 ¡xg/ml and a maximum of 1.0 ¡xg/ml. (Tr. 831)

266. The disclosure of the '304 patent is not as close to the Chang Patent claims as the disclosures in the Ashley References. (Tr. 844)

267. The '304 patent does not disclose, teach, or suggest the use of doses of doxycycline that do not have an antibiotic effect or doses with a maximum plasma concentration of 1.0 ¡xg/ml. (Tr. 200-01, 845-47; DTX 2119)

268. The '304 patent teaches away from the inventions of the Chang Patent because the '304 patent discloses and claims formulations in which both the IR and DR components are independently therapeutic and antibiotic doses. (DTX 2119 at col. 5 line 42-col. 6 line 49; see also Tr. 200-01)

269. Mylan’s expert, Dr. Friend, testified that one of ordinary skill in the art would not look to a patent relating to amphetamine drugs, such as the '819 patent, for guidance in formulating a once daily doxycycline product. (Tr. 848-49, 196-98, 925-27)

270. The physical and chemical characteristics of doxycycline and amphetamines are different. (Tr. 196-98, 849, 925-27)

271. The '819 patent teaches away from the inventions of the Chang Patent because the '819 patent teaches formulations that result in continually increasing plasma concentration levels of the drug. (Tr. 196-97, 849-50, 925-27)

272. The '819 patent does not mention doxycycline. (DTX 2116; see also Tr. 197-98)

273. The '819 patent does not disclose, teach, or suggest any composition that contains a 30 mg IR component or any composition that contains a 10 mg DR component. (Tr. 197-98, 850)

274. The '819 patent does not disclose, teach, or suggest any method of treating rosacea. (Tr. 197-98,850-51)

275. The '819 patent teaches away from the invention of the Chang Patent because it teaches formulations that result in Cmax levels greater than 1.0 p,g/ml. (Tr. 850)

276. Neither the '932 application, the '106 application, nor the '819 patent provide any motivation to combine their teachings. (Tr. 207-08)

277. Robert Ashley did not invent the inventions claimed in the Chang Patent and had no idea how to create any formulations that met the steady state blood levels claimed. (Tr. 869-70, 961-62, 966-67)

278. CollaGenex had “no meaningful idea what composition might achieve” a once-daily doxycycline product without antibiotic effect or if it was even possible to do so because CollaGenex lacked formulation expertise. (Tr. 869; see also Tr. 217-18, 913-16, 964-67)

279. Dr. Richard Chang and the other named inventors of the Chang Patent took the target blood level provided by CollaGenex and gave it “meaning.” (Tr. 915-16)

280. The named inventors of the Chang Patent conceived of and proposed the IR and DR combination and the claimed IR:DR bead ratio of 75:25 to CollaGenex. (Tr. 914-15, 938, 896-97, 910-11, 917-18, 964-65, 967-68)

281. Microtrol® technology is a marketing term used for business development purposes to broadly describe the general concept of having beads in a capsule and is not actually a fixed technology. (Tr. 892, 942)

282. As of the time of the invention of the Chang Patent, the inventors were in possession of data that demonstrated that the formulations of doxycycline claimed in the Chang Patent will give steady state blood levels of doxycycline of between 0.3 |j,g/ml to 0.8 |xg/ml. (PTX 5, claims 4 and 18; DTX 1305; Tr. 184)

VII. OBJECTIVE CONSIDERATIONS OF NON-OBVIOUSNESS

283. In 1998, CollaGenex attempted, in partnership with FH Faulding & Co. Limited (“Faulding”), to develop a once-daily controlled-release formulation of doxycycline for the treatment of rosacea. (Tr. 214-15, 944)

284. Faulding formulated three 40 mg doxycycline drug products intended for once-daily administration. (PTX 530; PTX 95; PTX 96; Tr. 214-15, 964-65)

285. Formulations developed by Faulding were not successful in achieving once daily administration of doxycycline because bioavailability was significantly compromised. (PTX 580; PTX 95; PTX 96; PTX 510; Tr. 215-17, 238, 944, 969-70)

286. It was unexpected that a therapeutic, controlled-release, onee-daily dosage form which provided steady state plasma concentrations of doxycycline of a minimum of 0.1 (ig/ml and a maximum of I.0 |xg/ml could be achieved. (Tr. 214)

287. Despite already marketing several different doses of doxycycline, including 50 mg, 100 mg, and 150 mg doses of doxycycline immediate-release tablets, Mylan still seeks to market a generic formulation of Oracea®. (Tr. 327-28, 498)

288. Oracea® is a commercial success. (Tr. 129, 214, 542)

289. According to IMS sales data maintained by Mylan, Oracea®’s sales (i.e., “brand dollars”) for the period of January 2007 through December 2007 were approximately $43.0 million. (DTX 2243 at MYL-D118537) Oracea®’s brand dollars for the period of January 2008 through December 2008 were approximately $80.4 million. (Id. at MYL-D118540) Oracea®’s brand dollars for the period of January 2009 through December 2009 were approximately $155.3 million. (Id.)

290. Mylan projected that Oracea®’s brand dollars for the period of January 2010 through December 2010 would be approximately $236.7 million. (DTX 2243 at MYL-D118540) Mylan projected that Oracea®’s brand dollars for the period of January 2011 through December 2011 would be approximately $258.1 million. (Id.)

291. Prior to Oracea®, there was a long-felt, unmet need for an effective, long-term oral treatment for rosacea without the side effects associated with long-term administration of antibiotics (e.g., gastrointestinal upset and phototoxicity). (Tr. 75-76, 540-43)

292. Oracea® is an effective, long-term oral treatment that does not have the undesirable side effects of traditional dose antibiotics. (PTX 426; Tr. 75-76, 128-30, 184, 540)

293. Prior to Oracea®, there was a long-felt, unmet need for a rosacea treatment without antibiotic effect that could be administered as a onee-daily formulation of doxycycline to increase patient compliance and therapeutic outcome. (PTX 5 at col. 2 lines 1-4; DTX 1640 at MYL-D098594; Tr. 214, 456, 785)

PROCEDURAL BACKGROUND

On March 19, 2009, Plaintiffs initiated a patent infringement lawsuit against Mylan pursuant to 35 U.S.C. § 271(e)(2)(A). (D.I. 1) In the complaint, Galderma asserts that Mylan’s ANDA, through which Mylan seeks to market a generic version of Oracea®, infringes Galderma’s rights in the Ashley Patents and the Amin Patents. (D.I. 1 at 5-8) On April 2, 2010, Galderma filed a motion for preliminary injunction and for a temporary restraining order. (D.I. 87) On June 28, 2010, the Court granted Galderma’s motion and entered a preliminary injunction. (D.I. 176; D.I. 188)

The Chang Patent issued on July 6, 2010. (PTX 5) Mylan subsequently brought suit against Galderma, seeking a declaratory judgment that its Generic Product does not infringe any claims of the Chang Patent and that the Chang Patent is invalid. (Civ. No. 10-892-LPS, D.I. 1) On December 1, 2010, the Court consolidated Mylan’s declaratory judgment action with Galderma’s ANDA action. (D.I. 239) The parties entered into a stipulation and order on March 11, 2011, in which Mylan conceded that its Generic Product infringes all asserted claims of the Chang Patent except claims 4 and 18. (D.I. 103)

The Court held a consolidated bench trial from July 5-9, 2011, addressing infringement and invalidity of the Ashley Patents, the Amin Patents, and the Chang Patent. (D.I. 270; D.I. 271; D.I. 272; D.I. 273) The parties completed post-trial briefing on July 29, 2011. (D.I. 265; D.I. 267; D.I. 274; D.I. 275)

DISCUSSION

I. THE ASHLEY PATENTS

A. Infringement

Galderma asserts that Mylan has infringed and/or will infringe (i) claims 1, 22, 23, 26, 28, and 30 of the '267 patent and (ii) claims 1, 12-15, 20, 21, 23, 24, and 26 of the '572 patent. Mylan counters that it does not infringe any of the asserted claims of the Ashley Patents, directly or indirectly, literally or under the doctrine of equivalents. The Court agrees with Mylan.

1. Galderma Failed To Prove That Mylan’s Generic Product Contains An Amount Of Doxycycline That Does Not Significantly Inhibit The Growth Of Microorganisms

Each of the asserted claims of the '267 and '572 patents require the administration of an amount of doxycycline “that does not significantly inhibit the growth of microorganisms, e.g., bacteria.” Galderma failed to prove that Mylan’s ANDA product does not significantly inhibit the growth of microorganisms. To the contrary, in vivo studies show that 40 mg doxycycline administered once-daily does significantly inhibit the growth of some microorganisms in some locations of some humans at some times. Galderma’s contention that Mylan’s Label acknowledges that Mylan’s Generic Product will infringe is incorrect. Galderma’s other arguments for infringement are also unpersuasive. Each of these conclusions is described further below.

a. In vivo studies

Nothing in the Court’s construction of the “amount” terms limits the “no significant inhibition in growth of microorganisms” limitation to certain portions of the human body, or to long-term effects, or to certain humans or certain microorganisms. Hence, the “amount” limitation applies to all microorganisms found in all parts of the human body at all times. (See Tr. 142 (Galderma’s Dr. Webster agreeing that Ashley Patents’ claims are not limited to any type of microbe or any particular part of human body); see also Tr. 556 (Dr. Chambers agreeing)) As there are approximately 100,000,000,000,000 bacterial cells that inhabit a typical human body at any moment (Tr. 149, 557), it may be impossible to prove infringement of a claim that requires no significant inhibition in the growth of any of them. In any event, here Galderma failed to prove that Mylan’s ANDA product will not significantly inhibit the growth of microorganisms.

To the contrary, although Mylan does not have a burden to show non-infringement, Mylan proved through in vivo studies that a 40 mg once-daily administration of doxycycline significantly inhibits the growth of microorganisms in the oral cavity over periods of two weeks, three months, and twelve months. (See Tr. 562-79; DTX2097 (Haffajee) at 152; DTX2121 (Thomas) at 1476-78; DTX2120 (Walker 2000) at 1466-67) As Mylan’s expert, Dr. Chambers testified: (a) Haffajee found a significant spike in the percentage of doxycycline-resistant microorganisms in the oral cavity following administration of 20 mg doxycycline twice-daily, which was explained by the killing of non-resistant microorganisms by the doxycycline; (b) Thomas found an increase in MIC50 values for certain species isolates, indicating emergence of drug resistant cells due to significant inhibition of susceptible cells, all resulting from administration of 20 mg doxycycline twice-daily; and (c) Walker 2000 found a statistically significant difference in the number of spirochetes between a group receiving 20 mg doxycycline twice-daily as compared to a group receiving a placebo.

Galderma’s expert on infringement of the Ashley Patents, D