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Galderma Laboratories, L.P. v. Sun Pharmaceutical Industries Ltd.

United States District Court, D. Delaware

September 30, 2019

GALDERMA LABORATORIES, L.P., NESTLE SKIN HEALTH S.A., and TCD ROYALTY SUB, LLC, Plaintiffs,
v.
SUN PHARMACEUTICAL INDUSTRIES LIMITED and SUN PHARMACEUTICAL INDUSTRIES, INC., Defendants. Term Galderma Construction Sun Construction Court's Construction Galderma Sun

          Jack B. Blumenfeld and Jeremy Tigan, MORRIS, NICHOLS, ARSHT & TUNNELL LLP, Wilmington, DE, Gerald J. Flattman, Jr., Evan D. Diamond, and Vanessa Y. Yen, KING & SPALDING LLP, New York, NY Attorneys for Plaintiffs

          Kelly E. Farnan and Nicole K. Pedi, RICHARDS, LAYTON & FINGER, P.A., Wilmington, DE Huiya Wu and Tiffany Mahmood, GOODWIN PROCTOR LLP, New York, NY Nicholas K. Mitrokostas and Todd Marabella, GOODWIN PROCTOR LLP, Boston, MA Attorneys for Defendants

          MEMORANDUM OPINION

          STARK, U.S DISTRICT JUDGE

         Galderma Laboratories, L.P., Nestle Skin Health S.A., and TCD Royalty Sub, LLC (together, "Galderma" or "Plaintiffs") sued Sun Pharmaceutical Industries Limited and Sun Pharmaceutical Industries, Inc. (together, "Sun" or "Defendants") under the Hatch-Waxman Act, 35 U.S.C. § 271(e). (See D.I. 1) Sun seeks to bring to market a new drug ("Sun's NDA Product" or "Sun NDA Product") which is bioequivalent to Galderma's Oracea Capsules ("Oracea"), a once-daily 40 milligram ("mg") administration of doxycycline for the treatment of the papules and pustules of acne rosacea. (D.I. 1 ¶ 17) Galderma alleges that Sun's NDA Product infringes U.S. Patent Nos. 8, 206, 740 ("Chang '740 patent"), 8, 394, 405 ("Chang '405 patent"), 8, 470, 364 ("Chang '364 patent"), and 7, 749, 532 ("Chang '532 patent") (collectively, the "Chang patents").[1] (See D.I. 1) The Chang patents are generally directed to low-dose doxycycline formulations with immediate-release and delayed-release portions, which are used for the treatment of the papules and pustules of acne rosacea.

         In December 2018, the Court held a three-day bench trial. (See D.I. 208-10 ("Tr.")) Thereafter, the parties submitted proposed findings of fact (D.I. 204, 206) and post-trial briefing (D.I. 205, 207, 211, 212). In August 2019, the Court ordered supplemental claim construction briefing. (See D.I. 222; see also D.I. 226, 227, 228, 229)

         Pursuant to Federal Rule of Civil Procedure 52(a), and having considered the entire record in this case and the applicable law, the Court concludes that: (1) Sun's NDA Product infringes the asserted claims of the Chang patents; and (2) the asserted claims of the Chang patents are not invalid for obviousness.

         The Court's findings of fact and conclusions of law are set forth in detail below.

         FINDINGS OF FACT

         I. Introduction

         1. This is a patent infringement action arising out of Defendant Sun Pharmaceutical Industries Limited's ("Sun") submission of New Drug Application ("NDA") No. 209259 to the U.S. Food and Drug Administration ("FDA") under § 505(b)(2) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 355(b)(2), seeking FDA approval of doxycycline hyclate tablets, 40 mg. (D.I. 1)

         2. Plaintiff Galderma Laboratories, L.P. ("Galderma") holds NDA No. 50-805 on Oracea capsules, which was approved by the FDA on May 26, 2006. (D.I. 1 at ¶ 17; D.I. 195 Ex. 1 at ¶ 58) Galderma purchased rights to the Oracea product and other assets from CollaGenex Pharmaceuticals, Inc. in 2008. (Grabowski Tr. at 481)[2]

         3. At trial, Galderma asserted infringement of claim I of the '740 patent, claims 1 and 3 of the '405 patent, and claims 1 and 2 of the '364 patent. (D.I. 202) Each of the asserted claims of these Chang patents covers a once-daily oral composition containing 30 mg or about 30 mg of immediate release ("IR") doxycycline and 10 mg or about 10 mg of delayed release ("DR.") doxycycline, resulting in a steady state doxycycline blood level of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml. Some claims are directed to the amounts of doxycycline in the form of ratios, such as 75% IR:25% DR.

         4. Sun contends that it does not infringe any of the asserted claims of the Chang patents because (i) the Sun NDA product does not contain the claimed amounts of IR formulation or portion of doxycycline; (ii) the Sun NDA product does not contain any DR formulation or portion of doxycycline; and (iii) Plaintiffs have presented no evidence that the administration of Sun's NDA Product results in the claimed steady-state blood levels.

         5. Sun further contends that the asserted claims of the Chang patents would have been obvious over the Ashley Applications (Published International Patent Application WO02/080932 ("the '932 publication") and U.S. Provisional Application No. 60/281, 854 ("the Ashley '854 application")) (together, the "Ashley Applications") in light of the available pharmacokinetic information concerning Periostat® ("the Periostat Package").

         II. Patents-in-Suit

         6. The Chang patents all claim priority back to Provisional Application No. 60/460, 963, filed on April 7, 2003. Thus, the priority date for the Chang patents is April 7, 2003. (PTX-4.1; Statement of Uncontested Facts (D.I. 195 Ex. 1) ("SUF") at ¶¶ 32, 36, 47; Chambliss Tr. at 306)

         7. Galderma asserts claim 1 of the Chang '740 patent against Sun. Claim 1 of the '740 patent recites:

An oral pharmaceutical composition of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 µg/ml, and a maximum of 1.0 µg/ml, the composition consisting of (i) an immediate release (IR) portion comprising 30 mg doxycycline; (ii) a delayed release (DR) portion comprising 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

         8. Galderma asserts claims 1 and 3 of the Chang '405 patent. Claim 1 of the '405 patent recites:

An oral pharmaceutical composition comprising about 40 mg of total doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml, wherein the composition consists of 70 to 80 percent of the doxycycline formulated as an immediate release (IR) formulation and 20 to 30 percent of the doxycycline formulated as a delayed release (DR) formulation.

         9. Claim 3 of the '405 patent recites "[t]he composition of claim 1, wherein the ratio of IR to DR is 75:25."

         10. Galderma asserts claims 1 and 2 of the Chang '364 patent. Claim 1 of the '364 patent recites:

An oral pharmaceutical composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

         11. Claim 2 of the' 3 64 patent recites:

An oral pharmaceutical composition comprising doxycycline, which at a once-daily dosage will give blood levels of the doxycycline of a minimum of 0.1 fag/ml and a maximum of 1.0 µg/ml, the composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; as [sic] a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

         III. Witnesses

         A. Galderma's Experts

         12. Dr. Edward Rudnic is the Chief Executive Officer of DisperSol Technologies, a biopharmaceutical company in Georgetown, Texas. (Rudnic Tr. at 102) Dr. Rudnic was offered and recognized as an expert in the invention, design, development, testing, manufacturing, and commercialization of drug products, including pharmaceutical formulations. (Rudnic Tr. 106)

         13. Dr, Henry Grabowski is the Director of the Duke University program in Pharmaceuticals and Health Economics. (Grabowski Tr. at 473) Dr. Grabowski was offered and recognized as an expert in economics in the pharmaceutical field, including in determining commercial success and nexus to patents. (Grabowski Tr. at 474)

         B. Sun's Experts

         14. Dr. Walter Galloway Chambliss is a Professor in Pharmaceutics and Drug Delivery, a Research Professor in the Research Institute of Pharmaceutical Sciences, and Interim Associate Vice Chancellor for Research at the University of Mississippi. (Chambliss Tr. at 267) Dr. Chambliss was offered and recognized as an expert in the field of pharmaceutical sciences and pharmaceutical formulations, including the development of pharmaceutical formulations with varying release mechanisms. (Chambliss Tr. at 271-72)

         15. Mr. Ivan Hofmann is a vice president and managing director at Gleason IP, an economics, finance, and accounting firm, where he is the head of the intellectual property practice. (Hofmann Tr. at 498) Mr. Hofmann was offered and recognized as an expert in pharmaceutical economics. (Hofmann Tr, at 501)

         C. Fact Witnesses

         16. Dr. Richard Rong-Kim Chang is one of the named inventors of the Chang patents. (Chang Tr. at 394-95; see also PTX-4; PTX-5; PTX-7)

         17. Dr. Chang was formerly employed at Shire Laboratories ("Shire") and at Supernus Pharmaceuticals, Inc. ("Supernus"), and was involved in the development of an oral doxycycline product. (Chang Tr. at 400)

         18. Mr. Arash Raoufraia is one of the named inventors of the Chang patents. (Raoufinia Tr. at 408; see also PTX-4; PTX-5; PTX-7) Mr. Raoufinia worked at Shire as a scientist between March 2002 and January 2004. (Raoufinia Tr. at 408)

         19. Dr. Romi Singh is the Vice President of Formulation Development in the Formulation Development Group at Sun. (Singh Tr. at 193-94) Dr. Singh previously led the Formulation Development Group for differentiated and complex oral products and was involved in the formulation development of Sun's NDA product. (Singh Tr. at 194-96)

         20. Dr. Rajeev Mathur is the Vice President and Head R&D Regulatory Affairs Gurgaon for Sun Pharmaceuticals. (Mathur Tr. at 230) Dr. Mathur works with Sun's global regulatory markets, and has knowledge of Sun's regulatory submissions. (Mathur Tr. at 231)

         21. Dr. Bharati Nadkarni is a Vice President at Sun Pharmaceuticals. (Nadkarni Tr. at 244)

         IV. Person of Ordinary Skill in the Art

         22. A person of ordinary skill in the art ("POSA") in the field of the Chang patents as of the priority date had education and experience in drug delivery and formulation. In this field, education and experience levels may vary among persons of ordinary skill, with some persons holding a Bachelor's degree with many years of experience and others holding higher degrees, but having less work experience, (Rudnic Tr. at 109) Through education or experience, a POSA would have knowledge and skill relating to the use, function, and formulation of pharmaceutical excipients; knowledge and training regarding the equipment, processes, and techniques used to analyze and test formulation materials; and an understanding of pharmacokinetic principles and how they relate to drug development. (Id.)

         V. Oracea Capsules

         23. Oracea capsules are an oral pharmaceutical composition indicated for once-daily use for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. (Webster Tr. at 69; see also PTX-309.6)

         24. The Oracea capsules composition is 40 mg hard gelatin capsule shells filled with two types of doxycycline beads, 30 mg immediate release beads and 10 mg delayed release beads. (Webster Tr. at 69, 153-54; Rudnic Tr. at 153-54; see also PTX-344.5)

         25. Oracea capsules are administered in an amount that is effective to treat the papules and pustules of rosacea. (Webster Tr. at 70-72; see also PTX-242.3)

         26. The patents-in-suit are listed in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations ("Orange Book") for Oracea capsules. (SUF ¶ 57)

         27. Study COL-101-SSPK-106 (the "Pivotal PK Study") is a clinical pharmacokinetic study of Oracea capsules and is the source of the steady-state pharmacokinetic data for Oracea capsules reported in the Oracea label. (PTX-309.6-7; PTX-344.5; Rudnic Tr. at 143-45)

         28. The Pivotal PK Study reports that 30 of 31 subjects who were administered Oracea capsules had plasma concentrations of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml at steady-state (Day 7). (PTX-309.6-7; PTX-327.1, 6-8; PTX-343.12; see also Rudnic Tr. at 141, 143-45) One subject (Subject No. 14) maintained plasma concentrations at steady-state of a minimum of 0.1 µg/ml but briefly exceeded a plasma concentration of 1.0 µg/ml (with a measured concentration of 1.08 (µg/ml). (PTX-343.12)

         VI. Sun's NDA Product

         29. Sun Ltd. submitted NDA No. 209259 to the FDA pursuant to § 505(b)(2) of the Federal Food, Drug and Cosmetic Act, seeking approval of Sun's NDA Product: a once-daily 40 mg doxycycline hyclate tablet. In order to demonstrate that Sun's NDA Product is safe and effective, Sun included in its application data showing that Sun's NDA Product is bioequivalent to Galderma's Oracea capsules. (PTX-327.5; see also Rudnic Tr, at 127-28; Nadkarni Tr. at 245; Mathur Tr. at 231-32; Singh Tr. at 197; Chambliss Tr. at 364-65) The FDA has tentatively approved Sun's NDA Product. (PTX-343.1)

         30. Sun's NDA Product is a once-daily doxycycline tablet product, with an active ingredient equivalent to that of Oracea capsules, as well as the same strength, route of administration, and indication for use as Oracea capsules. (PTX-343.11-12; Rudnic Tr. at 116; Chambliss Tr. at 351-52; Nadkarni Tr. at 244-45; Singh Tr. at 197)

         31. The active ingredient in Sun's NDA Product is doxycycline hyclate. (See, e.g., PTX-343.11; Singh Tr. at 204) The total amount of doxycycline in each tablet of Sun's NDA Product is 40 mg. (See, e.g., PTX-343.12; Rudnic Tr. at 116; Chambliss Tr. at 352; Singh Tr. at 197)

         32. The Sun NDA Product is a bilayer tablet consisting of two distinct layers, each of which contains doxycycline. (DTX-574.50-51, 126-27; Rudnic Tr. at 117, 168; Chambliss Tr. at 273-74)

         33. The Sun NDA describes these two layers as an immediate release ("IR") layer and a modified release ("MR") layer. (DTX-574.50-51, 126-27; Rudnic Tr. at 117; Chambliss Tr. at 273-74)

         34. The IR and MR layers of the Sun NDA Product are manufactured separately, using different ingredients and different processes. (DTX-574.126-27; Chambliss Tr. at 286-87)

         35. Sun's NDA Product contains pharmaceutical acceptable excipients, including at least the following: microcrystalline cellulose (Avicel PH 102); crospovidone (Type A) (Polyplasdone XL); povidone (i.e., polyvinylpyrrolidone) (Kollidon 30); colloidal silicon dioxide (Aerosil 200); iron oxide sicovit yellow; magnesium stearate (vegetable grade); microcrystalline cellulose (Avicel PH 200); hypromellose (Methocel K 4M Premium CR); hypromellose (Methocel K 100 Premium LV CR); opadry 03F570012 beige; and purified water. (PTX-328. 2-3; see also Singh Tr. at 205-06; Rudnic Tr. at 151, 153; Chambliss Tr. at 277, 285-86)

         A. The IR Layer

         36. The IR layer of the Sun NDA Product contains 26.4 mg of doxycycline, (DTX-574.50; Rudnic Tr. at 117-18, 168-69; Chambliss Tr. at 276-77)

         37. The IR layer of the Sun NDA Product is formulated with 1.75 % w/w of povidone and 3.0 % w/w of crospovidone, which corresponds to 3.5% w/w and 6% w/w of the IR layer. (DTX-574.50; Rudnic Tr. at 170-72, 184-87) Crospovidone is a superdisintegrant, which causes the IR layer of the Sun NDA Product to disintegrate within 60 seconds upon administration. (Rudnic Tr. at 132, 170, 183-87; PTX-330.85-87)

         38. The IR layer of the Sun NDA Product releases all 26.4 mg of its doxycycline immediately upon administration without any enhanced, delayed, or extended effect. (Rudnic Tr. at 132; Chambliss Tr. at 276-78)

         B. The MR Layer

         39. The MR layer of the Sun NDA Product contains 13.6 mg of doxycycline. (DTX-574.50-51; Rudnic Tr. at 117-18, 132-33, 168-69; Chambliss Tr. at 273-74, 285-86)

         40. The MR layer of the Sun NDA Product contains hypromellose ("HPMC") in two different viscosity grades: Methocel K4M and Methocel K100LV. (DTX-574.50-51; Rudnic Tr. at 132-33; Chambliss Tr. at 285-86) The doxycycline and HPMC are mixed together in a single' step in the process of manufacturing the MR layer Product and then blended. (DTX-574.127; Chambliss Tr. at 286-87)

         41. Methocel K100LV is a low viscosity grade of hypromellose. (DTX-574.73-74; Rudnic Tr. 132-33; Chambliss Tr. at 290-91) In contrast, Methocel K4M is a medium viscosity grade of hypromellose. (DTX-574.73-74; Chambliss Tr. 290-91, 294-99; Rudnic Tr. 132-33 (testifying that Methocel K4M is "higher viscosity polymer" than Methocel K100 LV))

         42. Both the Methocel K4M and Methocel K100 LV polymers, as used in the MR layer in the Sun NDA Product, control the release of doxycycline in the MR layer. (DTX-574.73-74; Rudnic Tr. at 172-73 ("Q: ... So the third line down, there's an excipient listed as hypromellose USP, methocel K4M? A: Yes. Q: That's defined as a release controlling excipient; is that correct? A: That's what they call it-----Q: In the next line down, there's hypromellose, USP methocel K100; is that correct? A: Correct. Q: That's also defined as a release controlling excipient; is that correct? A: That's what they call it."); Chambliss Tr. at 287-92)

         43. The MR layer releases doxycycline continuously - with no plateau or stoppage of release - starting immediately after administration and continuing until the MR layer is completely dissolved. (Chambliss Tr. at 292-94, 355-57; DTX-279.17)

         44. Sun's "MR Layer" was designed so that it would release some doxycycline (approximately 3.6 mg) in the first 30 minutes after administration, and release the remaining doxycycline (approximately 10 mg) later than 30 minutes after administration. (See, e.g., PTX-329.10-11; PTX-330.4, -65, -78, -82; PTX-331.1-3; Singh Tr. at 205-06, 211-12, 214-16, 218-19, 221-23; Rudnic Tr. at 119-27, 131, 133; Chambliss Tr. at 355-37, 362-64, 376)

         45. The mechanism that delays the release of about 10 mg doxycycline in Sun's NDA Product is: (1) the deliberate use of two hypromellose polymers that, once hydrated and set up into a gel, serve as an intervention that entangles the drag and slows the penetration of water into the "MR Layer" of Sun's NDA Product, precluding the release of approximately 10 mg until at least 30 minutes after oral administration; and (2) the location of the approximately 10 mg doxycycline on the interior part of Sun's "MR Layer," which has a plane hidden from the gastric fluid at the interface of the bilayer tablet. (See Rudnic Tr. at 136-37)

         46. By using a combination of low molecular weight (Methocel K 100 Premium LV) and higher molecular weight (Methocel K 4M Premium CR) hypromellose polymers, Sun's NDA Product allows for a burst of approximately 3.6 mg doxycycline from the surface of the "MR Layer" in the first 30 minutes after administration, before both polymers have gelled; and then, when both polymers have gelled, they "entangle" the remaining portion of approximately 10 mg doxycycline and prevent it from releasing until a time at least 30 minutes after oral administration. (See, e.g., PTX-330.78; Singh Tr. at 206, 220-23; Rudnic Tr. at 132-34, 136-37, 150, 157-58; Chambliss Tr. at 346-47, 353-56, 359-60)

         C. Pharmacokinetic Data

         47. In a single-dose clinical pharmacokinetic study reported in Sun's NDA, Sun's NDA Product was shown to be bioequivalent to Oracea Capsules under fasting conditions. (PTX-327.5; PTX-343.12; see also Rudnic Tr. at 127-28; Nadkarni Tr. at 245; Mathur Tr. at 231; Singh Tr. at 197; Chambliss Tr. at 364-65) The relevant pharmacokinetic parameters under fasting conditions are reproduced below:

Parameter

Reference Product (Qracea)

Sun's NDA Product

Tmax(h)

2.7071

2.2946

Cmax (ng/mL)

391.1515

397.5441

AUC0-t (ng*hr/mL)

6899.0348

6522.4895

AUC0-oo (ng*hr/mL)

7146.2988

6880.4922

Half-life (h)

16.9167

16.6048

(PTX-327.5-6) Sun noted that "[t]he 90% confidence intervals for the ratios of [Sun's NDA Product and Oracea] (least-squares means) for doxycycline derived from the analysis of log transformed pharmacokinetic parameters Cmax (87.62% - 107.89%), AUC0-t (86.14% - 100.13%) and AUC0-oo (89.20% -100.60%), were well within the 80-125% bioequivalence acceptance criteria." (Id.) Sun also noted that "[t]he ratios of [Sun's NDA Product and Oracea] (least-squares means) for doxycycline derived from the analysis of log transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-oo were 97.23%, 92.87% and 94.73%, respectively." (Id.)

         48. Sun has represented that all of the information contained in its NDA is true and correct. (Singh Tr. at 206-07; Mathur Tr. at 230, 233-34, 236; Nadkarni Tr. at 249; see also Chambliss Tr. at 347, 362)

         49. The FDA's tentative approval of the Sun NDA Product and Sun's label is based in part on the FDA's acceptance of Sun's single-dose pharmacokinetic study showing bioequivalence of Sun's NDA Product to Oracea capsules. (PTX-343.1-2; see also Chambliss Tr. at 364-67; Rudnic Tr. at 142-43)

         50. In order to obtain FDA approval, Sun relied on information regarding the clinical safety and efficacy of Oracea capsules from the Oracea label, including safety and efficacy data from the 16-week Phase III clinical studies for Oracea capsules in treating papules and pustules of rosacea, and information regarding the "long-term" results of clinical microbiology studies of up to 18 months. (See PTX-343.14; PTX-344.5; see also Rudnic Tr. at 142-43; Chambliss Tr. at 366-67)

         51. The therapeutically relevant blood levels for both Sun's NDA Product and Oracea capsules are the steady-state blood levels, and bioequivalence based on a single-dose study was sufficient for the FDA to tentatively approve Sun's NDA Product as safe and effective for long-term use. (See, e.g., PTX-343; Chambliss Tr. at 366-68; Rudnic Tr. at 142; see also PTX-376.11)

         52. As reflected in FDA policy, single-dose bioequivalence studies are generally more sensitive and discriminating than multiple-dose studies, and therefore are typically the best evidence to show that two products will be bioequivalent at steady-state. (Rudnic Tr, at 142-43; PTX-376.11, 18-19)

         VII. Facts Relating to Infringement of the Chang Patents

         53. The specifications of the Chang patents set forth the following definition for the claim term "immediate release formulation": "a dosage form that is intended to release substantially all of the active ingredient on administration with no enhanced, delayed or extended release effect." (Chang '740 patent, 4:5-8) The parties agree that this is the appropriate construction for IR formulation (see D.I. 205 at 8; D.I. 207 at 4; see also Rudnic Tr. at 110-12; Chambliss Tr. at 276) The Court adopts this construction of "immediate release formulation."

         54. The Court construed the claim term "delayed release" to mean "release of drug at a time other than immediately following oral administration." (D J. 78 at 5-7; see also Rudnic Tr. at 113; Chambliss Tr. at 282-83)

         55. Nothing in the Court's construction of "delayed release" limits the way in which that delay is created. Galderma Labs., L.P. v. Amneal Pharm., LLC, 337 F.Supp.3d 371, 406 (D. Del. 2018) "Amneal," "Amneal Trial Opinion," or "Amneal Tr. Op."); Rudnic Trial Tr. at 156; Chambliss Trial Tr. at 368-69)

         56. The Court's construction of "delayed release" does not require that to be a DR portion there needs to be substantially no release of drug at any time in the stomach or in an acidic environment and only requires that there be release at a time other than immediately following oral administration. (Amneal Tr. Op. at 50-51, 56-58; see also Rudnic Tr. at 156; Chambliss Tr. at 368-69)

         57. Nothing in the Court's construction of "delayed release" requires that there be no release or substantially no release of drug for a period of time (such as the plateau in release exhibited in the dissolution data for Oracea Capsules in acidic medium). (Amneal Trial Op. at 58-59; Rudnic Tr. at 156; Chambliss Tr. at 368-69)

         58. The Court's construction of "delayed release" does not exclude portions that also provide a "sustained release," so long as the release is at a time other than immediately following oral administration. (See, e.g., Amneal Op. at 57-58; see also Raoufinia Tr. at 413)

         59. The claim terms "formulation" and "portion" are used interchangeably across the asserted claims of the Chang patents (compare Chang '740 patent, cl. 1 with Chang '405 patent, cl. 1), and both sides' experts used these terms interchangeably (see generally Rudnic Tr. at 102-63; Chambliss Tr. at 266-344).

         60. The Court construed the claim term "about" as applied to the claimed amounts "about 30 mg" and "about 10 mg" of doxycycline to mean "within the pharmaceutically acceptable limits found in the United States Pharmacopeia (USP-NF-21), 2003 Annual Edition." (D.I. 78 at 9-10; see also Chambliss Tr. at 278)

         61. The General Notices and Requirements section of the USP provide "the basic guidelines for the interpretation and application of the standards, tests, assays, and other specifications of the [USP]" when no specific language is given to the contrary in the remainder of the USP. (DTX-237.8; Chambliss Tr. at 279) That same section of the USP defines "about" as a "quantity within 10% of the specified weight or volume." (DTX-237.12; see also Chambliss Tr. at 279)

         62. A POSA would rely on the definition of "about" in the General Notices section of the USP to interpret the claim terms "about 30 mg" and "about 10 mg" as used in the asserted claims of the Chang patents. (Chambliss Tr. at 278-79)

         63. A POSA would understand that "about 30 mg" of doxycycline represents at most a range of 27 to 33 mg of doxycycline. (Chambliss Tr. at 280)

         64. Dr. Rudnic testified that Sun chose a bilayer tablet to "hide a good portion" of the MR layer from hydrating until a time other than immediately following oral administration. (Rudnic Tr. at 137) A part of the MR layer begins to disintegrate in less than 60 seconds (PTX-330.85, Rudnic Tr. at 186-87), while the remaining about 10 mg of the doxycycline in Sun's MR layer does not dissolve until sometime well after oral administration.

         VIII. Facts Relating to Obviousness

         65. At trial, Sun contended that the asserted claims of the Chang patents were invalid as obvious in view of two prior art references: (1) the Ashley Applications, and (2) the Periostat Package. (Tr. at 265-66; Chambliss Tr. at 380-82; Rudnic Tr. at 425-26)

         66. None of the prior art cited by Sun, alone or in combination, discloses, teaches or suggests the claimed compositions of the asserted claims of the Chang patents. (Rudnic Tr. at 426, 454-55; Chambliss Tr. at 382-83)

         67. For example, none of the alleged prior art cited by Sun, alone or in combination, discloses, teaches, or suggests a 40 mg once-daily doxycycline composition consisting of an IR portion and a DR portion, or a composition consisting of IR and DR portions in a ratio of 3 0 mg IR and 10 mg DR. (Rudnic Tr. at 426; Chambliss Tr. 382)

         68. In addition, none of the alleged prior art cited by Sun, alone or in combination, discloses, teaches, or suggests a 40 mg once-daily doxycycline composition consisting of an IR portion and a DR portion wherein the IR/DR ratio is between 70% IR 30% DR and 80% IR 20% DR. (Rudnic Tr. at 427-28, 430-31, 437-38; Chambliss Tr. at 322-23, 382-83)

         69. The goal of the Chang patents was to provide a once-daily doxycycline composition that would yield steady-state blood levels sufficient to treat inflammatory conditions such as rosacea, while at the same time maintaining steady-state blood levels well below the threshold of 1.0 µg/ml, associated with the undesirable, antibacterial side effects of higher doses of doxycycline. (See, e.g., PTX-4 at 2:28-42, 2:64-67; Rudnic Tr. at 425)

         70. None of the alleged prior art cited by Sun, alone or in combination, would have motivated a POSA in 2002 or 2003 to make the claimed 30 mg IR, 10 mg DR doxycycline compositions of the asserted claims of the Chang patents, or would have given a POSA a reasonable expectation that such compositions would have succeeded in meeting the formulation goal addressed by the claimed invention of the Chang patents. (Rudnic Tr. at 426, 454-55)

         71. Sun's primary prior art references, the Ashley Applications, are not materially different from the Ashley prior art this Court considered - and rejected - in Mylan as a basis for the alleged obviousness of the Chang patents. See Research Found, of State Univ. of New York v. MylanPharm. Inc., 809 F.Supp.2d 296, 314-15, 332 (D. Del. 2011), aff'd in relevant part, 531 Fed.Appx. 1008 (Fed. Cir. 2013) ("Mylan Trial Opinion" or "Mylan Tr. Op."); Chambliss Tr. at 389-92; Rudnic Tr. At 428-29, 435-36)

         A. The Ashley Applications

         72. Doxycycline was first discovered in the 1960s and has long been commercially available. (Chambliss Tr. 307-08)

         73. Doxycycline was regularly prepared as a salt, such as doxycycline hydrochloride or "hyclate," and was known to be soluble in water. (Chambliss Tr. 308)

         74. Sun contends that the asserted claims of the Chang patents would have been obvious over Published International Patent Application WO02/080932 ("the Ashley '932 application") and U.S. Provisional Application No. 60/281, 854 ("the Ashley '854 application") (together, "the Ashley Applications"), in light of available pharmacokinetic information concerning Periostat Package."

         75. Neither the Ashley '932 application, nor the Ashley '854 application (which is incorporated by reference into the Ashley '932 application) discloses, teaches, or suggests the 40 mg IR/DR doxycycline compositions of the asserted claims of the Chang patents. (Rudnic Tr. at 427-28, 430-31; Chambliss Tr. at 382-84; see also Mylan Tr. Op. at 332)

         76. The Ashley '932 application did not disclose, teach, or suggest any 40 mg once-daily doxycycline composition consisting of an IR portion and a DR portion, or any IR/DR doxycycline ratios. (Rudnic Tr. at 426-31, 435-36; Chambliss Tr. at 382-84; Mylan Tr. Op. At 314 (¶¶261, 264), 332)

         77. The Ashley '932 application did not disclose, teach, or suggest any composition that contains a 30 mg IR portion or a 10 mg DR portion. (Rudnic Tr. at 426-29, 435-36; Chambliss Tr. at 382-84; Mylan Tr. Op. at 314, 332)

         78. Dr. Chambliss admitted that the Ashley Applications are the closest prior art to the asserted claims of the Chang patents. (Chambliss Tr. at 383)

         79. Dr. Chambliss admitted that the Ashley Applications are the only documents that he cited describing a 40 mg once-daily doxycycline dosage form that is controlled release (i.e., modified release, sustained release, delayed release, etc.). (Chambliss Tr. at 383)

         80. The Ashley '932 application generally discusses administering a tetracycline compound by "sustained release" which the Ashley '932 publication defines as "a method of drug delivery to achieve a certain level of the drug over a particular period of time." (Ashley '932 application (DTX-271) at 15; Rudnic Tr. at 429-30)

         81. The Ashley '932 application states that "[f]urther description of methods of delivering tetracycline compounds by sustained release" can be found in the Ashley '854 application. (DTX-271 at 15; Rudnic Tr. at 430; Chambliss Tr. at 314-16)

         82. The Ashley '854 application does not disclose, teach, or suggest any 40 mg once-daily doxycycline composition consisting of an IR portion and a DR portion, or any IR/DR doxycycline ratios. (Rudnic Tr. at 427, 430-31, 435-36; Chambliss Tr. at 382-84; see also Mylan Tr. Op. at 314)

         83. The Ashley '854 application does not disclose, teach, or suggest any composition that contains a 30 mg IR portion or a 10 mg DR portion. (Rudnic Tr. at 427, 430-31, 435-36; ...


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