Citations
- 337 F. Supp. 3d 371
Full opinion text
STARK, U.S. District Judge:
OPINION
In March 2016, Plaintiffs Galderma Laboratories, L.P. ("Galderma"), Nestlé Skin Health S.A. ("NSH"), and TCD Royalty Sub, LLC ("TCD" and, with Galderma and NSH, "Galderma" or "Plaintiffs") filed suit against Defendants Amneal Pharmaceuticals LLC and Amneal Pharmaceuticals Co. (I) Pvt. Ltd. (collectively, "Amneal" or "Defendants") under the Hatch-Waxman Act, 35 U.S.C. § 271(e). (See D.I. 1) Defendants seek to bring to market a generic version of Plaintiffs' Oracea ® Capsules, a once-daily 40 milligram ("mg") administration of doxycycline for the treatment of the papules and pustules of acne rosacea. (D.I. 1 at ¶ 10) Plaintiffs allege infringement of U.S. Patent Nos. 8,206,740 ("Chang '740 patent") ; 8,394,405 ("Chang '405 patent") ; 8,470,364 ("Chang '364 patent") ; 7,749,532 ("Chang '532 patent") (collectively, the "Chang patents"); 7,211,267 ("Ashley '267 patent"); 7,232,572 ("Ashley '572 patent"); 8,603,506 ("Ashley '506 patent"); and 9,241,946 ("Ashley '946 patent") (collectively, the "Ashley patents"). (See D.I. 1) The Chang and Ashley patents are generally directed to low-dose doxycycline formulations for the treatment of the papules and pustules of acne rosacea.
In February 2018, the Court held a five-day bench trial. (See D.I. 256, 258, 260-62 ("Tr."); D.I. 257 ("Sealed Tr. A"); D.I. 259 ("Sealed Tr. B") ) Thereafter, the parties submitted a joint Statement of Uncontested Facts ("SUF") (D.I. 215 Ex. 1), proposed findings of fact (D.I. 245, 247, 266, 273), and post-trial briefing (D.I. 244, 246, 264, 265).
Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire record in this case and the applicable law, the Court concludes that: (1) Amneal infringes claim 1 of the Chang '740 patent, claims 1 and 3 of the Chang '405 patent, and claims 1 and 2 of the Chang '364 patent ; (2) Amneal does not infringe claim 1 of the Chang '532 patent ; (3) Galderma is collaterally estopped from asserting infringement of claim 30 of the Ashley '267 patent and claims 14, 15, 23, 24, and 26 of the Ashley '572 patent; (4) Amneal infringes claims 3, 4, 5, 15, and 16 of the Ashley '506 patent and claims 13, 14, 15, and 16 of the Ashley '946 patent; (5) claim 30 of the Ashley '267 patent, claims 14, 15, 23, 24, and 26 of the Ashley '572 patent, claims 3, 4, 5, 15, and 16 of the Ashley '506 patent, and claims 13, 14, 15, and 16 of the Ashley '946 patent are not invalid for lack of enablement or written description or for obviousness; (6) claim 30 of the Ashley '267 patent, claim 15 of the Ashley '506 patent, and claim 13 of the Ashley '946 patent are not invalid as anticipated; and (7) claim 30 of the Ashley '267 patent and claims 14, 15, 23, 24, and 26 of the Ashley '572 patent are not invalid for indefiniteness.
The Court's findings of fact and conclusions of law are set forth in detail below.
FINDINGS OF FACT
This section contains the Court's findings of fact for issues raised by the parties during trial. Certain findings of fact are also provided in connection with the Court's conclusions of law.
I. The Parties
1. Plaintiff Galderma Laboratories, L.P. ("Galderma") is a privately-held partnership registered in the state of Texas, having a principal place of business at 14501 North Freeway, Fort Worth, Texas 76177. (SUF ¶ 1)
2. Plaintiff Nestlé Skin Health S.A. ("NSH") is a "societe anonyme" organized and existing under the laws of Switzerland, having a principal place of business at Avenue Gratta Paille 2, 1018 Lausanne, Switzerland. (SUF ¶ 2)
3. Plaintiff TCD Royalty Sub LLC ("TCD") is a limited liability company organized and existing under the laws of the State of Delaware, having a principal place of business at 222 Delaware Avenue, Suite 1200, Wilmington, DE 19801. (SUF ¶ 3)
4. Defendant Amneal Pharmaceuticals LLC ("Amneal Pharma") is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 400 Crossing Boulevard, Bridgewater, NJ 08807. (SUF ¶ 4)
5. Defendant Amneal Pharmaceuticals Co. (I) Pvt. Ltd. ("Amneal India") is an Indian corporation and a wholly-owned subsidiary and agent of Amneal Pharma, having a principal place of business at 882/1-871, Near Hotel Kankavati, Village Rajoda, Taluka Bavla, District Ahmedabad-382220, Gujarat, India. (SUF ¶ 5)
II. Rosacea and Its Treatment
6. Rosacea, or "acne rosacea," is a chronic inflammatory skin disorder that can cause pimple-like bumps known as "papules and pustules," which appear mainly in the center of the face. (Webster Tr. at 44-45 )
7. As of 2000-2001, rosacea was treated by oral administration of antibiotics at antibacterial dosages (typically 100-200 mg of doxycycline per day) and administration of topical gels and creams. (Webster Tr. at 45-46; Zhanel Tr. at 145)
8. Prior to the launch of Oracea ®, tetracylines were the most common oral treatment for rosacea. (Webster Tr. at 60; Zhanel Tr. at 145, 279)
9. Long-term use of tetracycline antibiotics can lead to significant undesirable side effects. (Webster Tr. at 48-49; Zhanel Tr. at 146-47)
III. Oracea ®
10. Plaintiff Galderma holds New Drug Application ("NDA") No. 50-805 on Oracea ® capsules ("Oracea ®"), which was approved by the U.S. Food and Drug Administration ("FDA") on May 26, 2006. (SUF ¶ 57)
11. Plaintiff Galderma markets Oracea® in the United States. (SUF ¶ 58)
12. The active ingredient in Oracea ® is doxycycline. (SUF ¶ 59)
13. Oracea ® is a capsule dosage form for oral administration. (SUF ¶ 60)
14. Oracea ® is an oral pharmaceutical composition of doxycycline indicated for once-daily use for the treatment of inflammatory lesions (papules and pustules) of rosacea in adult patients. (SUF ¶¶ 61-63)
15. Oracea ® is a hard gelatin capsule filled with two types of doxycycline beads, 30 mg immediate-release ("IR") beads and 10 mg delayed-release ("DR") beads. (SUF ¶ 64)
16. Oracea ®'s 10 mg doxycycline DR beads are coated with an enteric polymer. (SUF ¶ 65)
17. Oracea ® contains one or more pharmaceutical excipients. (SUF ¶ 66)
18. Oracea ® is approved by the FDA for the treatment of only the inflammatory lesions (papules and pustules) of rosacea in adult patients. (PTX-516 at GAL-ORACEA-0011389-90)
19. Oracea ®, when administered once-daily, is administered in an amount that is effective to treat the papules and pustules of rosacea. (Webster Tr. at 51; PTX-516 at GAL-ORACEA-0011394)
20. Oracea ®, when administered once-daily, will give steady state blood levels of doxycycline of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml. (Rudnic Sealed Tr. B at B-77-78; PTX-516 at GAL-ORACEA-0011393)
21. The low dose of doxycycline in Oracea ® is not an amount that would be useful to treat infections, but, surprisingly, is effective in treating the papules and pustules of rosacea. (Webster Tr. at 61; PTX-240 at 0001-03)
IV. Amneal's ANDA Product
22. Amneal submitted Abbreviated New Drug Application ("ANDA") No. 203278 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 ® ("Amneal's ANDA product") before the expiration of the patents-in-suit. (SUF ¶ 70)
23. ANDA No. 203278 describes a manufacturing process for the production of Amneal's ANDA product. (SUF ¶ 71)
24. The active ingredient in Amneal's ANDA product is doxycycline monohydrate, an antibiotic tetracycline compound. (SUF ¶ 73)
25. Amneal represents that its ANDA product is bioequivalent to Oracea ®. (SUF ¶ 75)
26. Amneal's ANDA product will contain the package insert approved by the FDA ("Amneal's Label"). (SUF ¶¶ 72, 78)
27. Amneal's ANDA product, when used in accordance with Amneal's Label, will be administered orally to humans in a dosage of one 40 mg capsule once-daily for the treatment of inflammatory lesions (papules and pustules) of rosacea. (SUF ¶¶ 74, 77; PTX-100 at Amneal-Doxy2016-00434868)
28. Amneal's ANDA product contains pharmaceutically acceptable excipients. (SUF ¶ 81)
29. Amneal's ANDA product does not contain a bisphosphonate compound, nor does Amneal's Label require or instruct patients and physicians that it be administered with a bisphosphonate compound. (PTX-100 at Amneal-Doxy2016-00434885-886)
30. Amneal's ANDA product is indicated "for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients." (PTX-100 at Amneal-Doxy2016-00434868) Amneal is not seeking any other indication and will not market its ANDA product for any other use. (Edwards Sealed Tr. B at B-55)
31. Amneal's ANDA Product, when administered once-daily, will be administered in an amount that provides a serum concentration in the range of about 0.1 to 0.8 µg/ml. (Webster Tr. at 67-68; PTX-100 at Amneal-Doxy2016-00434887)
V. The Patents-in-Suit
A. The Chang Patents
32. The Chang patents describe "pharmaceutical composition[s] of doxycycline that contain[ ] an immediate release (IR) component of the drug and a delayed release (DR) component of the drug, which are combined into one dosage unit for once-daily dosing." (E.g. , PTX-004 at 2:46-50)
i. The Chang '740 Patent
33. U.S. Patent Application No. 12/155,676, from which the Chang '740 patent issued, was filed on June 6, 2008. (SUF ¶ 30) The Chang '740 patent claims priority to U.S. Provisional Patent Application No. 60/460,963, filed on April 7, 2003, and U.S. Provisional Patent Application No. 60/547,964, filed on February 26, 2004. (SUF ¶ 31) The Chang '740 patent issued on June 26, 2012, naming Richard Rong-Kun Chang, Arash Raoufinia, and Niraj Shah as inventors, and listing Supernus Pharmaceuticals, Inc. as assignee. (SUF ¶ 32) The Chang '740 patent is set to expire on December 24, 2025. (SUF ¶ 33) Plaintiff TCD is the current owner of the Chang '740 patent. (SUF ¶ 34)
34. Plaintiffs assert claim 1 of the Chang '740 patent against Defendants. The asserted claim is reproduced below:
1. 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/m1 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.
(PTX-004 at 11:57-64)
ii. The Chang '405 Patent
35. U.S. Patent Application No. 12/926,932, from which the Chang '405 patent issued, was filed on December 17, 2010. (SUF ¶ 35) The Chang '405 patent claims priority to U.S. Provisional Patent Application No. 60/460,963, filed on April 7, 2003, and U.S. Provisional Patent Application No. 60/547,964, filed on February 26, 2004. (SUF ¶ 36) The Chang '405 patent issued on March 12, 2013, naming Richard Rong-Kun Chang, Arash Raoufinia, and Niraj Shah as inventors, and listing Supernus Pharmaceuticals, Inc. as assignee. (SUF ¶ 37) The Chang '405 patent is set to expire on April 7, 2024. (SUF ¶ 38) Plaintiff TCD is the current owner of the Chang '405 patent. (SUF ¶ 39)
36. Plaintiffs assert claims 1 and 3 of the Chang '405 patent against Defendants. Claim 1 recites:
1. An oral pharmaceutical composition comprising about 40 mg total doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 µg/m1 and a maximum of 1.0 µg/m1, 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.
(PTX-005 at 12:1-9)
37. Claim 3 depends from claim 2. Claim 2 recites: "The composition of claim 1, which at a once-daily dosage will give steady state blood levels of the doxycycline of between 0.3 µg/m1 to 0.8 µg/m1." (PTX-005 at 12:10-12) Claim 3 recites: "The composition of claim 2, which at a once-daily dosage will give blood levels of the doxycycline of between 0.3 µg/m1 to 0.8 µg/m1." (PTX-005 at 12:13-14)
iii. The Chang '364 Patent
38. U.S. Patent Application No. 12/926,933, from which the Chang '364 patent issued, was filed on December 17, 2010. (SUF ¶ 45) The Chang '364 patent claims priority to U.S. Provisional Patent Application No. 60/460,963, filed on April 7, 2003, and U.S. Provisional Patent Application No. 60/547,964, filed on February 26, 2004. (SUF ¶ 46) The Chang '364 patent issued on June 25, 2013, naming Richard Rong-Kun Chang, Arash Raoufinia, and Niraj Shah as inventors, and listing Supernus Pharmaceuticals, Inc. as assignee. (SUF ¶ 47) The Chang '364 patent is set to expire on April 7, 2024. (SUF ¶ 48) Plaintiff TCD is the current owner of the Chang '364 patent. (SUF ¶ 49)
39. Plaintiffs assert claims 1 and 2 against Defendants. The asserted claims are reproduced below:
1. 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.
2. 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 µg/m1 and a maximum of 1.0 µg/m1, the composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline ; as a delayed release formulation (DR) comprising about 10 mg doxycycline ; and optionally, (iii) one or more pharmaceutically acceptable excipients.
(PTX-007 at 12:1-14)
iv. The Chang '532 Patent
40. U.S. Patent Application No. 10/819,620, from which the Chang '532 patent issued, was filed on April 7, 2004. (SUF ¶ 26) The Chang '532 patent issued on July 6, 2010, naming Richard Rong-Kun Chang, Arash Raoufinia, and Niraj Shah as inventors, and listing Supernus Pharmaceuticals, Inc. as assignee. (SUF ¶ 27) The Chang '532 patent is set to expire on December 19, 2027. (SUF ¶ 28) Plaintiff TCD is the current owner of the Chang '532 patent. (SUF ¶ 29)
41. Plaintiffs assert claim 1 of the Chang '532 patent against Defendants. The asserted claim is reproduced below:
1. 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/m1 and a maximum of 1.0 µg/ml, the composition consisting of (i) an immediate release (IR) portion comprising a drug, wherein the drug consists of about 30 mg doxycycline ; (ii) a delayed release (DR) portion comprising a drug, wherein the drug consists of about 10 mg doxycycline, in which the DR portion is in the form of pellets coated with at least one enteric polymer; and (iii) one or more pharmaceutically acceptable excipients.
(PTX-003 at 11:64-12:6)
B. The Ashley Patents
42. The asserted claims of the Ashley patents generally cover methods of treating acne or rosacea by oral administration of a low daily dose doxycycline. (Webster Tr. at 61; Elder Tr. at 366)
i. The Ashley '267 Patent
43. U.S. Patent Application No. 10/117,709, from which the Ashley '267 patent issued, was filed on April 5, 2002. (SUF ¶ 6) The Ashley '267 patent claims priority to U.S. Provisional Patent Application No. 60/281,916, filed on April 5, 2001, and U.S. Provisional Patent Application No. 60/325,489, filed on September 26, 2001. (SUF ¶ 7) The Ashley '267 patent issued on May 1, 2007, naming Robert A. Ashley as inventor, and listing CollaGenex Pharmaceuticals, Inc. ("CollaGenex") as assignee. (SUF ¶ 8) The Ashley '267 patent is set to expire on April 5, 2022. (SUF ¶ 9) Plaintiff NSH is the current owner of the Ashley '267 patent. (SUF ¶ 10)
44. Plaintiffs assert claim 30 of the Ashley '267 patent against Defendants. The asserted claim is reproduced below:
30. A method according to claim 26, wherein the subantibacterial amount is an amount that results in no reduction of skin microflora during a six-month treatment.
(PTX-001 at 34:51-52)
ii. The Ashley '572 Patent
45. U.S. Patent Application No. 11/061,866, from which the Ashley '572 patent issued, was filed on February 18, 2005. (SUF ¶ 11) The Ashley '572 patent claims priority to U.S. Provisional Patent Application No. 60/281,916, filed on April 5, 2001, and U.S. Provisional Patent Application No. 60/325,489, filed on September 26, 2001. (SUF ¶ 12) The Ashley '572 patent issued on June 19, 2007, naming Robert A. Ashley as inventor, and listing CollaGenex Pharmaceuticals, Inc. as assignee. (SUF ¶ 13) The Ashley '572 patent is set to expire on April 5, 2022. (SUF ¶ 14) Plaintiff NSH is the current owner of the Ashley '572 patent. (SUF ¶ 15)
46. Plaintiffs assert claims 14, 15, 23, 24, and 26 of the Ashley '572 patent against Defendants. The asserted claims depend indirectly from claim 1. Claim 1 recites:
1. A method for treating papules and pustules of rosacea in a human in need thereof comprising administering orally to said human a tetracycline compound, or a pharmaceutically acceptable salt thereof, in an amount that is effective to treat the papules and pustules of rosacea, but has substantially no antibiotic activity, said amount being 10-80% of the antibiotic amount, wherein the tetracycline compound is an antibiotic tetracycline compound or a pharmaceutically acceptable salt thereof administered in an amount that results in no reduction of skin microflora during a six-month treatment, without administering a bisphosphonate compound.
(PTX-002 at 32:22-34)
47. Claim 14 depends from 12, as does claim 15 indirectly. Claim 12 recites: "A method according to claim 1, wherein said tetracycline compound is doxycycline or a pharmaceutically acceptable salt thereof." (PTX-002 at 33:5-7) Claims 14 and 15 recite:
14. A method according to claim 12, wherein said doxycycline or pharmaceutically acceptable salt thereof is administered in an amount of 40 milligrams.
15. A method according to claim 14, wherein said doxycycline or pharmaceutically acceptable salt thereof is administered by sustained release.
(PTX-002 at 33:10-15)
48. Claims 23 and 24 depend from claim 20. Claim 20 recites:
20. A method for treating papules and pustules of rosacea in a human in need thereof comprising administering orally to said human a hydrate of doxycycline in an amount that is effective to treat the papules and pustules of rosacea, but has substantially no antibiotic activity, said amount being 10-80% of the antibiotic amount, wherein the hydrate of doxycycline is administered in an amount that results in no reduction of skin microflora during a six-month treatment, said method not comprising administering a bisphosphonate compound.
(PTX-008 at 34:1-11)
49. Claims 23, 24, and 26 are reproduced below:
23. A method according to claim 20, wherein said hydrate of doxycycline is administered in an amount of 40 milligrams.
24. A method according to claim 20, wherein said hydrate of doxycycline is administered by sustained release.
26. A method according to claim 23, wherein said hydrate of doxycycline is administered once a day.
(PTX-002 at 34:18-27)
iii. The Ashley '506 patent
50. U.S. Patent Application No. 13/277,789, from which the Ashley '506 patent issued, was filed on October 20, 2011. (SUF ¶ 16) The Ashley '506 patent claims priority to U.S. Provisional Patent Application No. 60/281,916, filed on April 5, 2001, and U.S. Provisional Patent Application No. 60/325,489, filed on September 26, 2001. (SUF ¶ 17) The Ashley '506 patent issued on October 20, 2011, naming Robert A. Ashley as inventor, and listing Galderma Laboratories, Inc. as assignee. (SUF ¶ 18) The Ashley '506 patent is set to expire on April 5, 2022. (SUF ¶ 19) Plaintiff NSH is the current owner of the Ashley '506 patent. (SUF ¶ 20)
51. Plaintiffs assert claims 3, 4, 5, 15, and 16 of the Ashley '506 patent against Defendants. Claims 3, 4, and 5 depend indirectly from claim 1. Claim 1 recites:
1. A method for treating papules and pustules of rosacea in a human in need thereof, the method comprising administering orally to said human doxycycline, or a pharmaceutically acceptable salt thereof, in an amount that (i) is effective to treat the papules and pustules of rosacea ; (ii) is 10-80% of a 50 mg dose of doxycycline per day; and (iii) results in no reduction of skin microflora during a six-month treatment, without administering a bisphosphonate compound.
(PTX-008 at 31:61-32:3)
52. Claim 3 depends from claim 2, as do claims 4 and 5 indirectly. Claim 2 recites: "The method according to claim 1, wherein said doxycycline is doxycycline monohydrate." (PTX-008 at 32:4-5) Claims 3, 4, and 5 are reproduced below:
3. The method according to claim 2, wherein said doxycycline monohydrate is administered in an amount of 40 milligrams.
4. The method according to claim 3, wherein said doxycycline monohydrate is administered by sustained release.
5. A method according to claim 4, wherein said doxycycline monohydrate is administered once a day.
(PTX-008 at 32:6-12)
53. Claim 16 depends from claim 15. Claims 15 and 16 are reproduced below:
15. A method for treating papules and pustules of rosacea in a human in need thereof, the method comprising administering orally to said human doxycycline, or a pharmaceutically acceptable salt thereof, in an amount of 40 mg per day, wherein the amount results in no reduction of skin microflora during a six-month treatment, without administering a bisphosphonate compound.
16. The method according to claim 15, wherein said doxycycline is doxycycline monohydrate.
(PTX-008 at 32:46-54)
iv. The Ashley '946 Patent
54. U.S. Patent Application No. 14/753,544, from which the Ashley '946 patent issued, was filed on June 29, 2015. (SUF ¶ 21) The Ashley '946 patent claims priority to U.S. Provisional Patent Application No. 60/281,916, filed on April 5, 2001, and U.S. Provisional Patent Application No. 60/325,489, filed on September 26, 2001. (SUF ¶ 22) The Ashley '946 patent issued on January 26, 2016, naming Robert A. Ashley as inventor, and listing Galderma Laboratories, Inc. as assignee. (SUF ¶ 23) The Ashley '946 patent is set to expire on April 5, 2022. (SUF ¶ 24) Plaintiff NSH is the current owner of the Ashley '946 patent. (SUF ¶ 25)
55. Plaintiffs assert claims 13, 14, 15, and 16 of the Ashley '946 patent against Defendants. The asserted claims are reproduced below:
13. A method for treating acne in a human in need thereof, the method comprising administering orally to said human doxycycline, or a pharmaceutically acceptable salt thereof, in an amount of 40 mg per day, wherein the amount results in no reduction of skin microflora during a six-month treatment, without administering a bisphosphonate compound, wherein said doxycycline, or a pharmaceutically acceptable salt thereof, is administered in an amount which provides a serum concentration in the range of about 0.1 to about 0.8 µg/ml.
14. The method according to claim 13, wherein said doxycycline is doxycycline monohydrate.
15. The method according to claim 14, wherein said doxycycline monohydrate is administered by sustained release.
16. A method according to claim 15, wherein said doxycycline monohydrate is administered once a day.
(PTX-010 at 32:51-67)
VI. Witnesses
A. Fact Witnesses
56. Dr. Lawrence Feldman testified by deposition. Dr. Feldman is a physician who specializes in dermatology, including the treatment of patients with rosacea. (Feldman Tr. at 376-80)
57. Mr. Robert Ashley testified by deposition. Mr. Ashley is a named inventor of the Ashley patents. (Ashley Tr. at 653)
58. Mr. Richard Rong-Kun Chang testified by deposition. Mr. Chang is a named inventor of the Chang patents. (Chang Tr. at 686)
59. Dr. Robert Skidmore testified by deposition. Dr. Skidmore is the lead author of the paper Robert Skidmore, Effects of Subantimicrobial-Dose Doxycycline in the Treatment of Moderate Acne , 139 Archives Dermatology 459 (2003). (PTX-288) ("Skidmore ")
60. Mr. Jatin Gajjar testified by deposition. Mr. Gajjar is the Executive Vice President and head of Indian research and development at Amneal. (Gajjar Sealed Tr. A at A-22)
61. Ms. Candis Edwards testified by deposition. Ms. Edwards is the Senior Vice President of Regulatory Affairs at Amneal and is responsible for Amneal's NDA submissions, labeling, and bioequivalence. (Edwards Sealed Tr. B at B-48, B-50)
B. Galderma's Experts
62. Dr. Guy Webster, one of Plaintiffs' experts on infringement of the Ashley patents, received a bachelor's degree, Ph.D. degree, and M.D. degree from the University of Pennsylvania and completed his dermatology training at New York University. (Webster Tr. at 40, 44) Dr. Webster is a practicing dermatologist and member of the American Acne and Rosacea Foundation. (Webster Tr. at 41-42) Dr. Webster was recognized as an expert in clinical dermatology and microbiology associated with the skin. (Webster Tr. at 43)
63. Dr. George Zhanel, another of Plaintiffs' experts on infringement of the Ashley patents, received a Doctor of Clinical Pharmacy degree from the University of Minnesota and a Ph.D. degree in Medical Microbiology from the University of Manitoba in Winnipeg, Canada. (Zhanel Tr. at 138, 141-42) Dr. Zhanel is a professor of medical technology and infectious disease at the University of Manitoba and a research director of the Canadian Antimicrobial Resistance Alliance. (Zhanel Tr. at 137-38) Dr. Zhanel was recognized as an expert in clinical microbiology and antimicrobial stewardship in dermatology. (Zhanel Tr. at 141)
64. Dr. Edward Rudnic, Plaintiffs' expert on infringement of the Chang patents, received a bachelor's degree in Pharmacy, an M.A. degree in Science in Pharmaceutics, and a Ph.D. degree in Pharmaceutical Sciences from the University of Rhode Island. (Rudnic Tr. at 296, 302) Dr. Rudnic is the Chief Technology Officer at Dispersol Technologies and is an adjunct professor at the University of Maryland College of Pharmacy and University of Rhode Island College of Pharmacy. (Rudnic Tr. at 296, 299) Dr. Rudnic was recognized as an expert in the field of pharmaceutical formulation and drug development. (Rudnic Tr. at 302)
65. Dr. Henry Grabowski, Plaintiffs' expert on commercial success, received a bachelor's degree from Lehigh University and M.A. and Ph.D. degrees in Economics from Princeton University. (Grabowski Tr. at 843, 845) Dr. Grabowski is the Director of the Duke University program in Pharmaceuticals and Health Economics. (Grabowski Tr. at 843) Dr. Grabowski was recognized as an expert in pharmaceutical industrial economics, including determining whether a pharmaceutical product has achieved commercial success. (Grabowski Tr. at 844)
C. Amneal's Experts
66. Dr. Edmund Elder, Amneal's expert on infringement of the Chang patents and validity of the Ashley patents, received a bachelor's degree in Pharmacy and a Ph.D. degree in Pharmaceutical Sciences from the Medical University of South Carolina. (Elder Tr. at 315, 318) Dr. Elder is the Director of the Zeeh Pharmaceutical Experiment Station at the University of Wisconsin-Madison. (Elder Tr. at 314) Dr. Elder was recognized as an expert in pharmaceutical drug development and formulations. (Elder Tr. at 317)
67. Dr. Barry Kreiswirth, one of Amneal's experts on infringement and validity of the Ashley patents, received a Ph.D. degree from New York University. (Kreiswirth Tr. at 458, 460) Dr. Kreiswirth is the director of the Public Health Research Institute affiliated with Rutgers University. (Kreiswirth Tr. at 457-58) Dr. Kreiswirth was recognized as an expert in clinical microbiology. (Kreiswirth Tr. at 460)
68. Dr. Monte Meltzer, another of Amneal's experts on infringement and validity of the Ashley patents, received an M.D.
degree from Georgetown University School of Medicine and completed postgraduate training at Massachusetts General Hospital and a dermatology residency at Walter Reed Army Medical Center. (Meltzer Tr. at 572, 578-79, 599) Dr. Meltzer is the Director of Dermatology Services at the Union Memorial Hospital in Baltimore, MD and an Attending Physician in the Dermatology Residency Program at the University of Maryland Medical Center in Baltimore, MD. (Meltzer Tr. at 572) Dr. Meltzer was recognized as an expert in clinical dermatology. (Meltzer Tr. at 573)
VII. Person of Ordinary Skill in the Art
A. Chang Patents
69. A person of ordinary skill in the art ("POSA") in the field of the Chang patents as of 2002-2003 is someone with education and experience in drug delivery and formulation. Education and experience levels may vary, with some POSAs holding a bachelor's degree and having many years of experience and others holding higher degrees but having less work 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. (Rudnic Tr. at 304)
B. Ashley Patents
70. A POSA in the field of the Ashley patents as of 2000-2001 is someone who holds an M.D. or Ph.D. in dermatology, microbiology, or a related discipline and has three to five years of research or clinical experience, or someone who holds a bachelor's degree in a field related to pharmacy or pharmacology and has several years of practical experience relating to dermatologic or related conditions. (Webster Tr. at 63; Zhanel Tr. at 142-43; Elder Tr. at 327; Kreiswirth Tr. at 460-61; Meltzer Tr. at 573-74)
VIII. Facts Relating to Infringement of the Chang Patents
A. Prosecution History
71. The patent application that eventually issued as the Chang '532 patent was first filed as App. No. 10/819,620 (the "'620 application") on April 7, 2004, with 48 claims. (PTX-013.0001, .0028-32)
72. The applicant cancelled the original 48 claims and replaced them with newly-added claims 49-80 in a preliminary amendment. (PTX-013.380-85) New independent claim 49 read:
(New) An oral pharmaceutical composition comprising a pharmaceutically effective amount of doxycycline, which at a once daily dosage will give steady state blood levels of doxycycline of a minimum of about 0.1 µg/ml and a maximum of about 1.0 µg/ml, the composition comprising an immediate release (IR) portion comprising about 30 mg doxycycline and a delayed release (DR) portion comprising about 10 mg doxycycline.
(PTX-013.0381) (emphasis added)
73. The Examiner issued a Non-Final Rejection, rejecting the claims as obvious in view of prior art that disclosed an oral antibiotic composition "comprised of at least two portions, including an immediate release portion and a delayed release portion" intended to be administered once-daily. (PTX-13.435)
74. The applicant then amended the claims, changing "comprising" to "consisting essentially of." (PTX-13.447)
75. The Examiner issued a Final Rejection of these claims, noting the phrase "consisting essentially of" did not fully overcome the obviousness rejection. (PTX-013.458-61)
76. The applicant again amended claim 49 to read:
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 a drug, wherein the drug consists of about 30 mg doxycycline ; (ii) a delayed release (DR) portion comprising a drug, wherein the drug consists of about 10 mg doxycycline, in which the DR portion is in the form of pellets coated with an least one enteric polymer; and (iii) one or more pharmaceutically acceptable excipients.
(PTX-013.0537) (emphasis added)
77. The Examiner accepted this claim language and issued the patent. (PTX-13.553-55)
78. When the Chang patents were later challenged in inter partes review ("IPR"), Dr. Rudnic opined that the DR portion of Chang results in "no substantial release of doxycycline in the acidic stomach environment." (DTX-241 ¶ 176)
B. Doctrine of Equivalents
1. Amneal's ANDA Product
79. Amneal represents that it believes its ANDA product is bioequivalent to Oracea ®. (SUF ¶ 75)
80. Amneal's Label relies on the results of a pharmacokinetic study of Oracea ®, which were reported in the Oracea ® NDA and on its product labeling. (Rudnic Sealed Tr. B at B-74-75)
81. Amneal designed its ANDA product based on legal advice from attorneys. (Edwards Sealed Tr. B at B-49-50; Gajjar Sealed Tr. A at A-25-26)
82. Amneal's ANDA product is formulated to be administered orally. (SUF ¶ 74)
83. Amneal's ANDA product will be administered as a 40 mg dosage of doxycycline taken once-daily. (Rudnic Sealed Tr. B at B-59)
84. Amneal's ANDA product is [redacted] containing [redacted] (PTX-331 at Amneal-Doxy2016-00010320)
85. [redacted] are made by [redacted] (PTX-331 at Amneal-Doxy2016-00010402-403; Rudnic Sealed Tr. B at B-59-63; Gajjar Sealed Tr. A at A-22-24)
86. [redacted] of Amneal's ANDA product are manufactured using [redacted], resulting in [redacted]. (PTX-331 at Amneal-Doxy2016-00010392; Rudnic Sealed Tr. B at B-61-63)
87. [redacted] Amneal's [redacted] is designed so that, [redacted]. (PTX-331 at Amneal-Doxy2016-00010320; Rudnic Sealed Tr. B at B-142)
88. [redacted]. (PTX-331 at Amneal-Doxy2016-00010404; Rudnic Sealed Tr. B at B-79-80; Elder Sealed Tr. B at B-184)
89. [redacted] of Amneal's ANDA product does not [redacted] (Rudnic Sealed Tr. B at B-79-80; Elder Sealed Tr. B at B-188; PTX-331 at Amneal-Doxy2016-00010392, -426)
90. [redacted] in Amneal's ANDA product is [redacted]. (SUF ¶ 79)
91. "Immediate release" does not mean that all of the drug is released instantaneously. (Rudnic Sealed Tr. B at B-107) Rather, an "immediate" release formulation can take 30 minutes to an hour or more to release. (Rudnic Sealed Tr. B at B-110-14)
2. Dissolution Data
92. Oracea ®'s dissolution data shows that 30 mg of doxycycline is released in the first 30 minutes, followed by "no appreciable change" in the amount of doxycycline released until the two-hour mark. (Rudnic Sealed Tr. B at B-170-71) At the two-hour mark, the pH of the body environment in which the medicine is found switches to a buffer, and the 10 mg DR portion of Oracea ® is released. (Elder Sealed Tr. B at B-195; Rudnic Sealed Tr. B at B-171; PTX-045 at Amneal-Doxy2016-00309561)
93. The in vitro dissolution data for Amneal's ANDA product shows that [redacted], Amneal's ANDA product releases [redacted]. (PTX-054 at Amneal-Doxy2016-00313476; Rudnic Sealed Tr. B at B-70-72, B-172 (agreeing Amneal's ANDA product releases [redacted] ); Elder Sealed Tr. B at B-194; Gajjar Sealed Tr. A at A-34) From [redacted], Amneal's ANDA product releases [redacted]. (Rudnic Sealed Tr. B at B-172; Elder Sealed Tr. B at B-195 (stating [redacted] is released from Amneal's product" [redacted] ) ) By [redacted], Amneal's ANDA product releases [redacted]. (Rudnic Sealed Tr. B at B-172) At [redacted] the [redacted] of Amneal's product releases. (Elder Sealed Tr. B at B-195; Rudnic Sealed Tr. B at B-172-73)
94. The dissolution data measures the total release of doxycycline but does not indicate where the released doxycycline has come from within the dosage form. (Elder Sealed Tr. B at B-190)
95. Plaintiffs did not test [redacted] of Amneal's ANDA product to determine when release of the [redacted] occurred. (Rudnic Sealed Tr. B at B-171-72)
96. Amneal did not test [redacted] of its product's dissolution or provide scientific studies showing [redacted] of Amneal's [redacted] dissolves i[redacted]. (Elder Sealed Tr. B at B-214-15, B-227-28)
97. Amneal chose [redacted] for [redacted] because [redacted] (PTX-331 at Amneal-Doxy2016-00010400)
98. Amneal's ANDA describes quality controls for [redacted], preparation of [redacted], and [redacted]. (PTX-331 at Amneal-Doxy2016-00010553-556)
3. Sheth
99. In the IPRs, Dr. Rudnic submitted declarations in support of the nonobviousness of the challenged Chang patents over U.S. Patent No. 5,348,748 ("Sheth"), in combination with the Ashley '932 publication. (E.g. , DTX-241 at 84; DTX-0271)
100. The formulation disclosed in Sheth contains a "secondary loading portion" that is coated with "a blend of pH-sensitive polymer and water-soluble polymer." (Rudnic Sealed Tr. B at B-135; see also DTX-241 ¶ 172)
101. The Sheth formulation's water-soluble polymer can be HPMC, which is known as a "pore former." (DTX-241 ¶ 175; Elder Sealed Tr. B at B-186-87)
102. Dr. Rudnic argued during the IPRs that the HPMC coating of Sheth "immediately dissolve[d] to create 'pores' or 'channels' through which drug can slowly diffuse out in a slow, sustained release fashion beginning promptly after administration," while the DR portion claimed in the Chang patents "delayed release (i.e. , preventing release until a later time) to all of the drug contained in that portion." (DTX-241 ¶¶ 175, 181) (emphasis in original)
103. Dr. Rudnic also argued that the Sheth coating "was intentionally designed to be 'leaky' in the stomach," while "the Chang [patents] expressly state[ ] that for the 'DR portion' described and claimed therein, 'there is no substantial release of doxycycline in the acidic stomach environment ...." (DTX-241 ¶ 176) (emphasis in original)
104. Dr. Rudnic stated that the time it took for the HPMC to wet and dissolve to form pores before any drug could release was a "lag" but "would not be considered a 'delay.' " (DTX-271 at 13)
105. The Patent Trial and Appeal Board ("PTAB") found that the secondary loading portion of Sheth was not a "delayed release" portion within the meaning of the Chang patents because it releases drug immediately following oral administration. (DTX-0232 at Amneal-Doxy2016-00437460-461)
106. The blended polymer film coat surrounding the secondary loading portion of Sheth is [redacted]. (Rudnic Sealed Tr. B at B-140)
107. The secondary loading portion of Sheth does not have another drug portion or any other layer on top of its blended polymer coating. (Rudnic Sealed Tr. B at B-91-92; Elder Sealed Tr. B at B-219-20) Thus, following oral administration, the polymer coating of Sheth is immediately subject to gastric fluid. (Rudnic Sealed Tr. B at B-91; Elder Sealed Tr. B at B-221-22)
4. The Chang '532 Patent
108. The Chang '532 patent has an additional limitation that the 10 mg DR portion be "in the form of pellets coated with at least one enteric polymer." (PTX-003 at 13:6-7)
109. The [redacted] in Amneal's ANDA product and [redacted] in Amneal's ANDA Product are [redacted] (Rudnic Sealed Tr. B at B-97; see also PTX-331 at Amneal-Doxy2016-00010320)
110. The Chang '532 patent defines "enteric materials" as "polymers that are substantially insoluble in the acidic environment of the stomach, but are predominantly soluble in intestinal fluids at specific pHs." (PTX-003 at 7:15-18) The Chang '532 specification also states that "[w]ith the enteric coated pellets, there is no substantial release of doxycycline in the acidic stomach environment of approximately below pH 4.5." (PTX-003 at 7:47-49)
111. The [redacted] of Amneal's ANDA product that is [redacted]. (Elder Sealed Tr. B at B-199)
112. Amneal's [redacted] releases [redacted]. (Elder Sealed Tr. B at B-204)
IX. Facts Relating to Infringement of the Ashley Patents
A. Collateral Estoppel
113. In Research Foundation of State University New York v. Mylan Pharmaceuticals Inc. , 809 F.Supp.2d 296 (D. Del 2011) (" Mylan "), the Court determined that Mylan's ANDA product, a 40 mg once-daily dose of doxycycline, did not infringe the Ashley '267 or '572 patents ("Ashley I patents"). (DTX-201 at 22-27)
114. In Galderma Laboratories Inc. v. Amneal Pharmaceuticals, LLC , 921 F.Supp.2d 278 (D. Del. 2012) (" Amneal I "), the Court held that Plaintiffs were collaterally estopped from asserting that Amneal's previous ANDA product infringed the Ashley I patents based on the Court's finding of non-infringement in Mylan .
115. Galderma expressly stated to the Court that the clarified claim constructions it sought (and obtained) in this case do not change the scope of the claims. (See D.I. 85 at 32, 33, 35)
B. Doctrine of Equivalents
116. In Mylan , the Court made a finding of fact that Oracea ® and Mylan's ANDA product, both 40 mg once-daily dosages of doxycycline, were administered in an amount that results in no reduction of skin microflora during a six-month treatment. (DTX-201 ¶¶ 32, 77)
117. The Court was not asked, however, to construe or analyze infringement of the skin microflora limitation in Mylan . (DTX-201 at 22-27)
118. Approximately 100,000,000,000 bacterial cells inhabit the human body. (Zhanel Tr. at 222)
119. Bacteria exist all over normal skin, and the types of bacteria on the skin can vary dramatically based on their location. (Zhanel Tr. at 22-23)
120. The sampling site one chooses to examine "is a major determinant of the microbial composition" one obtains. (Webster Tr. at 126; see also DTX-638 at 2)
121. Doxycycline is a potent and broad-spectrum antimicrobial agent, meaning it affects a large number of organisms. (Zhanel Tr. at 224)
122. When administered orally, doxycycline is absorbed into the bloodstream and travels wherever blood goes in the body, including all areas of the skin. (Zhanel Tr. at 224-25)
1. Amneal's ANDA Product
123. Amneal's ANDA Product is to be administered as a 40 mg capsule of doxycycline once-daily. (PTX-100 at Amneal-Doxy2016-00434868)
124. Amneal has not conducted its own clinical microbiology studies of its ANDA product, but instead relies on clinical microbiology studies submitted to the FDA in connection with the Oracea ® NDA because Amneal has represented that its ANDA product is bioequivalent to Oracea ® (in the fed and fasted states). (Zhanel Tr. at 158; Edwards Sealed Tr. B at B-49, B-51-52)
125. Amneal's Label states: "In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long term effects on bacterial flora of the oral cavity, skin, intestinal tract and vagina." (PTX-100 at Amneal-Doxy2016-00434890)
126. This statement was approved by the FDA for inclusion in the Oracea ® Label following the FDA's review of, among others, Skidmore . (Zhanel Tr. at 177-78)
2. Skidmore /Example 38
127. The purpose of the Skidmore study, which was funded by CollaGenex, was to determine the effects of a six-month treatment of a 40 mg daily doxycycline dosage (20 mg twice-daily) on skin microflora. (PTX-288 at PTX-288 at GLD0083628, -630; Zhanel Tr. at 165) 128. Patients in the Skidmore study received either (1) 20 mg of doxycycline hyclate twice-daily or (2) placebo. (PTX-288 at GLD0083629)
129. Samples of the skin surface were taken by swabbing the glabella, an area on the center of the forehead between the brows, at baseline, two months, four months, and six months. (PTX-288 at GLD0083630; Webster Tr. at 121, 720; Zhanel Tr. at 168-69)
130. Each sample was measured to determine the total number of anaerobic and facultative bacteria, reported as total microbial colony counts. (PTX-288 at GLD0083630)
131. Figure 3 reports that there was no statistically significant difference in total microbial colony count for each target organism from baseline to six months. (PTX-288 at GLD008361-362; Zhanel Tr. at 165-66; Webster Tr. at 78-80)
132. Each sample was also measured to determine the total number of isolates resistant to at least 4 µg/ml doxycycline, as well as the minimum inhibitory concentration (MIC) values for those bacteria, identified by genus and species. (PTX-288 at GLD0083630; Zhanel Tr. at 173-75)
133. Four µg/ml is the clinical breakpoint for doxycycline. (Zhanel Tr. at 167) Organisms with a MIC less than 4 µg/ml are susceptible to doxycycline, while those with a MIC more than 4 µg/ml are resistant to doxycycline. (Zhanel Tr. at 167)
134. Figure 3 reports that there was no increase in the number of bacteria resistant to 4 µg/ml, and there was no increase in MIC values for bacteria resistant to 4 µg/ml doxycycline. (DTX-288 at GLD008361-362; Zhanel Tr. at 167)
135. There were also no strong correlations between resistance to doxycycline and resistance to any of the other five antibiotics tested, and no difference between the correlation coefficients for cross-resistance in the doxycycline 6-month samples and either the placebo 6-month samples or the doxycycline baseline samples. (PTX-288 at GLD0083631-632; Zhanel Tr. at 167)
136. The findings of Skidmore demonstrate that 20 mg twice-daily doxycycline results in no change in the composition of the normal skin flora and does not result in the emergence of doxycycline-resistant organisms. (PTX-288 at GLD008361; Zhanel Tr. at 165-67; Webster Tr. at 78-80)
137. It is possible for an organism to have a MIC less than 4 µg/ml. (Zhanel Tr. at 269-70; Kreiswirth Tr. at 518-89) Testing at 4 µg/ml would not capture changes in resistance below 4 µg/ml. (Kreiswirth Tr. at 518-19)
138. The microbiology and clinical efficacy testing described in Skidmore is also described in Ashley Example 38. (E.g. , PTX-001 at 20:4-21:17)
139. Example 38 reports that a six-month treatment with a 40 mg daily dose of doxycycline (20 mg twice-daily) "resulted in no reduction of skin microflora ... nor an increase in resistance counts when compared with placebo." (E.g. , PTX-001 at 21:7-9)
140. Example 38 does not specify on which part of the body sampling occurred but specifies that subjects have "moderate facial acne." (E.g. , PTX-001 at 20:21)
141. Example 38 is the strongest intrinsic evidence of what the applicant intended to convey by the term "results in no reduction of skin microflora during a six-month treatment." (PTX-378 at 0007)
142. Amneal's Label relies on the results of Skidmore . (PTX-100 at Amneal-Doxy2016-00434890)
143. Sampling the sebaceous facial skin was the standard method as of 2001 for studying the effects on skin microflora of acne or rosacea drugs compared to placebo. (Webster Tr. at 80-82; Zhanel Tr. at 168-69)
144. Amneal's experts agreed that it would be "impractical" and "prohibitively expensive" to assay the entire skin surface to study the effects of doxycycline on skin microflora. (Meltzer Tr. at 620; Kreiswirth Tr. at 546)
145. Dr. Meltzer testified that sampling 20 regions of the body by swabbing, scraping, and performing punch biopsies would not be sufficient to prove there was no reduction in skin microflora. (Meltzer Tr. at 615-20)
146. Dr. Kreiswirth testified that it would be "reasonable" to sample at least three regions of the skin, but did not know how many samples would be needed to prove no reduction in skin microflora and did not know of any study conducted prior to 2001 utilizing the procedures he proposed. (Kreiswirth Tr. at 547-49)
147. Amneal has not presented any study contradicting the methodology or results of the Skidmore study. (Webster Tr.
at 84, 121; Zhanel Tr. at 283; Kreiswirth Tr. at 536-37; Edwards Tr. at B-57-58)
148. Amneal has not presented any evidence that changing the sampling location of the Skidmore study would have led to different results or conclusions. (Webster Tr. at 121; Zhanel Tr. at 283)
3. Indirect Infringement
149. Amneal's Label instructs patients, and directs doctors to instruct patients, to take one 40 mg oral capsule of Amneal's ANDA product once-daily for the treatment of inflammatory lesions (papules and pustules) of rosacea. (See PTX-100 at Amneal-Doxy2016-00434868)
150. Amneal's ANDA product is indicated "for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients." (PTX-100 at Amneal-Doxy2016-00434868) Amneal is not seeking any other indication and will not market its ANDA product for any other use. (Edwards Sealed Tr. B at B-55)
X. Facts Relating to Validity of the Ashley Patents
A. Enablement and Written Description
151. The Ashley patents state that a patient's blood level should be above a therapeutic floor of 0.1 µg/ml and below a sub-antibiotic ceiling of 1.0 µg/ml. (E.g. , PTX-002 at 6:52-62)
152. The Ashley patents state that "[i]n an especially preferred embodiment, doxycycline hyclate is administered at a 20 milligram dose twice daily. Such a formulation is sold for the treatment of periodontal disease by CollaGenex Pharmaceuticals, Inc. of Newtown, Pa. under the trademark Periostat®." (E.g. , PTX-008 at 5:59-63)
153. The Periostat® Label and Periostat® Approval Package would allow a POSA to readily ascertain information about the single-dose and steady-state pharmacokinetic properties of Periostat® (including Cmax, Tmax, and half-life) in various modes of administration. (See PTX-519 at Amneal-Doxy2016-00023434; PTX-518 at Amneal-Doxy2016-00290255, -281, -320, -334-47)
154. The Periostat® Approval Package would also tell a POSA that 40 mg IR doxycycline administered once-daily would achieve a maximum steady-state blood level of 0.834 µg/ml. (PTX-518 at Amneal-Doxy2016-00290343-347)
155. As of 2000-2001, a POSA would have known doxycycline absorbs primarily in the upper gastrointestinal ("GI") tract, and does not absorb well in the colon or lower GI tract. (See PTX-518; Rudnic Tr. at 780-81)
156. The Ashley patents disclose administration of 40 mg doxycycline by "sustained release," which the Ashley patents define as delivering drug "to achieve a certain level of the drug over a particular period of time." (E.g. , PTX-008 at 9:7-10)
157. The Ashley patents incorporate by reference the patent application, "Controlled Delivery of Tetracycline and Tetracycline Derivatives," filed on April 5, 2001, and assigned to CollaGenex (the "Ashley '854 application"). (E.g. , PTX-008 at 9:11-19)
158. The Ashley '854 application describes "methods of delivering tetracycline compounds by sustained release." (PTX-008 at 9:11-12)
159. The Ashley '854 application discloses a preferred embodiment of a controlled release composition where "the controlled-release composition is entrapped in the upper portion of the gastrointestinal tract, for example, in the stomach or duodenum." (DTX-206 at 16:9-14)
160. The Ashley '854 application explains such compositions are "typically manufactured by utilizing controlled-release agents of a larger particle size, as known in art," and "[i]t is preferred that at least 50%, more preferably greater than 80%, of the tetracycline in the composition be released in the upper [gastrointestinal] tract." (DTX-206 at 16:11-14)
161. There were at least 19 patents and patent applications covering gastroretentive technologies as of 2001. (Rudnic Tr. at 785-86; PTX-125; PTX-126; PTX-197; PTX-198; PTX-199; PTX-200; PTX-201; PTX-202; PTX-203; PTX-204; PTX-205; PTX-206; PTX-207; PTX-208; PTX-209; PTX-210; PTX-211; PTX-212; PTX-215)
162. The literature as of 2000-2001 described the use of tetracyclines, including doxycycline, in gastroretentive technologies. (Rudnic Tr. at 790)
163. U.S. Patent No. 6,120,803 ("the '803 patent"), issued on September 19, 2000, disclosed a once-daily gastroretentive controlled release dosage "adapted to deliver in the stomach, as a single dose and over a prolonged time period," intended to sustain release for up to 24 hours. (Rudnic Tr. at 790; PTX-208 at 6-8) The '803 patent identified doxycycline as an "agent[ ] for which the invention is particularly useful." (PTX-208 at 19)
164. WO 00/38650 ("WO '650") was published on July 6, 2000. (Rudnic Tr. at 791; PTX-212) WO '650 detailed a formulation with a swellable layer "adapted to swell in the stomach to facilitate retention of the dosage form in the stomach over a prolonged period of time." (Rudnic Tr. at 791; PTX-212 at 8) WO '650 identified doxycycline as a specific compound for which the disclosed formulations could be used. (Rudnic Tr. at 791; PTX-212 at 42)
165. U.S. Patent No. 6,207,197 (the "'197 patent"), issued on March 27, 2001, described gastroretentive controlled release microspheres that release drug in the stomach for a prolonged period of time. (Rudnic Tr. at 791-92; PTX-209 at 4-5) The '197 patent described the microspheres as useful for once-daily dosing and identified doxycycline as a compound for which the formulations could be used. (Rudnic Tr. at 791-92; PTX-209 at 9)
166. The '803 patent, WO '650 application, and '197 patent were available to a POSA as of 2001. (Rudnic Tr. at 792; PTX-208; PTX-212; PTX-209)
167. Gastroretentive compositions, which swell and stay in the stomach, would have been known to a POSA as of 2000-2001. (Rudnic Tr. at 784)
168. The Ashley patents do not provide working examples of a once-daily or SR formulation. (Elder Tr. at 328)
169. The exact absorption window of doxycycline was not known as of 2001. (Elder Tr. at 333-34)
170. In the late 1990s, CollaGenex hired Faulding Pharmaceuticals to conduct a non-public study to determine doxycycline's absorption window and create a once-daily 40 mg doxycycline product. (Elder Tr. at 335-36; DTX-565 at 1)
171. While Faulding was successful in discovering doxycycline's absorption window, its attempts at formulating a once-daily doxycycline dosage were not successful. (Elder Tr. at 336-37; DTX-0565; DTX-201 at 21)
172. CollaGenex then hired Shire Laboratories to "conduct a feasibility study" of once-daily 40 mg doxycycline formulations. (Ashley Tr. at 672-73; DTX-593 at 1)
173. Shire developed and patented a once-daily 40 mg doxycycline formulation. (Chang Tr. at 686)
174. Dr. Chang testified that no once-daily doxycycline formulations existed before he developed one while working at Shire. (Chang Tr. at 686)
175. In Mylan , the Court found "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." (DTX-201 at 20)
176. In Mylan , the Court found that "[i]t was unexpected that a therapeutic, controlled-release, once-daily dosage form which provided steady state plasma concentrations of doxycycline of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml could be achieved." (DTX-201 at 21)
177. While prosecuting the Chang patents, the applicant told the PTO that as of 2003, "the art did not provide guidance for a single immediate release pharmaceutical dosage form that would deliver 25 mg to 40 mg doxycycline and still achieve subantimicrobial effect." (PTX-17 at 285) (emphasis in original)
178. Dr. Rudnic opined during the Chang IPRs that a POSA would "view the combination of the Ashley [specification] and the Ashley, 854 application as articulating a mere wish for a low-dose once-daily doxycycline formulation, without guidance on how to obtain one, or any demonstration that Mr. Ashley had obtained such a formulation or knew how to do so." (DTX-241 ¶ 94) (emphasis in original)
179. Dr. Rudnic also argued that the Ashley '854 application "does not disclose or teach any actual formulation that at once-daily dosage will give steady state blood levels" within the required therapeutic window. (DTX-241 ¶ 94) (emphasis in original)
180. Dr. Rudnic further stated that "a skilled artisan would have to engage in excessive trial-and-error experimentation ... to determine, which, if any, of the numerous hypothetical formulations within the broad scope of the Ashley references might actually work to meet the goals of the Chang '740 patent inventors - a once-daily doxycycline formulation that ... would effectively treat inflammatory conditions like rosacea while remaining below blood levels linked to antibacterial side effects." (DTX-241 ¶ 128)
181. In Amneal I , Amneal submitted a "Statement of Contested Facts" to the Court, indicating what it intended to litigate at trial. (PTX-129)
182. In that submission, Amneal stated that the claims of the Ashley patents, including the claims reciting administration "once a day" and by "sustained release," are enabled. (E.g. , PTX-129 ¶¶ 102, 124) Amneal stated that the Ashley patents expressly disclose "once-daily" and "sustained release" administration of 40 mg doxycycline that achieves the desired blood levels of the invention; the Periostat® Label and Periostat® Approval Package would provide a POSA with substantial information, including that 40 mg IR doxycycline administered once-daily would achieve a maximum steady-state blood level of 0.834 µg/ml; and the Ashley patents incorporate by reference the Ashley '854 application, which describes formulation approaches for achieving "once-daily" dosing and "sustained release" with low dose doxycycline. (E.g. , PTX-129 ¶¶ 156, 159, 160, 121-22, 180, 191, 234-35, 536, 542-43)
183. The Ashley, 854 application contains a hand-drawn figure of potential release profiles of "instantaneous release," "sustained release," and "delayed release" doxycycline. (DTX-206 at 23)
184. When shown the figure, Mr. Ashley testified his "understanding of [the drawing] would be that these are just hypothetical, wholly hypothetical, profiles of release." (Ashley Tr. at 657) Mr. Ashley added he "really ha[d] no understanding of what [the controlled release agents described in the Ashley '854 application] would mean." (Ashley Tr. at 655)
185. Mr. Ashley also testified that "there's really no guidance, meaningful guidance, in [the Ashley, 854 application], and I had no idea at the time how one might achieve" a controlled release formulation. (Ashley Tr. at 654-55)
186. During the Chang IPRs, Dr. Rudnic stated that the Ashley '932 publication"does not present a single example of an actual formulation that was developed or even contemplated by Mr. Ashley." (DTX-241 ¶ 95)
187. Mr. Ashley is not a formulator and viewed his invention as being "the notion of a flat or relatively flat release profile or relatively flat pharmaco-serum profile." (Ashley Tr. at 654-55)
B. Anticipation and Obviousness
188. Periostat® is an oral antibiotic tetracycline compound that provides a 40 mg daily dose of doxycycline. (PTX-008 at 5:59-63; Feldman Tr. at 387-88)
189. The Ashley patents identify Periostat® as "an especially preferred embodiment" of the inventions. (E.g. , PTX-008 at 5:59-63)
190. Dr. Feldman suffers from rosacea, including the papules and pustules of rosacea. (Feldman Tr. at 388)
191. In October 1998 or 1999, Dr. Feldman attended a dermatology conference in Las Vegas, Nevada where he learned about "new[ ] ideas" for the treatment of rosacea, including the use of Periostat®. (Feldman Tr. at 383, 385)
192. While taking Periostat® for gingivitis, Dr. Feldman's rosacea improved. (Feldman Tr. at 387, 389)
193. In January 2000, Dr. Feldman contacted CollaGenex and requested "professional courtesy samples of Periostat" to continue his use. (Feldman Tr. at 413-14)
194. CollaGenex provided Dr. Feldman with 300-400 professional courtesy samples of Periostat®. (Feldman Tr. at 413-14)
195. In late January or early February 2000, Dr. Feldman used the professional courtesy samples of Periostat® to treat his rosacea and experienced a reduction in his pustules. (Feldman Tr. at 388-89)
196. On February 19, 2000, Dr. Feldman diagnosed a patient as suffering from rosacea, including rosacea pustules, and gave his patient a three-month prescription for Periostat® and one three-month refill. (Feldman Tr. at 400-01)
197. Dr. Feldman prescribed "Periostat 20 milligrams B.I.D. [twice daily] due to its anti-inflammatory effect with decreased risk of side effects." (Feldman Tr. at 401-02)
198. Dr. Feldman's personal use of Periostat® led him to anticipate that Periostat® would improve his patient's condition. (Feldman Tr. at 403, 406-08)
199. 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. (Feldman Tr. at 412)
200. Dr. Feldman was free to discuss his own personal use of Periostat® to treat rosacea. (Meltzer Tr. at 601-02)
201. Dr. Feldman's patient was free to discuss her use of Periostat® to treat rosacea. (Meltzer Tr. at 601-02)
202. Dr. Feldman stored the patient record in a secure locked stor