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Shire LLC v. Abhai, LLC

United States District Court, D. Massachusetts

March 22, 2018

SHIRE LLC and SHIRE U.S. INC., Plaintiffs,
v.
ABHAI, LLC, Defendant.

          FINDINGS OF FACT, RULINGS OF LAW, AND ORDER FOR JUDGMENT

          WILLIAM G. YOUNG DISTRICT JUDGE

         I. INTRODUCTION

         On November 20, 2015, the plaintiffs Shire LLC and Shire U.S. Inc. (collectively, “Shire”), brought this action against the defendant Abhai, LLC (“Abhai”), for patent infringement of the United States Reissued Patent No. RE42, 096 (the “‘096 Patent”), in violation of 35 U.S.C. § 271(e)(2)(A) (count I), and patent infringement of the United States Reissued Patent No. RE41, 148 (the “‘148 Patent”) in violation of 35 U.S.C. § 271(e)(2)(A) (count II). Compl. ¶¶ 1, 20-33.

         This is an Abbreviated New Drug Application (“ANDA”) patent case. Abhai is pursuing an ANDA with the Food and Drug Administration (“FDA”). Compl. ¶ 1. Controlling statutory law encourages such applications and rewards successful, first-to- file applicants as a means toward controlling pharmaceutical prices. See generally FTC v. Actavis, Inc., 570 U.S. 136 (2013). At the same time, the law protects existing patent rights and encourages prompt litigation to assay the limits of those rights. See generally In re Nexium (Esomeprazole) Antitrust Litig., 842 F.3d 34 (1st Cir. 2016). This is such litigation.

         The challenge for Abhai here is to design a pharmaceutical product that falls just beyond the reach of Shire's patents yet is sufficiently bioequivalent and therapeutically equivalent to Shire's product to satisfy the FDA of its efficacy.

         On February 3, 2016, Abhai filed an amended answer to the complaint and counterclaims requesting a declaration of non-infringement of the ‘096 Patent (count I), and a declaration of non-infringement of the ‘148 Patent (count II). Def.'s Am. Answer, Defenses, & Countercls. (“Def.'s Am. Answer”) ¶¶ 18-29, ECF No. 35. On February 17, 2016, Shire filed its answer to Abhai's counterclaims. Counterdefs.' Answer, ECF No. 38.

         On March 1, 2016, the case was referred to mediation, provided by Judge Marianne B. Bowler. Elec. Clerk's Notes, ECF Nos. 44-46. The case returned to this session's running trial list on January 13, 2017 after both parties failed to come to an agreement. Elec. Clerk's Notes, ECF Nos. 93-94; Report Alternative Dispute Resolution Provider, ECF No. 96.

         The bench trial began on March 27, 2017. Elec. Clerk's Notes, ECF No. 148. On April 4, 2017, after four days of trial, Abhai filed a motion to amend its pretrial memorandum to include eight new trial exhibits. Def.'s Mot. Amend Pretrial Mem., ECF No. 153; Def.'s Mem. Supp. Mot. Amend Pretrial Mem., ECF No. 154. The exhibits purported to show that the dissolution tests reported by Abhai on its product were performed incorrectly and the data was invalid. Def.'s Mem. Supp. Mot. Amend Pretrial Mem. 1. The Court held a hearing on the motion on April 4, 2017. Elec. Clerk's Notes, ECF No. 157. The Court, after hearing from counsel, suspended the proceedings for 90 days and entered an order requiring full discovery on the incorrect data and tests. Id. The fifth day of trial resumed on September 5, 2017. Elec. Clerk's Notes, ECF No. 282. The ninth and final day of trial was on September 15, 2017. Elec. Clerk's Notes, ECF No. 328. Closing arguments were held on October 18, 2017. Elec. Clerk's Notes, ECF No. 336. The Court now makes the following findings of fact and rulings of law.

         II. FINDINGS OF FACT

         A. The Parties

         Shire LLC is a limited liability company located in Florence, Kentucky. Am. Joint Pretrial Mem. (“Admitted Facts”) ¶ 1, ECF No. 139. Shire LLC is a direct, wholly-owned subsidiary of Shire U.S. Inc., a New Jersey corporation whose principal place of business is in Lexington, Massachusetts. Id. at ¶ 3; Compl. ¶ 3. Shire LLC is the owner and assignee of the ‘096 and ‘148 Patents. Admitted Facts ¶ 2. Shire Development LLC, an affiliate of Shire, is the holder of the New Drug Application (“NDA”) No. 21-303, for delayed-release capsules containing dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate. Id. at ¶ 15. Shire markets this drug under the name Adderall XR. Id. at ¶ 16. Adderall XR is marketed for the treatment of Attention-Deficit/Hyperactivity Disorder (“ADHD”). Id. at ¶ 17. The ‘096 Patent and the ‘148 Patent are listed in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations for Adderall XR. Id. at ¶ 19.

         Abhai is a limited liability company located in Saint Augustine, Florida. Id. at ¶ 4. Abhai seeks approval from the FDA to market its Abbreviated New Drug Application No. 207489 (“ANDA Product”). Id. at ¶ 5. Adderall XR is the Reference Listed Drug for Abhai's ANDA Product. Id. at ¶ 7. Abhai's ANDA Product has the same active ingredients and is bioequivalent to Adderall XR. Id. at ¶¶ 8-9.

         B. The Patents

         The ‘096 Patent, titled “Oral Pulsed Dose Drug Delivery System, ” was issued by the United States Patent and Trademark Office (“PTO”) on February 1, 2011. Admitted Facts ¶ 20. U.S. Application No. 11/091, 011, later issued as the ‘096 Patent, was filed with the PTO on March 24, 2005. Id. at ¶ 21. The ‘096 Patent is a reissue of U.S. Patent No. 6, 322, 819 (the “‘819 Patent'”). Id. at ¶ 22. The ‘819 Patent was issued by the PTO on November 27, 2001. Id. U.S. Application No. 09/176, 542, issued as the ‘819 Patent, was filed with the PTO on October 21, 1998. Id. at ¶ 23.

         The ‘148 Patent, also titled “Oral Pulsed Dose Drug Delivery System, ” was issued by the PTO on February 23, 2010. Id. at ¶ 25. U.S. Application No. 11/091 was issued as the ‘148 Patent. Id. at ¶ 26. The ‘148 Patent claims priority to PCT/US99/24554, which was filed on October 29, 1999. Id. at ¶ 27. Its PCT Publication Number is WO00/23055 and its PCT Publication Date is April 27, 2000. Id. The ‘148 Patent is a reissue of U.S. Patent No. 6, 605, 300 (the “‘300 Patent”). Id. at ¶ 28. U.S. Application No. 09/807, 462, which led to the ‘300 Patent, was filed with the PTO on July 19, 2001. Id. at ¶ 29. The ‘300 Patent is a continuation-in-part of the ‘819 Patent. Id. at ¶ 30. Beth A. Burnside, Xiaodi Guo, Kimberly Fiske, Richard A. Couch, Rong-Kun Chang, Donald J. Treacy, Charlotte M. McGuiness, and Edward M. Rudnic are listed as inventors of the ‘096 and ‘148 Patents. Id. at ¶¶ 24, 31.

         C. The Asserted Claims

         Shire asserts that Abhai's ANDA Product infringes on Claim 1 of the ‘096 Patent. Admitted Facts ¶ 1. Shire asserts that Abhai's ANDA Product infringes Claims 1, 11 (as it depends from Claims 1, 2, and 7), and 13 of the ‘148 Patent. Id. Abhai raises one affirmative defense, asserting that Shire cannot meet its burden of proof to prove that Abhai's ANDA product will infringe any enforceable claims of the ‘096 and ‘148 Patents. Def.'s Am. Answer at 6. Abhai advances two counterclaims: (1) Abhai's ANDA Product did not infringe the ‘096 Patent and it is entitled to a declaration asserting that there is no infringement; and(2) Abhai's ANDA Product did not infringe on the ‘148 Patent and it is entitled to a declaration asserting that there is no infringement. Id. at ¶¶ 18-29. Shire asserts as an affirmative defense to the counterclaims that Abhai's counterclaims fail to state claims upon which relief can be granted. Counterdefs.' Answer at 7.

         D. Shire's Adderall XR

         The FDA approved Shire's product, Adderall XR, on October 11, 2001, and it is indicated for the treatment of ADHD. Admitted Facts ¶ 17. Adderall XR is marketed in six dosage strengths: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg. Id. at ¶ 18. The drug contains a combination of amphetamine sulfate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and dextroamphetamine saccharate. Id. at ¶ 15. Adderall XR has the same active ingredients as Abhai's ANDA Product. Trial Tr. Day 9 at 53:19-22; Admitted Facts ¶ 8. Adderall XR contains two types of drug-containing beads designed to provide a “double-pulsed delivery of amphetamines.” Trial Tr. Day 9 at 53:23-54:4; Trial Ex. 61 at 1.

         The different dosage strengths of Adderall XR contain “Immediate-Release (IR) pellets” (the “IR Beads”) and “Delayed-Release (DR) pellets” (the “DR Beads”). Trial Tr. Day 9 at 54:10-14; Trial Ex. 24 at 48. The IR and DR Beads in Shire's Adderall XR start with a sugar sphere, which is then covered with a drug layer containing dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate, mixed with hydroxypropyl methylcellulose, a binder. Admitted Facts ¶ 15; Trial Tr. Day 9 at 54:15-23; Trial Ex. 24 at 48. This drug layer is covered with a coating of Opadry Beige. Trial Tr. Day 9 at 54:22-24; Trial Ex. 24 at 48. In the DR Beads, the drug layer and Opadry Beige layer are covered with a coating containing Eudragit L30D-55, triethyl citrate, and talc. Trial Tr. Day 9 at 54:21-55:1; Trial Ex. 24 at 48-49. Shire calls this layer the “polymeric layer” or “polymeric coating.” Trial Ex. 24 at 48-49, Trial Ex. 365 at 279. Abhai refers to this as the enteric coating. Trial Tr. Day 9 at 56:18-25. The DR Beads in Adderall XR contain the same ingredients as Abhai's ANDA Product. Trial Tr. Day 9 at 55:7-19. They both contain the same enteric coating polymer. Id. The IR Beads in Adderall XR also contain the same ingredients as Abhai's ANDA Product. Trial Tr. Day 9 at 55:2-4.

         The DR Beads in Adderall XR are manufactured by covering the IR Beads with the enteric coating. Trial Ex. 365 at 279; Trial Ex. 391 at 3. This is similar to the manufacturing process of DR Beads in Abhai's ANDA Product. Trial Ex. 391 at 3. No. other change is made to the IR Beads. Trial Ex. 365 at 279. Shire manufactured its Adderall XR using an 18” Wurster Column in a Glatt GPCG-30 fluid bed processor. Trial Ex. 365 at 279, 282. As part of its NDA, Shire indicated that the commercial batches of Adderall XR sold after product approval would be manufactured using a Glatt GPCG-200 fluid bed processor equipped with a 46” Wurster column. Trial Ex. 365 at 279, 286. The difference is due in part to the fact that the larger commercial batches of Adderall XR require equipment with larger capacity. Trial Ex. 365 at 279.

         Shire measured the coating thickness of the polymeric layer in Adderall XR and found it to be an average of 40 microns. Trial Ex. 386 at 3; Trial Tr. Day 9 at 56:23-25.

         E. Abahi's ANDA Product

         Abhai's ANDA Product is designed to be available in five dosage strengths: 10 mg, 15 mg, 20 mg, 25mg, and 30 mg. Admitted Facts ¶ 32. Each dosage strength contains a combination of amphetamine sulfate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and dextroamphetamine saccharate. Id.

         Abhai's ANDA Product is a capsule filled with two types of beads: IR Beads and DR Beads. Admitted Facts ¶ 38. The IR Beads contain a core particle, which consists of sugar spheres, 30 to 50 mesh, NF white. Trial Tr. Day 8 at 16:25-17:3. The core particle is then surrounded by a drug layer, consisting of four active ingredients and a binder. Id. at 17:5-13. The active ingredients are dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate. Id. at 17:8-12; Trial Ex. 28. Hydroxypropyl methyl cellulose, Methocel E5 Premium LV, acts as the binder. Trial Ex. 28. The drug layer is covered by a seal coating comprised of Opadry Beige YS-1-17274-A. Trial Tr. Day 8 17:13-16; Trial Ex. 28. The IR Beads in all strengths contain the same ingredients. Trial Tr. Day 8 at 17:17-22. The DR Beads contain the same core particle, drug layer, and seal coating as the IR Beads. Id. at 18:6-13. On top of the seal coating in the DR Beads, there is a delayed release coating polymer (“DR Polymer Layer”) made up of an acid/methacrylic acid copolymer dispersion (Eudragit L30D55). Id. at 18:13-17. It is plasticized with triethyl citrate and followed by antistatic agents talc and silicon dioxide. Id. at 18:17-19; Trial Ex. 28.

         The DR Beads in all strengths contain the same ingredients. Id. at 18:20-24. The DR beads are created by covering IR Beads with the DR Polymer Layer. Trial Ex. 26 at 36.

         F. Dissolution Testing and the FDA-Recommended Method Used by Abhai

         Using an in vitro dissolution method, Abhai tested all strengths of its ANDA Product to determine the amount of drug release at different time points. Trial Exs. 11 at 23; 10 at 5; 9 at 3, 8. The method used is recommended by the FDA for Adderall XR and any generic equivalent. Trial Ex. 8 at 1; Trial Tr. Day 2 at 5:12-21; Trial Tr. Day 5 at 14:10-24; Trial Tr. Day 8 at 25:16-26:1. The method includes: (1) placing capsules in the vessels of an apparatus called USP Apparatus II (commonly known as a “paddle apparatus”) and stirring the paddle at 50 rpm; (2) using 750 milliliters of dilute hydrochloric acid (with a pH of 1.1) for the first two hours of testing; (3) after two hours, adding 200 milliliters of 200 mM phosphate buffer to bring the pH up to 6.0 for the remainder of the test (for a total volume of 950 milliliters); and (4) sampling the drug release at 0.5, 1, 2, 3, and 4 hours. Trial Tr. Day 5 at 14:25- 15:4, 16:16-17:5; Trial Tr. Day 8 at 26:4-21; Trial Tr. Day 2 at 7:5-19; Trial Ex. 8 at 1.

         The FDA-recommended two-stage test attempts to replicate the conditions under which a product similar to Adderall XR or Abhai's ANDA Product performs in the body. Trial Tr. Day 8 at 30:2-13; Trial Tr. Day 1 at 125:10-19. The pH of 1.1 in the first stage of the FDA-recommended test simulates the lower end of the observed pH in the stomach. Trial Tr. Day 1 at 66:14-18; Trial Tr. Day 8 at 27:7-11; Trial Tr. Day 1 at 117:21-22. The IR Beads in Abhai's ANDA Product will release their active ingredients when they hit the stomach. Trial Tr. Day 1 at 117:14-17. The DR Beads will leave the stomach and travel into the small intestine, where they will release their active ingredients. Id. at 117:17-21. The higher pH of 6.0 used in the second stage of the dissolution tests simulates the pH in the upper small intestine. Trial Tr. Day 1 at 66:19-21, 117:23- 24; Trial Tr. Day 8 at 27:12-16; Trial Ex. 12 at 6; Namburi 2016 Dep. 81:6-16. Switching the pH levels at two hours simulates the initiation of the “delayed pulsed enteric release” in Claim 1 of the '096 Patent. Trial Tr. Day 9 at 25:5-15. This is point at which the DR Beads move from the stomach to the intestines. Id. The FDA-recommended two-stage test is two hours at the pH 6.0 stage because it resembles the approximate transit time through the upper part of the small intestine. Trial Tr. Day 8 at 28:15-19, 29:22-30:1; Trial Ex. 18 at 5 (fig. 2).

         The USP II (Paddle) apparatus used in the FDA-recommended two-stage test has six vessels. Trial Tr. Day 5 at 16:12-15. At specific times, aliquots of the dissolution medium are removed and analyzed to determine the amount of drug released from the formulation. Trial Tr. Day 5 at 20:17-21:1 (discussing sampling); Trial Ex. 319 (Lab Notebook 3004) at 8, 11, 14, 18, 27.

         Shen Yung Luk, Ph.D. (“Dr. Luk”) performed dissolution tests on Abhai's ANDA Product for Shire.[1] Dr. Luk used high performance liquid chromatography (“HPLC”) with ultraviolet light absorption spectroscopy to analyze the dissolution media and determine the amount of drug release from the formulation. Trial Tr. Day 5 at 13:15-22, 23:22-25. This is a common method used in the pharmaceutical industry. Id. at 23:23-25. Ultraviolet light absorption spectroscopy measures the amount of light absorbed by a solution. Trial Tr. Day 5 at 25:10-16. The measurements obtained using the ultraviolet light absorption spectroscopy method are compared against solutions of known concentration to calculate the concentration of the compound dissolved. Id. HPLC is used with ultraviolet light absorption spectroscopy to separate a compound from any other substances in the sample. Trial Tr. Day 5 at 13:15-22. The separation occurs when the sample solution is passed over a tube or “column” containing fine particles, to which the different compounds in the solution adsorb (stick to) in varying degrees. Trial Tr. Day 5 at 23:22-24:10. Liquid (“eluent”) is passed through the column and extracts different compounds from the column. Id. Due to the differences in adsorption, each compound is drawn through the column at a different and characteristic time (otherwise known as the retention time), allowing each compound to be measured separately. Id. The output from the HPLC and UV analysis is a plot of UV light absorbance versus time called a chromatogram. Id. at 25:8-18; Luk Supp. Report ¶¶ 26-28Each peak corresponds to different compounds. Id. The height or area of a resulting peak is measured, and it is proportional to the amount of material in the sample. Trial Tr. Day 5 at 27:21- 22; Trial Ex. 320.

         G. Stability Dissolution Testing on Abhai's ANDA Product

         Abhai reported dissolution data over the proposed shelf life of its ANDA Product, for each of its five dosage strengths. Trial Ex. 130 at 43, 46, 50, 54, 57, 60, 64, 67. Abhai is seeking an expiration date for its ANDA Product of 24 months, based on the stability data generated for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules.

         Trial Ex. 131 at 2; 192 at 1. Abhai conducted various testings, including dissolution testing, to support its proposed expiration date. Trial Exs. 130, 240. Abhai is representing to the FDA, based on the stability testing on its ANDA Product, that a person can take its ANDA Product effectively up until 24 months. Trial Tr. Day 2 at 96:7-10.

         1. Original, Now-Repudiated, Stability Testing in Abhai's ANDA Product

         Abhai tested its ANDA Product at seven sample ages (initial, three months, six months, nine months, twelve months, eighteen months, and twenty-four months) and at five sample times (0.5 hours, one hour, two hours, three hours, four hours). Trial. Ex. 130 at 43, 46, 50, 54, 57, 60, 64, 67. The following batches were tested: D0482 (10 mg), D0537 (15 mg), D0480 (20 mg), D0541 (25 mg), and D0449 (30 mg). Id. These were the same batches used in the batch dissolution testing. See Trial Exs. 9 at 3, 8; 10 at 5, 13; 11 at 23. At the time of the March trial, no 24 month stability dissolution testing had been conducted on the 15 mg and 25 mg strengths of Abhai's ANDA Product. Trial Ex. 130. For the following strengths, 10 mg, 20 mg, and 30 mg, 24 month stability dissolution testing was conducted but only the 2-hour and 3-hour sample times were recorded. Trial Ex. 130 at 46, 57, and 67.

         2. Errors in Original Stability Testing on Abhai's ANDA Product

         After a Rule 30(b)(6) deposition of Abhai, conducted on October 14, 2016, Abhai discovered that it incorrectly performed its 18 month dissolution test for the 15 mg and 25 mg sample dosage, and it incorrectly performed its 24 month dissolution test for the 10, 20, and 30 mg sample dosage for its ANDA Product. Def's Mem. Supp. Mot. Amend Pretrial Mem. 5; Trial Ex. 240 at 4, 6, 8, 10, 18, 20, 22, 24, 32, 34; Trial Tr. Day 9 at 13:18-14:1. Abhai conducted its original 18-month stability testing on the 15 mg strength from May 25 to May 31, 2016.

         Trial Ex. 225 at 3. Abhai conducted its original 18 month stability testing on the 25 mg strength from May 25 to May 31, 2016. Trial Ex. 226 at 3. Abhai conducted its original 24 month stability dissolution testing on the 30 mg strength from March 29 to April 4, 2016. Trial Ex. 230 at 36. Abhai conducted its original 24 month stability dissolution testing on the 10 mg strength on April 6, 2016. Trial Ex. 227 at 36. Abhai conducted its original 24 month stability dissolution testing on the 20 mg strength on April 5, 2016. Trial Ex. 229 at 55.

         Five out of the thirty-three sets of dissolution testing completed prior to the discovery of the incorrect testing were performed incorrectly. Trial Tr. Day 6 at 126:24-130:20. The original 24 month dissolution test for the 10, 20, and 30 mg strengths and 18 month dissolution test for the 15 and 25 mg strengths were performed incorrectly. Trial Tr. Day 9 13:18-14:1; Trial Ex. 220 at 9-12. Technicians collected samples from the dissolution medium after the ANDA Product had been in the buffer solution (pH 6.0) for three hours (5 hours after testing began), instead of one hour (3 hours after testing began). Id.

         After an investigation of the testing was conducted, Abhai determined that “poor method clarity” was the “root cause” of the testing errors. Trial Tr. Day 9 at 32:19-22; Trial Ex. 220 at 9-10. The 30 mg strength had been tested using Finished Product Test Method MOA No. 142, Rev No. 05. Trial Ex. 220 at 9. The analysts used similar testing methods for the 10 mg, 15 mg, 20 mg, and 25 mg, dosage strengths. Id. at 11. Shorter testing durations comprised another part of the testing error. Id. Samples were also taken later than called for in the revised stability dissolution method: at five hours, instead of three. Trial Tr. Day 9 at 34:3-9. The mistakes made in Abhai's stability dissolution testing indicate that neither the analysts nor their supervisors understood the FDA-recommended two-stage dissolution method. Trial Tr. Day 9 at 38:18-39:5. Abhai revised its dissolution procedure for each strength of its ANDA Product following the investigation. Trial Ex. 220 at 11. The revised test methods are dated October 25, 2016. Trial Ex. 220 at 18-27.

         3. Revised Stability Testing on Abhai's ANDA Product

         The 15 mg strength was manufactured in August 2014. Trial Ex. 240 at 8; Trial Ex. 130 at 50. Re-testing of the 15 mg strength at the “18-month” storage age was conducted from November 7 to November 9, 2016. Trial Ex. 225 at 14. The 15 mg samples were 27 months old at the time. Trial Tr. Day 9 at 14:16-20. The 15 mg samples were tested for the “24 month” storage age at the same time they were re-tested for the 18-month storage age. Trial Ex. 225 at 14.

         The 25 mg strength was originally manufactured in October 2014. Trial Ex. 240 at 22; Trial Ex. 130 at 60. Re-testing of the 25 mg strength for the “18-month” storage age was conducted from November 8 to November 9, 2016. Trial Ex. 212 at 3. The 25 mg samples were 25 months old at the time of re-testing. Trial Tr. Day 9 at 14:16-20. The 25 mg samples were tested for the “24-month” storage age at the same time they were re-tested for the “18-month” storage age. Trial Ex. 212 at 3. The 10 mg strength was manufactured in February 2014. Trial Ex. 240 at 1; Trial Ex. 130 at 43. Retesting of the 10 mg strength for the “24-month” storage age took place from November 7 to November 9, 2016. Trial Ex. 213 at 3. At the time of the retesting, the 10 mg samples were 33 months old. Trial Day 9 at 14:9-15. The original 20 mg strength was manufactured in February 2014. Trial Ex. 240 at 15; Trial Ex. 130 at 54. Retesting of the 20 mg strength for the “24-month” storage age took place from November 8 to November 9, 2016. Trial Ex. 214 at 3. The 20 mg samples were 33 months old at the time of the retesting. Trial Tr. Day 9 at 14:9-15. The 30 mg strength was manufactured in February 2014. Trial Ex. 240 at 29; Trial Ex. 130 at 64. Re-testing of the 30 mg strength for the “24-month” storage age took place from November 8 to November 9, 2016. The 30 mg samples were 33 months old during retesting. Trial Tr. Day 9 at 14:9-15. Results from the re-testing were submitted to FDA as the “18-month” results for the 15 and 25 mg strengths, and as the “24-month” results for the 10, 20, and 30 mg strengths. Trial Ex. 240 at 4, 8, 18, 22, 32.

         H. Bioequivalence Studies on Abhai's ANDA Product

         Abhai performed and submitted to the FDA three bioequivalence studies of its ANDA Product. Trial Exs. 68-70. As part of the studies, Abhai administered its ANDA Product to adult volunteer subjects. Trial Exs. 68 at 3; 69 at 3; 70 at 3. Blood samples were then taken at specific time points, from times zero to 60 hours. Trial Exs. 68 at 36; 69 at 38; 70 at 35. Abhai analyzed the blood samples to measure the amount of d-amphetamine and l-amphetamine in the subject's blood plasma. Trial Exs. 68 at 44; 69 at 45; 70 at 43. Abhai then collected and presented the data in its ANDA, along with graphs of the drug concentration data over time. Trial Exs. 71, 75, 81. The clinical studies were performed during the following gastric states: (i) Fasted, meaning the subjected fasted for ten hours prior to dosing; (ii) Fed, meaning the subjects consumed a standardized high-fat breakfast thirty minutes prior to dosing; and (iii) Sprinkled, meaning the subjects consumed one tablespoon of applesauce on which the contents of one capsule were sprinkled. Trial Exs. 68 at 3; 69 at 3; 70 at 3. Twenty-eight individual subjects participated in Abhai's Fasted ANDA Study; 40 individual subjects participated in Abhai's Fed ANDA Study, and 28 individual subjects participated in Abhai's Sprinkled ANDA Study. Trial Exs. 68 at 6; 69 at 7; 70 at 6.

         III. RULINGS OF LAW

         A. Abhai's Proposed ANDA Product Infringes Claim 1 of the ‘096 Patent

         Claim 1 of the ‘096 patent includes:

A pharmaceutical composition for delivery of one or more pharmaceutically active amphetamine salts, comprising: (a) one or more pharmaceutically active amphetamine salts covered with an immediate release coating; and (b) one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating that provides for delayed pulsed enteric release, wherein said enteric release coating releases essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric [release] release; wherein the pharmaceutically active amphetamine salts in (a) and (b) comprise mixed amphetamine salts.

Trial Ex. 1 at Claim 1.

         Abhai admits that its ANDA Product meets the following limitations of claim 1 of the ‘096 Patent: (1) “a pharmaceutical composition for delivery of one or more pharmaceutically active amphetamine salts”; (2) “one or more pharmaceutically active amphetamine salts covered with an immediate release coating”; and (3) “the pharmaceutically active amphetamine salts . . . comprise mixed amphetamine salts.” Admitted Facts ¶¶ 37, 42, 47; see also Trial Ex. 1 at Claim 1. Abhai only disputes that its ANDA Product meets the following limitations of claim 1: (1) “one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating the provides for delayed pulsed enteric release”; and (2) “wherein said enteric release coating releases essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric release.” The active ingredients in Abhai's ANDA Product are amphetamine sulfate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and dextroamphetamine saccharate. Admitted Facts ¶ 35. These are pharmaceutically active amphetamine salts. Id. at ¶ 36; Trial Tr. Day 8 at 20:4-9. They are contained in the drug layer of the DR Beads. Trial Tr. Day 8 at 20:12-15; Trial Exs. 26 at 34; 28 at 2; 29 at 1. The drug layer is then covered by a seal coat, then a DR Polymer Layer. Trial Tr. Day 8 at 18:11-19; Trial Ex. 26 at 34. The DR Polymer Layer is made up of Eudragit L30D-55, triethyl citrate, and talc. Trial Tr. Day 8 at 18:13-19; Trial Ex. 26 at 28. Eudragit L30D-55 is used for the enteric coating. Trial Tr. Day 8 at 21:1-5; Trial Exs. 26 at 38; 32 at 22; 26 at 39; 2 at 10:59-11:1. According to the ‘096 Patent, enteric polymers include Eudragit L30D-55 and can be used in enteric coatings. Trial Ex. 1 at 17.

         The purpose of the enteric coating is to prevent release of the drug in the stomach, while still ensuring that drug release from the dosage form will occur at some point in the digestive tract distal to the stomach. Trial Exs. 5 at 36; 6 at 13. Eudragit L30D-55 is designed to delay release of active ingredients until the pH of gastric juices reaches above 5.5, indicative of the small intestine. Trial Ex. 15 at 6; Trial Tr. Day 8 at 19:20-20:1, 28:6-14; Trial Ex. 12 at 6; Namburi 2016 Dep. 80:9-15, 81:21-24.

         The Eudragit L30D-55 in Abhai's ANDA Product is manufactured by Evonik. Trial Ex. 30 at 32. Evonik describes Eudragit L30D-55 as an “effective and stable enteric coating[] with a fast dissolution in the upper Bowel.” Trial Ex. 7 at 1. During his deposition, Ranga Namburi, Ph.D. (“Dr. Namburi”)[2]admitted that the Eudragit L30D-55 in Abhai's ANDA Product was used as an enteric coating. Namburi 2016 Dep. 114:12-15. Therefore, the DR Polymer Layer in Abhai's ANDA Product, comprising Eudragit L30D-55, constitutes an “enteric release coating.” Trial Tr. Day 8 at 22:12-14; Trial Ex. 1 at Claim 1. This “enteric release coating” covers the one or more pharmaceutically active amphetamine salts in the DR Beads of Abhai's ANDA Product. Trial Tr. Day 8 at 22:17-22.

         The parties agree that “delayed pulsed enteric release” as used in the patent means “rapid and complete release of drug (after a first dose by immediate release) designed to be delayed until the drug has passed through the stomach into the intestines.” Am. Joint Claim Construction Statement at A-1, ECF No. 77. Testifying for Shire, Jennifer Dressman, Ph.D. (“Dr. Dressman”)[3] explained that she applied a standard for complete release that required release of 75-80% from the enteric coated dosage form, based on guidance from the FDA and chapters from the U.S. Pharmacopeia (“USP”), as well as the specifications and claims of the asserted patents. Trial Tr. Day 8 at 31:2-8; Trial Exs. 5, 19, 21. The FDA allows manufacturers to end sampling from their dissolution testing after 80% drug release. Trial Ex. 5 at 10. This threshold is applied to dissolution testing of enteric-coated dosage forms. Trial Ex. 5 at 35-36; Trial Tr. Day 8 at 31:21-32:24. This suggests that complete release has occurred. Trial Tr. Day 8 at 32:25-34:1.

         The FDA's guidance, provided to the PTO during prosecution of the ‘096 Patent, anticipates that enteric-coated dosage forms need to release 80% of the drug in order for the release to be considered “complete” as required in “delayed pulsed enteric release.” Trial Tr. Day 8 at 31:18-20, 32:25-33:13; Trial Ex. 3 at 3168-3219. According to the USP, 75-80% of the label claim is the typical acceptance value for dissolution specifications. Trial Tr. Day 8 at 35:16-36:1; Trial Ex. 19 at 8. This represents an essentially complete release of the drug. Id. Therefore, the FDA and USP guidance confirm that “complete” release means that at least 75-80% of the enteric coated drug has been released.

         In its Claim Construction Order, the Court construed the term “a delayed enteric release dosage form that provides delayed release upon oral administration, ” as “a dosage form that provides rapid and complete release of drug (after a first dose by immediate release) intended to be delayed until the drug has passed through the stomach into the intestines after oral administration.” Claim Construction Order at 13, ECF No. 85. The term occurs in Claims 1, 11, and 13 of the ‘148 patent and parallels the construction of “delayed pulsed enteric release” in the '096 Patent. The Court specifically noted that Figure 6 of the '096 and '148 Patents supports a pulsed release invention. Claim Construction Order at 11-12. The Court rejected Shire's argument that Figure 6 supported a sustained release invention in the '148 Patent. Claim Construction Order at 11-12. Therefore, Figure 6 of the asserted patents illustrates the rapid and complete (“pulsed”) release claimed in both the '096 and '148 Patents. Claim Construction Order at 11- 12.

         The ‘096 and ‘148 Patents describe Figure 6 as “illustrat[ing] the drug release profile of coated pellets described in Example 4 which exemplifies the delayed release components of the present invention.” Trial Ex. 1 at 6:49-52; Trial Tr. Day 8 at 41:18-24. Example 4 of the ‘096 Patent describes the formulation for enteric-coated mixed amphetamine salts pellets. Trial Ex. 1 at 11:45-12:13. Figure 6 shows a staged in vitro dissolution test where the pellets were exposed to pH 1.1 for two hours. See, e.g., Trial Ex. 1 at Fig. 6; Trial Ex. 1 at 11:45-12:13; 6:49-52; 11:45-12:13. The pH was then increased to pH 6.0 for one hour to represent the movement of the dosage form from the stomach into the intestines, initiating the delayed enteric release. Trial Tr. Day 8 at 41:25-42:5. The pH was increased to 7.5 for the remainder of the test. Trial Ex. 1 at Fig. 6; id. at 11:45-12:13. The enteric release continues for at least six hours after it is initiated, and over time about 80% of the enteric-coated drug is released. Trial Ex. 1 at Fig. 6; Trial Tr. Day 8 at 42:9-16. Therefore, a “rapid and complete” release according to the construction for “delayed pulsed enteric release” may take as long as six hours and is consistent with release of about 80% of the enteric-coated drug. Trial Ex. 1 at Fig. 6; Claim Construction Order at 11-12. The term “delayed pulsed enteric release” does not require release of 100% of the drug within about 30-60 minutes. Trial Tr. Day 8 at 38:6-13, 40:13-17.

         Claim 13 of the ‘096 Patent, which claims a “protective layer over the enteric release coating, ” also requires that the composition provide a “rapid and complete release, ” regardless of the protective layer, because the construction of “delayed pulsed enteric release, ” which is part of Claim 13, requires “rapid and complete release.” Trial Tr. Day 6 at 40:9-18; Trial Tr. Day 7 at 23:19-24:4; Trial Ex. 1 at Claim 13. Abhai claimed that Figure 6 is an embodiment of Claim 20 of the '148 Patent, which requires “a protective coating layer.” Trial Tr. Day 7 at 25:10-14; Trial Ex. 2 at Claim 20. Claim 20 is a dependent claim that depends from Claim 1. Trial Ex. 2 at Claim 20. Claim 1 requires “a delayed enteric release dosage form that provides delayed release upon oral administration, ” and the Court has construed it to include a “rapid and complete” release. Trial Tr. Day 7 at 26:12-21; Trial Ex. 2 at Claim 1.

         Therefore, as a dependent claim, Claim 20 of the '148 Patent requires a rapid and complete release. Thus, by admitting that Figure 6 embodies Claim 20, Abhai has admitted that “rapid and complete” release is shown in Figure 6. The Patents' specifications and Abhai's expert Diane Burgess, Ph.D. (“Dr. Burgess”)[4] recognize that the recited “protective ...


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