Shire LLC v. Abhai, LLC (298 F. Supp. 3d 303, 2018)

WILLIAM G. YOUNG, DISTRICT JUDGE

I. INTRODUCTION

On November 20, 2015, the plaintiffs Shire LLC and Shire US 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, 133 S.Ct. 2223, 186 L.Ed.2d 343 (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 US 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 at 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. 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 ¶¶ 26-28 Each 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. Retesting 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") 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") 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") recognize that the recited "protective layer" can provide for rapid and complete release. Trial Tr. Day 6 at 40:22-25; Trial Ex. 2 at 5:44-46.

The data submitted at trial shows rapid and complete release. The parties first "normalize" the data to measure the amount of drugs released from the DR Beads. Trial Tr. Day 6 at 14:23-15:9. "Normalization" refers to the calculations that experts from both parties performed to estimate the amount of amphetamine in the DR Beads and the percent released from those beads, while excluding the amount of amphetamine released from the IR Beads. Id.

In order to calculate the amount of drug released from the DR Beads in the first hour of exposure to pH 6.0, Dr. Dressman first divided the amount of drug released after the first hour in pH 6.0 by the amount of the label claim released over the full two hours in pH 6.0. Trial Tr. Day 9 at 6:17-7:17. The results were multiplied by 100% to calculate the percentage. Id. This is referred to as "4-hour normalization." Trial Tr. Day 9 at 5:22-6:1; Trial Tr. Day 6 at 63:5-6.

Both parties' experts use the "Assay Normalization" when dissolution data is not available at the four-hour mark. Trial Ex. 399; Trial Tr. Day 9 at 51:19-20. An assay is a method of determining the percentage of label claim or the amount of drug present (on average) in a given batch, compared to the amount of drug listed on the label. Trial Tr. Day 1 at 124:14-19. The assay value is used to calculate the amount of drug released from the DR Beads in the first hour of exposure to pH 6.0. See generally Trial Ex. 399. This type of normalization method assumes that the assay amount for a given batch of product is the actual amount of drug contained in each capsule of that product. Trial Tr. Day 2 at 13:25-14:2

Dr. Burgess also used a different of four-hour normalization method where time points subsequent to three hours indicate that a plateau has been reached. She then chose the highest release value observed and treated it as the capsule content. Trial Tr. Day 6 at 17:22-18:10.

"Label claim normalization" is also used when no four-hour dissolution value is available. Trial Tr. Day 9 at 20:1-3. Using this method, normalization is achieved by dividing the amount of release in the first hour of exposure to pH 6.0 by 50%, which represents the expected amount of amphetamine in the DR Beads. Trial Tr. Day 9 at 19:24-20:4; Trial Ex. 394.

The most appropriate method to normalize release data from extended release mixed amphetamine salt dosage forms is to use the four-hour normalization method. Trial Tr. Day 9 at 8:14-20. Observed release data after four hours shows that a drug release plateau is reached at the beginning of the fourth hour. Trial Tr. Day 9 at 7:20-8:21. This means that drug release will be complete by the end of the fourth hour. Id. The result of Dr. Dressman's four-hour normalization and Dr. Burgess's "highest percentage release" normalization methods thus will be approximately the same. Id.; Trial Tr. Day 6 at 18:1-10, 63:4-10.

In May of 2017, Dr. Luk performed dissolution testing on each strength of Abhai's ANDA Product. Trial Tr. Day 5 at 12:24-13:4. His testing showed a plateau that began at four hours, which meant that release from the DR Beads in Abhai's ANDA Product had finished after four hours. Trial Tr. Day 9 at 7:20-8:20. Dr. Luk's testing of Abhai's ANDA Product back in October 2016 also showed a drug release plateau starting at four hours. Trial Ex. 199. Shire's testing of NDA batches of Adderall XR also showed a similar amount of release at the end of four hours (two hours in pH 6.0) as at the end of five hours. Trial Exs. 25 at 231, 236, 241; 382 at 34, 39, 44. Teva's testing of Adderall XR in 2006 also showed a similar amount of drug release at four hours (two hours in pH 6.0) as at 4.5 hours. Trial Ex. 358 at 26, 30, 34, 38, 42, 46; Trial Tr. Day 9 at 43:6-10. Andrx's testing of Adderall XR in 2007 similarly showed a plateau in drug release between four hours (two hours in pH 6.0) and 6 hours. Trial Ex. 390 at 1, 2, 3, 4, 5, 6; Trial Tr. Day 9 at 44:11-17.

Abhai claims that the four-hour normalization is not accurate because, after conducting a dissolution test on the 20 and 30 mg strengths of Abhai's ANDA Product, with the second stage conducted at a pH of 6.8 instead of the FDA-recommended pH of 6.0, the total release observed was higher than the release observed in other tests conducted according to the FDA-recommended two stage method. Trial Tr. Day 6 at 92:5-93:1. Therefore, Abhai argues, there must have been additional, unreleased drugs in the capsules that were tested according to the FDA-recommended method. Trial Tr. Day 6 at 92:5-93:1. The pH 6.8 testing, however, was conducted on different capsules than those used in the testing that Dr. Luk performed according to the FDA-recommended two-stage method, and the contents of each individual capsule varied substantially. Trial Tr. Day 5 at 111:13-112:5. As Dr. Dressman explained, it is not a fair comparison, and it is misleading to compare the two sets of data because the content of each capsule was different. Trial Tr. Day 5 at 103:20-104:18.

Abhai's testing of its ANDA Product shows rapid and complete release. Abhai tested 12 capsules of each strength of its ANDA Product using the FDA's recommended in vitro dissolution method. Trial Exs. 9 at 3, 8; 10 at 5, 13; 11 at 23. Applying four-hour normalization to Abhai's batch dissolution data, the results showed rapid and complete release from the DR Beads. Trial Tr. Day 9 at 12:14-17. For the 10 mg strength, the percent release was 84.9%; for the 15 mg strength, the percent release was 85.7%; for the 20 mg strength, the percent release was 76.1%; for the 25 mg strength, the percent release was 87.5%; and for the 30 mg strength, the percent release was 73.8%. Trial Exs. 26 at 98, 89, 80; 32 at 55, 64.

Abhai's retest of its ANDA Product also shows rapid and complete release. Abhai normalized its results using the four-hour, assay value, and label-claim normalization methods. Trial Exs. 394; 240 at 1, 4, 8, 11, 15, 18, 22, 25, 29, 32; Trial Tr. Day 9 at 19:19-24:4, 22:6-15. Under these methods, Abhai obtained many values exceeding both 75% and 80%, and over 90% in some instances. Trial Tr. Day 9 at 19:19-20:4, 20:16-22:1, 22:6-15, 22:25-23:4; Trial Exs. 330; 240 at 1, 4, 8, 11, 15, 18, 22, 25, 29, 32; 394. These numbers show rapid and complete release of the drug from the DR Beads over the first hour of exposure to pH 6.0. Trial Tr. Day 9 at 22:2-5, 23:5-9.

Dr. Luk's dissolution testing also shows rapid and complete release. Trial Tr. Day 9 at 10:22-25. In May of 2017, Dr. Luk performed dissolution testing on six capsules of all strengths of Abhai's ANDA Product using steel sinkers conforming to the USP dissolution monograph specification. Trial Ex. 319 at 3, 7, 10, 13, 17, 26; Trial Tr. Day 5 at 37:17-24, 39:18-40:1; Trial Ex. 20 at 4. Dr. Luk placed the capsules in a dissolution media, first prepared on May 12, 2017. Trial Ex. 319 at 1. He also used a USP II (Paddle) dissolution apparatus, set to 50 rmp. Trial Tr. Day 5 at 16:12-15, 61:1-24. The dissolution bath was started at pH 1.1, and one capsule was added. Trial Tr. Day 5 at 18:25-19:12; Trial Ex. 319 (Lab Notebook 3004) at 8, 11, 14, 18, 27. Capsules were then added at intervals of five minutes. Trial Tr. Day 5 at 19:13-19. A five-minute interval was used to allow sufficient time for the addition of the 200 mM phosphate buffer and adjustment of pH to 6.0 at the two-hour time point. Trial Tr. Day 5 at 20:4-14, 22:2-4. The testing mirrored Abhai's dissolution testing procedures. Trial Tr. Day 5 at 21:7-9; Trial Exs. 40 at 18; 284 at 17.

Dr. Luk took samples at additional time points beyond those required by the FDA prior to the pH being adjusted to 6.0, and then again after it was adjusted. Trial Tr. Day 5 at 23:2-7. The results from each sample collected were compared against the results from a standard solution with a known concentration of amphetamine. Trial Tr. Day 5 at 25:8-16.

Dr. Luk conducted two dissolution tests on Abhai's ANDA Product. Trial Ex. 392. His first test, conducted on October 2016, showed rapid and complete release from the DR Beads for the 20 mg and 30 mg strengths. Trial Tr. Day 1 at 57:11-16, 64:15-20; Trial Exs. 195; 8 at 1. Over 90% of the drug from the DR Beads was released after the first hour of exposure to pH 6.0. Trial Tr. Day 9 at 10:22-11:5. It is of no consequence that the samples tested by Dr. Luk were beyond the 2-month shelf life because all the testing performed met the dissolution specifications provided in Abhai's ANDA Product. Trial Tr. Day 2 at 109:4-110:22; Trial Exs. 199; 130 at 57-59, 67-69.

Dr. Luk's second test, performed on May of 2017 on all dosage strengths, showed rapid and complete release of the drug from the DR Beads for the first hour of exposure to pH 6.0. Trial Ex. 392. He obtained values for percent release of drug from the DR Beads that exceeded 90% for the first hour of exposure to pH 6.0 for each strength. Trial Tr. Day 9 at 11:2-5. Using sinkers to perform the dissolution testing did not distort the results because industry standard dictates that a sinker should be used whenever the dosage form would float without the use of the sinker, and Abhai's ANDA Product floats when placed in dissolution media. Trial Tr. Day 5 at 32:18-33:6, 33:14-18, 34:2-4, 41:8-20; 42:1-6, 44:22-45:7; Trial Exs. 20 at 4; 324 at 7; 318 at 11; 289 at 3; 306 at ¶ 4.

Moreover, using HPLC instead of ultra-high performance liquid chromatography ("UPLC") as the analytical method when performing dissolution testing did not affect the results because both are based on the same process, and by using HPLC, Dr. Luk used the same methods of USP. Trial Tr. Day 5 at 13:15-22; 51:23-52:2; 52:22-24. Using a different dissolution media did not have an effect on the analysis. Trial Tr. Day 5 at 49:6-18.

Abhai's dissolution testing results are unreliable. Abhai conducted dissolution testing on commercial batches of Adderall XR, in accordance with the FDA-recommended testing methods for its ANDA submission. Trial Exs. 26, at 80, 89, 98; 32 at 55, 64; 11 at 15, 19; Trial Tr. Day 9 at 39:9-15, 40:20-23. Other generic drug companies also conducted dissolution testing on commercial batches of Adderall XR for their own submissions. Trial Tr. Day 9 at 42:18-46:23. When compared to the dissolution rates obtained by the other generic drug companies testing Adderall XR, Abhai's dissolution rates were lower. Trial Tr. Day 9 at 46:13-23, 48:12-18; Trial Ex. 397. Abhai also obtained lower dissolution testing results than Shire when testing Adderall XR. Compare Trial Exs. 396; 26 at 98, 89, 80; 32 at 55, 64; 30 at 6; 121 at 6, with Trial Exs. 25 at 231, 234, 236, 239, 241; 382 at 31, 34, 36, 39, 41, 44. When applying the four-hour and assay normalization to Abhai's dissolution testing results for Adderall XR, the normalized percent release of drugs from the DR Beads during the first hour of exposure to pH 6.0 is as follows: 85.4% and 90.9% for the 10 mg strength; 83.7% and 86.1% for the 15 mg strength; 79.2% and 82.1% for the 20 mg strength; 81.3% and 81.3% for the 25 mg strength; and 76.1% and 73.5% for the 30 mg strength. Trial Exs. 396; 26 at 98, 89, 80; 32 at 55, 64; 30 at 6; 121 at 6. When applying the four-hour and assay normalization to Shire's dissolution testing results for Adderall XR, the normalized percent release of drugs from the DR Beads during the first hour of exposure to pH 6.0 is as follows: 94.4% and 104.9% for the 10 mg strength; 96.2% and 106.2% for the 15 mg strength; 88.7% and 99.8% for the 20 mg strength; 96.2% and 104.6% for the 25 mg strength; and 89.6% and 87.4% for the 30 mg strength. Trial Exs. 25 at 231, 234, 236, 239, 241; 382 at 31, 34, 36, 39, 41, 44.

Abhai's ANDA Product contains an enteric release coating that 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," as stated in the '096 Patent. Trial Ex. 1 at 12:62-65. Dissolution and stability data from Abhai's ANDA product, as well as Dr. Luk's testing, confirm that within 60 minutes after the initiation of the delayed pulsed enteric release, essentially all of the amphetamine in the DR Beads of Abhai's ANDA Product is released, and each strength exhibits complete release from the DR Beads within 60 minutes. Trial Tr. Day 9 at 25:16-24. Therefore, "essentially all" of the contents of the DR Beads are released within about 60 minutes. Thus Abhai's ANDA Product infringes claim 1 of the '096 Patent.

B. Abhai's ANDA Product Infringes Claims 1, 11, and 13 of the '148 Patent

Claim 1 of the '148 Patent is an independent claim. Trial Ex. 2 at 13:28-55. Claim 11 is a dependent claim that depends from Claim 10, which is a multiple dependent claim depending from Claims 1-4, 6, or 7. Id. at 14:11-18. Shire asserts Claim 11 only as it depends from Claims 1, 2, and 7. Admitted Facts at 1. Claim 13 is a dependent claim that depends from Claim 12. Trial Ex. 2 at 14:46-47.

Claim 1 of the '148 patent includes:

A pharmaceutical formulation for delivery of a mixture of amphetamine base salts effective to treat ADHD in a human patient comprising: an immediate release dosage form that provides immediate release upon oral administration to said patient; a delayed enteric release dosage form that provides delayed release upon oral administration to said patient; and a pharmaceutically acceptable carrier; wherein said amphetamine base salts comprise dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate; wherein said pharmaceutical formulation is sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt, and the peak plasma concentration of amphetamine base salts reached after release of said delayed enteric release dosage form exceeds the peak plasma concentration previously reached after release of said immediate release dosage form; and wherein said pharmaceutical formulation, when containing about a total dose of 20 mg, will produce in a human individual a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of about 467 to about 714 ng hr/ml.

Id. at 13:28-55.

Claim 10 recites: "A formulation of one of claims 1-4, 6 or 7 wherein said delayed enteric release dosage form comprises a coating of a thickness of [at least] greater than 20 µm which comprises dried about 30% (dry substance) aqueous dispersion of an anionic copolymer based on methacrylic acid and acrylic acid ethyl ester, said coating being soluble at a pH of about 5.5 upwards." Id. at 14:10-16. Claim 11 recites: "A formulation of claim 10 wherein said thickness is at least 25 µm." Id. at 14:17-18. Claim 2, which is incorporated into asserted Claim 11 through Claim 10, provides: "A formulation of claim 1 wherein said plasma concentration curve has a maximum concentration (Cmax) of about 22.5 to about 40 ng/ml for about a total dose of 20 mg." Id. at 13:56-58. Claim 7, which is incorporated into asserted Claim 11 through Claim 10, provides: "A formulation of claim 2 wherein Cmax is about 40 ng/ml." Id. at 14:4-5.

Claim 12 provides:

A pharmaceutical formulation for delivery of a mixture of amphetamine base salts effective to treat ADHD in a human patient comprising: an immediate release dosage form that provides immediate release upon oral administration to said patient; a delayed enteric release dosage form that provides delayed release upon oral administration to said patient, wherein said enteric release dosage form comprises a coating of a thickness of [at least] greater than 20 µm which comprises dried aqueous dispersion of an anionic copolymer based on methacrylic acid and acrylic acid ethyl ester, said coating being soluble at a pH of about 5.5 upwards; and a pharmaceutically acceptable carrier; wherein said amphetamine base salts comprise dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate; wherein said pharmaceutical formulation is sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt, and the peak plasma concentration of amphetamine base salts reached after release of said delayed enteric release dosage form exceeds the peak plasma concentration of said salts previously reached after release of said immediate release dosage form.

Id. at 14:19-45.

Claim 13 provides: "[a] formulation of claim 12 wherein said thickness is at least 25 µm." Id. at 14:46-47. Claim 13 does not contain any limitation relating to AUC or Cmax. Id. at 14:19-47.

Abhai admits that its ANDA Product meets the following limitations of the asserted claims of the '148 Patent : (1) "Abhai admits that its ANDA Product meets the following limitations of claim 1 of the '096 Patent"; (2) "an immediate release dosage form that provides immediate release upon oral administration to said patient"; (3) "a pharmaceutically acceptable carrier"; (4) "wherein said amphetamine base salts comprise dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate"; (5) "a coating ... which comprises dried about 30% (dry substance) aqueous dispersion of an anionic copolymer based on methacrylic acid and acrylic acid ethyl ester"; and (6) "said coating being soluble at a pH of about 5.5 upwards." Admitted Facts ¶¶ 48-51, 54; Trial Ex. 2 at Claims 1, 10, and 12.

Abhai disagrees that its ANDA Product meets the following limitations in the asserted claims of the '148 Patent : (1) "a delayed enteric release dosage form that provides delayed release upon oral administration to said patient" (Claims 1, 11, and 13); (2) "wherein said pharmaceutical formulation is sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt" (Claims 1, 12); (3) "the peak plasma concentration of amphetamine base salts reached after release of said delayed enteric release dosage form exceeds the peak plasma concentration previously reached after release of said immediate release dosage form" (Claims 1, 12)"; (4) "will produce in a human individual a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of about 467 to about 714 ng hr/ml" (Claims 1, 11); (5) "said plasma concentration curve has a maximum concentration (Cmax) of about 22.5 to about 40 ng/ml for about a total dose of 20 mg" (Claim 11); "wherein Cmax is about 40 ng/ml" (Claim 11); and (6) "a thickness of greater than 20 µm" (Claims 10, 12)/ "said thickness is at least 25 µm" (Claims 11, 13). Trial Ex. 2 at Claims 1, 10, 11, 12, 13.

Abhai's ANDA Product contains "a delayed enteric release dosage form that provides delayed release upon oral administration,"

thus infringing on claims 1, 11 and 13 of the '148 Patent. This Court construed the language "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. The construction of "delayed pulsed enteric release" and the construction of "a delayed enteric release dosage form that provides delayed release upon oral administration" mirror each other. Trial Tr. Day 9 at 27:3-11; Am. Joint Claim Construction Statement at A-1; Claim Construction Order at 13. Both require a rapid and complete release of the drug from the enteric coated dosage form in Abhai's ANDA Product (the DR Beads), following a dose by immediate release, that is intended or designed to be delayed until the drug has passed into the intestines. Trial Tr. Day 9 at 27:12-14; Am. Joint Claim Construction Statement at A-1; Claim Construction Order at 13. As stated above, Abhai's ANDA Product has "a delayed enteric release dosage form that provides delayed release upon oral administration." Supra at 30. The term "a delayed enteric release dosage form that provides delayed release upon oral administration" does not require release of 100% of the drug within 30-60 minutes. Trial Tr. Day 8 at 38:6-13; Trial Ex. 2 at Claims 1, 12. There is no requirement that "essentially all" of the drug be released within an hour of exposure to pH 6.0. Trial Tr. Day 9 at 27:15-21. As explained above, Figure 6 in both asserted patents supports a pulsed release invention. Supra at 32.

When applying assay normalization to Abhai's revised stability data, the percent release from the DR Beads after two hours of exposure to pH 6.0 shows rapid and complete release. Trial Exs. 395; 130 at 43, 50, 54, 60, 64; Trial Tr. Day 9 at 28:18-29:2, 30:2-4. At the initial storage age, the percent release from the DR Beads was 100.59% for the 10 mg strength; 96.27% for the 15 mg strength; 93.36% for the 20 mg strength; 96.71% for the 25 mg strength; and 86.42% for the 30 mg strength. Trial Exs. 395; 130 at 43, 50, 54, 60, 64; Trial Tr. Day 9 at 28:18-29:2. For the 3, 6, 9, 12, 18, and 24 months storage age, the percent values were above 75% for each of the dosage strengths, except for those where the release was not measured. Id. For some of the dosage strengths for some of the sample ages, there is over 95% release from the DR Beads during the first two hours of exposure to pH 6.0, and in some cases 100% release or more. Trial Tr. Day 9 at 29:12-19. Therefore, Abhai's ANDA Product has "a delayed enteric release dosage form that provides delayed release upon oral administration."

Abhai's ANDA Product also meets the "effective level" imitation in claims 1, 11, and 13 of the '148 Patent. The "effective level" limitation of the '148 Patent requires that the pharmaceutical formulation be "sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt." Trial Ex. 2 at 13:42-45. Abhai's ANDA Product infringes on this claim for the following reasons: (1) Abhai's label demonstrates that its ANDA Product is a long-acting, once-daily product that can be substituted for a twice-daily dosing regimen of Adderall and has been demonstrated to reduce symptoms over the course of at least 8 hours; (2) Abhai's ANDA Product is a therapeutic equivalent of Adderall XR, which has been shown to reduce ADHD symptoms over the course of 8 hours; and (3) Abhai's studies show that its ANDA Product will have a rapid onset of effects that will continue for at least 4 hours after maximum concentration is reached, meaning that the product will reduce ADHD symptoms over the course of at least 8 hours.

Abhai's proposed label for its ANDA Product states that it is an "extended-release" product, with direction to the patient to take the medication "once daily." Trial Ex. 31 at 8; Trial Tr. Day 3 at 8:22-9:6. It also states that those patients who are "taking divided doses of immediate-release" Adderall "may be switched [to Abhai's ANDA Product] at the same total daily dose taken once daily." Trial Ex. 31 at 8; Trial Tr. Day 3 at 9:7-10:3. In its initial form, before Adderall XR came to be, Adderall treatment required multiple doses throughout the day in order to provide relief from ADHD symptoms for at least 8 hours. Trial Ex. 2 at 3:16-40; Trial Tr. Day 2 at 143:22-147:4; Trial Tr. Day 3 at 16:12-18:7 Trial Ex. 86. Therefore, the proposed label demonstrates that one daily dosage of Abhai's ANDA Product would provide the same relief from ADHD symptoms for at least 8 hours, as two dosages of Adderall. The proposed label confirms that Abhai's ANDA Product is created to produce long-lasting effects after it is administered. Trial Ex. 31 at 8; Trial Tr. Day 3 at 9:2-6.

Abhai's ANDA Product is also the therapeutic equivalent to Adderall XR and meets the "effective level" limitation. When submitting its ANDA to the FDA, Abhai stated that "[t]he active ingredient, indications, including route of administration, dosage form and qualitative composition [of its ANDA Product] are the same as that of Adderall XR." Trial Ex. 145 at 1; Trial Tr. Day 3 at 4:14-5:19. Abhai also requested that FDA designate its product as a "therapeutic equivalen[t]" to Adderall XR and represented that its product "is of the same pharmacological and therapeutic class as that of [Adderall XR] and can be expected to have the same therapeutic effect as [Adderall XR] when administered per label claims." Id. In doing so, Abhai represented to the FDA that its product will have the same duration effect as Adderall XR. Trial Tr. Day 3 at 4:14-5:19.

Abhai's ANDA Product is also bioequivalent to Adderall XR, meaning the two produce plasma concentration versus time curves that are sufficiently equivalent. Trial Tr. Day 3 at 7:5-17; 8:13-18. In its proposed label, Abhai cites to studies, also cited in Adderall XR's label, that report a reduction of ADHD symptoms over the course of at least 8 hours. Trial Ex. 117; Trial Tr. Day 3 at 22:24-23:5. The FDA allows Abhai to cite to those studies without requiring it to perform its own safety and efficacy clinical trials, because the similarity between the pharmacokinetic profiles of the two products means