Casio 4738

[Delmiro Fain]

Pursuantto 28 U.S.C. 1407, the Judicial Panel on Multidistrict Litigation consolidated for pre-trial purposes before this court the patent infringement suits filed by Astra Aktiebolag, Aktiebolaget Hssle, Astra Merck Enterprises Inc., Astra Merck Inc., KBI-E Inc., KBI Inc., Astra Pharmaceuticals L.P., and AstraZeneca L.P. in response to various pharmaceutical companies' requests for permission from the Food and Drug Administration ("FDA") to market generic versions of Prilosec, Astra's highly profitable gastric acid inhibiting drug. At various points in this litigation, Plaintiffs have asserted as many as eight different patents against Defendants. At the time of trial, five of those patents remained in the suit. This consolidated trial resolves claims raising issues of infringement and validity asserted in eight different lawsuits involving four groups of Defendants.[2] The case was tried to the court sitting without a jury for fifty-two trial days between December 6, 2001, and June 13, 2002. The court has considered over six thousand pages of trial testimony, volumes of deposition testimony, thousands of exhibits, and pre-trial and post-trial briefing submitted by all parties. The court has made determinations as to the relevance and materiality of the evidence and assessed the credibility of each witness. Upon the record before the court, pursuant to Federal Rule of Civil Procedure 52(a), the court finds the following facts to have been proven by the appropriate standard of proof and sets forth its conclusions of law.

Plaintiff Astra Aktiebolag is a company organized and existing under the laws of Sweden, having its principal place of business at Sdertlje, Sweden. Plaintiff Aktiebolaget Hssle ("Hssle") is a company organized and existing under the laws of Sweden, having its principal place of business at MIndal, Sweden. Plaintiff Astra Merck Enterprises, Inc. is a Delaware corporation, having its principal place of business at Wilmington, Delaware. Plaintiff Astra Merck, Inc. is a Delaware corporation, having its principal place of business at Wayne, Pennsylvania. Plaintiff KBI-E, Inc. is a Delaware corporation, having its principal place of business at Wilmington, Delaware. Plaintiff KBI, Inc. is a Delaware corporation having its principal place of business at Whitehouse Station, New Jersey. Plaintiff Astra Pharmaceuticals, L.P. is a limited partnership organized under the laws of Delaware having its principal place of business at Wayne, Pennsylvania. Plaintiff AstraZeneca, L.P. is a limited partnership organized under the laws of Delaware having its principal place of business at Wayne, Pennsylvania. Plaintiffs are referred to collectively as "Astra."

Defendant Andrx Pharmaceuticals, Inc. ("Andrx") is a Florida corporation, having its principal place of business at Davie, Florida. Defendant Cheminor Drugs, Ltd. is a public, limited-liability company incorporated and existing under the laws of India and having a principal place of business in Hyderabad, India. Defendant Reddy-Cheminor, Inc. is a New Jersey corporation, having its principal place of business at Ridgewood, New Jersey. Defendant Schein Pharmaceutical, Inc. is a Delaware corporation, having its principal place of business at Florham Park, New Jersey. These three Defendants are referred to collectively as "Cheminor." Defendant Genpharm Inc. ("Genpharm") is a Canadian corporation, having its principal place of business in Ontario, Canada. Defendant Kremers Urban Development Co., a wholly-owned subsidiary of Schwarz Pharma, Inc. ("Schwarz"), is a Wisconsin corporation, having its principal place of business in Mequon, Wisconsin. Defendant Schwarz is a Delaware corporation, having its principal place of business at Mequon, Wisconsin. These last two Defendants are referred to collectively as "KUDCo."

First, Astra's formulation scientists tried dissolving omeprazole in oil to protect the omeprazole from gastric juice, but this approach did not work because omeprazole is unstable in oil. (Pilbrant Tr. 1328:21-1329:11.) A very rapidly dissolving dosage form was investigated on the theory that the rate of absorption of omeprazole into the body would be faster than the rate of degradation in the stomach. That also did not work; more than 50% of the drug was lost due to degradation. (Pilbrant Tr. 1329:12-1330:8.) Omeprazole was administered with food on the theory that food would increase the pH in the stomach and allow the omeprazole to survive long enough to be absorbed. This approach also failed; almost 90% of the dose was lost. (Pilbrant Tr. 1330:9-1331:2.) Studies to determine the target point in the digestive system for omeprazole release were undertaken, and Astra's formulation scientists concluded that omeprazole should be released in the proximal part of the small intestine. (Pilbrant Tr. 1326:25-1328:7; 1587:16-21.)

When Astra first tested omeprazole in humans, a buffered suspension was used to make the highly acidic stomach environment more alkaline. (Carlsson Tr. 172:4-13.) Although this buffered suspension was not practical for commercial use, it was used in initial studies in humans, the "Phase I" studies. (Carlsson Tr. 172:14-18.) Drs. Pilbrant and Lvgren decided to try enteric-coated formulations to see if an enteric coat would protect the omeprazole from gastric acid in the stomach. (Pilbrant Tr. 1331:3-1332:4, 1587:25-1588:5.) An enteric coating is typically a polymer film that is insoluble in stomach acid, but soluble in the intestine, (Pilbrant Tr. 1331:8-22, 1332:5-11), so the enteric-coating protects material that degrades in the acidic environment of the stomach until it reaches the small intestine. Drs. Pilbrant and Lvgren did a number of pre-formulation studies to determine whether enteric coatings, which are polymeric polyacids, would have a deleterious effect on omeprazole. The results of the studies showed that the enteric coating materials had approximately the same interaction as most other common pharmaceutical excipients if these excipients did not contain a lot of water. Astra determined that an enteric coating was a viable approach to explore further. (Pilbrant Tr. 1331:17-1333:9.)

The Astra scientists studied a number of different types of cores to be used in formulation, including tablet and pellet-type cores. (Pilbrant Tr. 1333:21-24.) Astra also tried a number of different processes for making pellet-type cores. First, Dr. Pilbrant and his group tested cores formed by compressing omeprazole together with pharmaceutical excipients. The Astra scientists also experimented with melt granulations, in which omeprazole was dissolved or dispersed in material that had been heated to its melting point and then cooled down to form a solid core. Dr. Pilbrant and his group constructed cores by depositing an active drug layer of omeprazole onto an inert sugar sphere. Finally, the Astra scientists experimented with extrusion spheronization. Astra eventually settled on that extrusion spheronization process for preparing its cores. (Pilbrant Tr. 1333:25-1335:4.) In Astra's extrusion spheronization work, water was added to a powder mixture to make a dough. When the plasticity was suitable, the dough was pressed through a machine to make spaghetti-like strings. These strings were then sectioned in small parts that were put on a rotating plate where the small parts were rounded. (Pilbrant Tr. 1335:5-14.)

To develop a new formulation that could be used in Phase III long term clinical trials and sold commercially, Astra tested many potential formulations. Some had good stability in the gastric juice in the stomach, but inadequate shelf-life stability. Others had adequate shelf-life stability but inadequate stability in the stomach. (Carlsson Tr. 183:20-184:10; P609.) Drs. Pilbrant and Lvgren and the other Astra scientists tried numerous approaches to solve the dual, and apparently conflicting, problems of long term stability and adequate gastric acid resistance. (Pilbrant Tr. 1344:3-1345:23.) Including certain alkaline substances in the core as with the Phase II formulation solved the problem of the chemical stability of omeprazole by stabilizing the omeprazole during manufacturing and storage, but it exacerbated the problem of gastric acid resistance. (Pilbrant Tr. 1344:9-23.) During development, the Astra scientists learned that if the amount of alkaline material in the core was increased, this could weaken the enteric coat and decrease gastric acid resistance. This would increase the risk that water would leak in through the enteric coating and promote a reaction between the acidic enteric coating and the alkaline *437 material in the core, which in turn would cause degradation of the enteric coating and worsen gastric acid resistance. (Pilbrant Tr. 1344:24-1345:23, 1610:1-5.) Water permeation has a deleterious effect on the omeprazole core because, if sufficient water diffuses in, it may cause an alkaline solution inside the coating to dissolve the enteric coating from the inside, which, in turn, will worsen gastric acid resistance. (Pilbrant Tr. 1345:12-23.)

To solve the gastric resistance problem without sacrificing stability, Astra tried numerous modifications to the formulation. (See Pilbrant Tr. 1345:24-1349:15.) For example, Drs. Pilbrant and Lvgren tried to make the enteric coating tighterless permeable to gastric juice. (Pilbrant Tr. 1345:24:-1346:4.) Dr. Pilbrant tried a thicker enteric coating, and he tried to make the enteric coating more hydrophobic, or water-repellent, by adding hydrophobic plasticizers of different kinds. (Pilbrant Tr. 1346:5-1347:4.) Dr. Pilbrant tried adding a water insoluble polymer within the enteric-coating itself to see if that would improve diffusion tightness. (Pilbrant Tr. 1347:5-18.) He tried mixing different enteric coating materials. He even tried putting one enteric coating on top of another to see if that would improve tightness. (Pilbrant Tr. 1347:19-1348:4.) Dr. Pilbrant tried putting an outer coating with a hydrophobic substance on top of the enteric coating, and he tried this with different amounts of the hydrophobic substance. Astra found, however, that if they used only a small amount of hydrophobic substance, it did not improve gastric acid resistance. On the other hand, if they used a large amount of hydrophobic substance outside the enteric coating, this improved gastric acid resistance, but it caused reduced omeprazole release. (Pilbrant Tr. 1348:5-17.) None of these things worked to improve gastric resistance, and repeated attempts to improve the tightness of the enteric coat had failed. (Pilbrant Tr. 1345:9-1349:15.)

3a8082e126