Free Proposed Findings of Fact - District Court of Delaware - Delaware

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE ITEM DEVELOPMENT AB, ASTELLAS US LLC, ) and ASTELLAS PHARMA US, INC., ) ) Plaintiffs, ) ) v. ) ) SICOR INC. and ) SICOR PHARMACEUTICALS, INC., ) ) Defendants. ) )

Civil Action No. 05-336-SLR

PLAINTIFFS' POST-TRIAL PROPOSED FINDINGS OF FACT AND CONCLUSIONS OF LAW CONCERNING U.S. PATENT NO. 5,731,296
Dated: May 9, 2007 Richard K. Herrmann #405 Mary B. Matterer #2696 MORRIS JAMES LLP 500 Delaware Avenue, Suite 1500 Wilmington, DE 19801 (302) 888-6800 [email protected] Charles E. Lipsey FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP Two Freedom Square 11955 Freedom Drive Reston, VA 20190-5675 (571) 203-2700 Susan H. Griffen David P. Frazier FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP 901 New York Avenue Washington, D.C. 20001-4413 (202) 408-4000 Attorneys for Plaintiffs Astellas US LLC and Astellas Pharma US, Inc. Paul M Lukoff #96 David E. Brand #201 PRICKETT JONES & ELLIOTT, P.A. 1310 King Street Wilmington, DE 19801 (302) 888-6520 [email protected] John Scheibeler WHITE & CASE LLP 1155 Avenue of the Americas New York, NY 10036 (212) 819-8200 Attorneys for Plaintiff Item Development AB

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TABLE OF CONTENTS PLAINTIFFS' PROPOSED FINDINGS OF FACT........................................................................1 I. THE PARTIES.....................................................................................................................1 A. B. II. III. Plaintiffs...................................................................................................................1 Defendants ...............................................................................................................1

THE NATURE OF THE CASE ..........................................................................................2 FACTUAL BACKGROUND..............................................................................................4 A. Historically, Adenosine Was Not Considered Appropriate for Human Administration .........................................................................................................4 1. Adenosine Was Rejected as a Human Pharmaceutical Agent Seventy Years Ago Because of Its Effects On Electrical Conduction in the Heart ...............................................................................5 In the 1960s, Dr. Robert Berne Developed the "Adenosine Hypothesis," Predicting a Role for Adenosine as an Endogenous Regulator of Blood Flow in the Heart, Not As an Exogenously Administered Pharmaceutical Agent. ....................................7 In the Early 1980s, Dr. Berne and His Colleagues Discovered that Adenosine's Effects on Cardiac Conduction Could be Used to Treat A Limited Population of Patients with Abnormal Heart Rhythms .............................................................................................8 Drug Development Efforts in the 1970s Sought Analogs to Harness the Vasodilating Ability of Adenosine While Avoiding Its Adverse Effects on the Heart ................................................................10 The Prior Art Suggested Infusion of Dipyridamole, Not Adenosine, as a Pharmacologic Stress Agent for Myocardial Perfusion Imaging......................................................................................12 Adenosine Triphosphate (ATP) Was a Separate Molecule Whose Characteristics Were the Subject of Separate Laboratory and Clinical Studies.................................................................14 a. ATP Was Known to Have Unique Properties and Its Own Receptors and Had Been Shown to Be a More Potent Vasodilator Than Adenosine ..............................................14

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b. c.

Prior Art Studies Identified ATP as a Powerful Vasodilator in Its Own Right .........................................................15 ATP Was Known to be Metabolized into Various Compounds, Including Adenosine, But Its Greater Potency as a Vasodilator Showed that it Also Worked Through Its Own Receptor.............................................................16 The Effects of ATP and the Extent of Its Metabolism Into Adenosine Were Highly Species Dependent..........................18

d. B.

Dr. Alf Sollevi Countered Conventional Wisdom and Pioneered the Use of Adenosine Infusion in Humans ..................................................................19 1. Dr. Sollevi's First Studies Used Low Dose Administration of Adenosine in Conjunction with Dipyridamole Pretreatment to Induce Surgical Hypotension.....................................................................20 Dr. Fukunaga Later Recommended Using Dipyridamole Pretreatment to Avoid Problems Associated with Administering ATP Infusions ....................................................................22 Animal and In Vitro Models Regarding Adenosine and Human Studies of ATP Infusion Suggested That Dipyridamole Pretreatment Greatly Reduced the Effective Dose of Adenosine..............24 Dr. Sollevi Unexpectedly Discovered that Adenosine Could Selectively Vasodilate Arteries and Safely Induce Surgical Hypotension Without Dipyridamole Pretreatment ...................................26 Dr. Sollevi Envisioned and Tested Additional Uses for Adenosine as a Selective Arterial Vasodilator and Filed a Patent Application that Issued as the `296 Patent......................................28 The Leaders in the Field Were Surprised that Adenosine Infusion Could Be Safely Administered at Therapeutically Significant Doses .......................................................................................28 a. Dr. Berne Was Surprised That Dr. Sollevi Had Been Able to Reduce Blood Pressure by Adenosine-Mediated Vasodilation Without Inducing AV Block ....................................29 Dr. Francis Robicsek Also Questioned the Safety of Adenosine Infusion in a Letter to a Medical Journal.....................30

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b. IV.

NOVELTY OF THE ASSERTED CLAIMS ....................................................................32 A. The Asserted Claims ..............................................................................................32

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B. C. V.

Fukunaga 1982 Does Not Describe or Disclose the Administration of Adenosine at Any Dose .........................................................................................33 The Reportedly "Maintained" Cardiac Output in Fukunaga 1982 Does Not Demonstrate Consistent Selective Arterial Vasodilation................................35

FACTS CONCERNING NONOBVIOUSNESS OF THE ASSERTED CLAIMS ............................................................................................................................36 A. B. C. Scope and Content of the Prior Art........................................................................36 Level of Ordinary Skill in the Art..........................................................................39 Differences Between the Claimed Invention and the Prior Art .............................39

VI.

THE PRIOR ART TAUGHT AWAY FROM ADMINISTERING AN ADENOSINE INFUSION ALONE AS A SELECTIVE ARTERIAL VASODILATOR ...............................................................................................................40 A. One of Ordinary Skill Would Have Been Discouraged from Administering Adenosine Without Dipyridamole Pretreatment Because of Concerns About Side Effects with Larger Doses of Adenosine. .............................................................................................................40 One of Ordinary Skill in the Art Would Have Concluded that the Effect of Dipyridamole Pretreatment Lasted Throughout the Period of Hypotension in Dr. Sollevi's Studies.....................................................................43 The Fukunaga 1982 and Fukunaga 1984 Abstracts Taught Away From Administering Adenosine Without Dipyridamole Pretreatment..................45

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C. VII.

IT WAS UNEXPECTED THAT DIPYRIDAMOLE PRETREATMENT COULD BE ELIMINATED WITHOUT A LARGE INCREASE IN THE DOSE OF ADENOSINE INFUSED .................................................................................47 ADENOSCAN IS A HIGHLY SUCCESSFUL COMMERCIAL PRODUCT ................48 A. Adenoscan is a Highly Successful Commercial Product .......................................48 1. Adenoscan Went From Newcomer To Market Leader, Becoming a Very Successful Product for Astellas Even in the Face of Competition from Generic Dipyridamole .....................................48 Sales of Adenoscan Were Driven by the Attributes of the Claimed Invention, Not Marketing and Promotion ...................................50 Sicor's Arguments Regarding Commercial Success .................................51 Adenoscan's Promotion Was Typical In The Industry..............................52 iii

VIII.

2. 3. 4.

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5.

Sicor's Economic Expert Was Unreliable And His Theories Not Supported By The Record...................................................................53

PLAINTIFFS' PROPOSED CONCLUSIONS OF LAW .............................................................57 I. II. CONTROLLING AUTHORITY.......................................................................................57 THE `296 PATENT IS PRESUMED VALID AND SICOR, AS THE PATENT CHALLENGER, BEARS THE BURDEN OF PROVING THE CONTRARY BY CLEAR AND CONVINCING EVIDENCE........................................57 THE ASSERTED CLAIMS OF THE `296 PATENT ARE NOT INVALID FOR ANTICIPATION.......................................................................................................58 A. B. A Prior Art Reference Does Not Anticipate Unless It Discloses Each Limitation of the Claimed Invention......................................................................58 Sicor Failed to Prove Fukunaga 1982 Discloses Each Limitation of the Asserted Claims Either Expressly or Inherently....................................................59 1. 2. Sicor Failed to Prove Fukunaga 1982 Discloses Administration of Adenosine ..............................................................................................59 Sicor Failed to Prove that Fukunaga 1982 Disclosed Selective Arterial Vasodilation or Dosages within the Ranges set Forth in Claims 3 or 7..............................................................................................60

III.

IV.

THE CLAIMS OF THE `296 PATENT ARE NOT INVALID FOR OBVIOUSNESS ................................................................................................................61 A. Sicor Must Prove Obviousness by Clear and Convincing Evidence Based on the Four Broad Factual Findings............................................................61 1. 2. The Law of Obviousness and the Supreme Court's Decision in KSR ............................................................................................................62 Objective Evidence, Including Contemporaneous Statements of Skepticism by Experts In the Field and Commercial Success, Is Highly Probative of Nonobviousness ........................................................63

B.

Sicor Failed to Prove the Claimed Invention Would Have Been Obvious in View of the Methods Described in the Sollevi I and Sollevi II Abstracts and the Background Prior Art ................................................65 1. 2. Level of Ordinary Skill in the Art..............................................................65 Differences Between the Prior Art and the Claimed Invention .................65

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3. C.

Objective Evidence of Nonobviousness: Skepticism, Commercial Success, Unexpected Results, and Copying..........................67

The Skepticism and Ultimate Praise Expressed In the Letters By Dr. Berne and Dr. Robicsek Is Highly Probative Objective Evidence of Nonobviousness .....................................................................................................67 The Unexpectedly Low Dose of Adenosine Required in the Absence of Dipyridamole is Further Evidence of Nonobviousness.....................................70 Sicor's Interest in Copying the Invention Also Demonstrates its Nonobviousness .....................................................................................................70 The Commercial Success Of Adenoscan Is Objective Evidence Of Nonobviousness .....................................................................................................70 1. 2. 3. 4. 5. There is a Nexus Between the Sales of Adenoscan and the Claims of the Patent ...................................................................................72 Sicor Failed To Prove that Sales of Adenoscan® are Not Driven by the Attributes of the Claimed Method ..................................................73 Market Circumstances Cannot Sever Proper Nexus..................................73 Clinical Attributes Determine Success of Pharmacologic Stress Agents, Not Promotion ..............................................................................74 Dr. Leffler's Opinion Is Contrary To The Evidence..................................76

D. E. F.

V.

DR. BINKLEY WAS NOT CREDIBLE AND OFFERED OPINIONS BEYOND THE SCOPE OF HIS EXPERT REPORTS ....................................................77

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This matter was tried before the Court on February 12, 2007 through February 28, 2006. Being duly advised, the Court now issues its findings of fact and conclusions of law pursuant to Fed. R. Civ. P. 52(a). To the extent that any of the findings of fact set forth below is a conclusion of law, it is hereby adopted as a conclusion of law. To the extent any of the conclusions of law set forth below is a finding of fact, it is hereby adopted as a finding of fact.

PLAINTIFFS' PROPOSED FINDINGS OF FACT
I. THE PARTIES A. Plaintiffs

1. Plaintiffs Astellas US LLC and Astellas Pharma US, Inc. (collectively "Astellas") are corporations engaged in the business of research, development, and sale of pharmaceutical products throughout the world. (D.I. 1 ¶ 4.) 2. Both Astellas US LLC and Astellas Pharma US, Inc. are organized and existing under the laws of the State of Delaware, with their principal places of business at Three Parkway North, Deerfield, Illinois 60015-2548. (D.I. 127, Ex. 1 ¶ 1.) 3. Astellas was formed from a merger between two pharmaceutical companies, Fujisawa Pharmaceutical Co., Ltd. and Yamanouchi Pharmaceutical Co., Ltd. (White 1227:15-17.) 4. Plaintiff Item Development AB ("Item") is a Swedish corporation having an office and principal place of business at Svanholmsvagen 2A, Stocksund, 18207, Sweden. (D.I. 127, Ex. 1 ¶ 2.) B. 5. Defendants Defendants Sicor Pharmaceuticals Inc. and Sicor Inc. (collectively "Sicor") are in

the business of making and selling generic drugs, which they distribute in Delaware and throughout the United States. (D.I. 127, Ex. 1 ¶¶ 3, 4, 14.)

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6.

Both Sicor Pharmaceuticals Inc. and Sicor Inc. are corporations organized and

existing under the laws of the State of Delaware having principal places of business at 19 Hughes, Irvine, California 92618. (D.I. 127, Ex. 1 ¶¶ 3-4.) 7. Defendant Sicor Pharmaceuticals Inc. is a wholly owned subsidiary of Sicor Inc.

(D.I. 127, Ex. 1 ¶ 5.) II. THE NATURE OF THE CASE 8. Plaintiffs Item and Astellas brought this suit against (i) Sicor and (ii) Teva

Pharmaceuticals USA (a Delaware corporation) and Teva Pharmaceutical Industries, Ltd. (an Israeli corporation) (collectively "Teva") for infringement of Item's United States Patent No. 5,731,296 ("the `296 patent"). (E.g., D.I. 1 ¶¶ 29-30.) 9. The `296 patent issued in 1998 and was assigned to and is owned by Item. (D.I.

127, Ex. 1 ¶ 9; TX-275.) The sole inventor of the invention claimed in the `296 patent is Dr. Alf Sollevi (TX-275.) The `296 patent claims, inter alia, methods of selectively vasodilating the arteries of a human patient without inducing significant venous dilation and without pretreatment with dipyridamole by continuously infusing the chemical compound known as adenosine. (TX-275, claims 1, 3, 7, and 9.) 10. Astellas is the exclusive licensee of certain rights under the `296 patent. (D.I.

127, Ex. 1 ¶ 10.) Pursuant to those rights, Astellas markets a product known as Adenoscan®.1 (D.I. 1 ¶ 18.) 11. Adenoscan was approved by the United States Food and Drug Administration (the

"FDA") in 1995. Adenoscan, an adenosine solution, is labeled for use as an adjunct to thallium-201 myocardial perfusion scintigraphy and as such it is administered to patients

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Adenoscan® (hereinafter "Adenoscan") is a registered trademark of Astellas.

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undergoing cardiac stress tests who are unable to exercise adequately on a treadmill. (D.I. 1 ¶ 18; D.I. 127, Ex. 1 ¶ 12; TX-75.) Thus, Adenoscan is known as a "pharmacologic stress agent." Adenoscan is the most widely prescribed pharmacologic stress agent on the market today. (See TX-21; Hay 1731:23-1733:3; DTX-2030.) 12. On December 6, 2004, Sicor filed an Abbreviated New Drug Application

("ANDA") under the Drug Price Competition and Patent Term Restoration Act of 1984, 98 Stat. 1585 (popularly known as the Hatch-Waxman Act), seeking approval to market generic copies of Astellas's Adenoscan upon expiration of the `296 patent. (TX-4.) On April 16, 2005, Sicor amended its ANDA to seek permission to sell its generic product before expiration of the `296 patent and to include a certification (i) that its proposed product would not infringe the `296 patent and/or (ii) that the `296 patent was invalid or unenforceable. (TX-7.) Item and Astellas then filed suit against Sicor and Teva alleging infringement of the `296 patent under 35 U.S.C. § 271(e)(2)(A).2 (D.I. 1 ¶¶ 29, 30.) 13. This action arises under the patent laws of the United States, Title 35, United States Code, including 35 U.S.C. §271(b), (c), and (e)(2). The Court has subject matter jurisdiction over this case under the Hatch Waxman Act and 28 U.S.C. §§ 1331, 1338(a), 2201, 2202. 14. Plaintiffs seek an order (i) prohibiting FDA approval of the Defendants' generic adenosine product labeled for use in myocardial perfusion scintigraphy (also called myocardial perfusion imaging or "MPI") prior to the expiration of the `296 patent, in accordance with 35 U.S.C. § 271(e)(4)(A); and (ii) enjoining the Defendants from the commercial manufacture, use,

Astellas is also exclusive licensee of rights under U.S. Patent No. 5,077,877 (the `877 patent), which is owned by King Pharmaceuticals Research and Development, Inc. ("King"). King and Astellas also filed suit against Sicor in the parallel action copending in this Court. See CV No. 05-0337-SLR.

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offer to sell, sale, or importation of their adenosine product labeled for use in myocardial perfusion imaging, in accordance with 35 U.S.C. § 271(e)(4)(B). (E.g., D.I. 1, Prayer for Relief). 15. The parties filed a Stipulation of Dismissal of Complaint as to Teva, in which Teva agreed to be bound by the decision of the Court herein and the Court entered an order approving this Stipulation on August 9, 2005. (D.I. 10 ¶ 1.) 16. Sicor admitted "that making, using, offering to sell, importing, or selling Sicor's Adenosine Injection USP labeled for use in myocardial perfusion imaging in the United States would infringe asserted claims 1, 3, 7, and 9 of United States Patent No. 5,731,296."3 (D.I. 129, ¶ 2.) III. FACTUAL BACKGROUND A. Historically, Adenosine Was Not Considered Appropriate for Human Administration

17. Adenosine is a naturally occurring molecule that was isolated from the human body and recognized to have powerful pharmacologic effects more than 70 years ago. (See TX-35; Klabunde 516:4-22.) 18. Despite its early discovery, adenosine infusions were not administered to humans for any medical purpose until Dr. Sollevi, the inventor of the `296 patent, conducted his initial experiments with adenosine in the early 1980s. (Sollevi 437:21-438:7.) 19. The scientific literature demonstrates that this long gap between the discovery of adenosine and its use according to the claimed methods of the invention was not by chance, but

For the purposes of this litigation, Plaintiffs Astellas and Item are asserting only claims 1, 3, 7, and 9 of the `296 patent. (See D.I. 129, Ex. 2, ¶ 1.)

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because of the recognized potential for exogenously administered adenosine to cause harmful effects in humans. (See, e.g., TX-35; TX-187; TX-48 at 2229; Klabunde 521:5-23.) 1. Adenosine Was Rejected as a Human Pharmaceutical Agent Seventy Years Ago Because of Its Effects On Electrical Conduction in the Heart

20. The first animal experiments with adenosine were reported by Drury and SzentGyorgyi in 1929, in an article described as "one of the foundation articles, recognizing and describing the actions of adenosine. . . ." (Binkley 101:13-17; see also TX-35; TX-36 at 1254; Klabunde 516:4-7, 517:6-17.) 21. Although demonstrating that adenosine was a vasodilator, the studies also revealed adenosine's ability to slow or stop electrical conduction in the heart, resulting in "AV block." "AV block" is the interruption of conduction in the AV node of the heart, which was known to coordinate the beating of the upper chambers of the heart (the atria) and the lower chambers (the ventricles). (TX-35 at 236; TX-36 at 1254; Binkley 244:13-245:17; Klabunde 517:6-17; 519:8-520:18.) 22. There are three degrees of AV block. In "first degree" AV block, there is some delay in the conduction going through the AV node, but all the impulses will travel through. (Klabunde 519:8-520:18.) "Second degree" AV block is more severe and not all of the impulses will go from the atria into the ventricles; therefore, the atrial rate may be higher than the ventricular rate. (Id.) Third degree AV block, also known as "complete AV block," is the most severe because the action potentials or electrical currents going through the AV node are completely blocked, preventing any activity from the atria from getting into the ventricles. (Id.) 23. Studies published a few years after the work of Drury and Szent-Gyorgyi showed that adenosine could also decrease heart rate or even arrest the heart beat in humans. (TX-48 at 2229; Klabunde 516:11-22, 521:5-18.) 5

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24. For example, in 1934, Jezer published an article entitled "The Effect of Adenosine on Cardiac Irregularities in Man" and describing his study involving the bolus administration of between 25 to 45 mg of adenosine to eight human patients. (TX-187.) Similar to Drury and Szent-Gyorgyi's animal experiments, Jezer observed adenosine causing serious effects on the heart, including AV block. (TX-187.) In fact, Jezer observed cessations of heart beat (ventricular standstill) for up to nine seconds following the administration of adenosine. (TX-187 at 256, 258; Strauss 766:7-15.) 25. Not mere historical oddities, these and other early studies of adenosine's effects shaped the understanding of those of ordinary skill in the art for decades. As recounted by Biaggioni in 1986: Adenosine was first administered to human subjects in 1930 and 1933 to treat cardiac arrhythmias. The development of serious side effects with large boluses of the drug (temporary cardiac arrest) led the authors to conclude that adenosine was not "a useful therapeutic preparation for the treatment of heart disease", a view which discouraged further research. (TX-48 at 2229 (internal citations omitted); Klabunde 520:23-522:2; see also TX-36 at 1254 (referring to animal and human studies in the 1920s and 1930s that demonstrated adenosine's ability to slow heart rate and cause AV block); Klabunde 517:2-17.) 26. Similarly, a commentary published in a reliable medical journal in 1990 stated, "[d]espite these interesting characteristics, adenosine never achieved clinical usefulness; rather it found a staid, but secure, role over the years as a short acting vasodilating agent in experimental animal studies, especially those involving the coronary circulation." (Binkley 313:24-315:25.)4

TX-47, the source for this quotation, was not itself offered into evidence but the pertinent section was read into evidence pursuant to Fed.R.Evid. 803 (18), the reference having been established as reliable. (See Binkley 313:24-315:13; see also Binkley 311:8-312:19.)

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2.

In the 1960s, Dr. Robert Berne Developed the "Adenosine Hypothesis," Predicting a Role for Adenosine as an Endogenous Regulator of Blood Flow in the Heart, Not As an Exogenously Administered Pharmaceutical Agent.

27. By the 1960s, studies of adenosine were directed at answering basic scientific questions about the endogenous compound's effects in the body, not developing new therapeutic or diagnostic uses for the drug. (See Klabunde 1076:20-1078:19; Strauss 766:19-767:13.) 28. Dr. Robert Berne, a physician-scientist at the University of Virginia, was recognized as the dean of the adenosine field. (Binkley 317:19-318: 15.) Dr. Berne was an "outstanding physiologist and scientist" and a "well-recognized expert in cardiovascular physiology." (Id.) 29. Dr. Berne was trained as an M.D. and was the Chairman of Physiology at the University of Virginia in Charlottesville, which was recognized as the leading center for adenosine research during the sixties, seventies, and the early to mid-eighties. (Klabunde 499:23-500:9.) 30. In 1963, Dr. Berne published a "classic" paper in which he proposed that adenosine might be the physiological molecule responsible for coronary vasodilation in response to low oxygen levels (hypoxia) in cardiac tissue. (See TX-113 at 317; Klabunde 1071:25-1072:3.) Dr. Berne's proposition set forth in this paper became known as the "Adenosine Hypothesis." (TX-113; Binkley 247:8-12.) 31. The Adenosine Hypothesis proposed that when the heart needed to increase its oxygen supply, such as during stress, endogenous adenosine would be formed by the breakdown of ATP, resulting in coronary artery vasodilation and an increase in circulation of blood within the coronary tissue. (TX-113 at 321; Klabunde 499:5-19.) 32. The entire focus of the Adenosine Hypothesis was the role of endogenous adenosine in the heart, not in the systemic circulatory system. (See Klabunde 1076:20-1078:19.) Indeed,

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nothing in the scientific literature cited by Sicor would have suggested any connection between the Adenosine Hypothesis and potential medical uses of adenosine. (Id.) Thus, the Adenosine Hypothesis in the early 1980s was little more than a framework for ongoing studies of the role of endogenous adenosine in the body, following which there was "lots and lots of research," described in up to 20,000 publications, explaining the physiological effects of adenosine. (See Strauss 766:19-767:13.) 33. Illustrating this point, Dr. Berne wrote another review article on advances in adenosine physiology and the Adenosine Hypothesis in 1980, seventeen years after his initial publication. (See TX-228.) Like the earlier article, the later publication did not mention, much less recommend, that exogenously administered adenosine might have utility in human patients as a selective arterial vasodilator. (Id.) 3. In the Early 1980s, Dr. Berne and His Colleagues Discovered that Adenosine's Effects on Cardiac Conduction Could be Used to Treat A Limited Population of Patients with Abnormal Heart Rhythms

34. Prior to Dr. Sollevi's work, the only medical use for adenosine reported in the prior art was a use that took advantage of the heart-stopping action of the compound. That clinical application was studied by Dr. Berne and his colleagues at the University of Virginia in the early 1980s, when they investigated using adenosine as a potential short-acting therapeutic in patients suffering from cardiac arrhythmia. (See TX-36; TX-45.) 35. Specifically, in a pair of publications published in 1983 and August 1985, Dr. Berne, together with lead author Dr. John DiMarco and their colleagues from the University of Virginia, reported that adenosine could be administered by a short, rapid bolus injection to terminate an arrhythmia termed "paroxysmal supraventricular tachycardia" ("PSVT"), in which the heart beats very rapidly. (TX-36; TX-45; Klabunde 522:3-523:23; Binkley 325:14-18.)

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36. This treatment was based on adenosine's ability to slow conduction and beating of the heart, an effect that would be highly undesirable in a drug whose purpose was to induce selective arterial vasodilation in patients. (Klabunde 523:24-524:25.) 37. Also leading away from the potential intravenous infusion of adenosine as a vasodilator, the University of Virginia authors noted that the electrical effects of adenosine were dose dependent and warned that "[t]he need to individualize dosage for each patient is an important factor that must be considered before adenosine is widely used clinically." (TX-45 at 423.) The reason for this warning was that "[o]verdosage might lead to prolonged asystole [cardiac arrest], hypotension or other tachyarrhythmias." (Id.) 38. In addition, Dr. DiMarco noted that, although the effects of adenosine on the beating heart were short in duration, "their duration seems to be proportional to the dose in each patient and these side effects could be serious in certain patients." (TX-45 at 423; Binkley 325:11-326:8.) Thus, one of ordinary skill in the art would have recognized that, regardless of the method of administration, a given dosage of adenosine would have the ability to dramatically slow or impede the beating of the heart and that dose would vary widely and unpredictably from patient to patient. (See, e.g., TX-45 at 423.) This would have led one away from the potential intravenous infusion of adenosine as a vasodilator. (Klabunde 524:4-20.) 39. While the investigators using adenosine for treatment of PSVT succeeded in avoiding serious adverse events by titrating the dose of adenosine administered to their patients so that only the lowest necessary dose was administered, such individualized dosing was in the context of a rapid bolus administration in which the desired effect, instantaneous resetting of the heart beat, took advantage of the normally undesirable capacity of adenosine to alter electrical conduction in the heart. (TX-36 at 1256-57, 1261; TX-45 at 423; Klabunde 524:4-20.)

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40. Continuous intravenous infusion to cause selective vasodilation would have raised a different problem in that one could not have predicted whether the desired vasodilatory effect could be obtained at a dose below a dose that affected the heart. Moreover, in the case of vasodilation, stopping the infusion to eliminate side effects would also eliminate the desired vasodilation. (See Klabunde 557:10-558:19.) 41. Indeed, even the University of Virginia investigators acknowledged, in the context of PSVT treatment, that chronic prophylaxis would be impossible because of adenosine's brief duration of action and that, while a longer-acting adenosine analog might work, use of such an analog would have to take into account adenosine's many other effects in the body. (TX-45 at 423; Binkley 326:9-22.) 42. Consequently, the use of adenosine for treatment of PSVT would have strongly discouraged, not encouraged, the use of adenosine for vasodilation. Indeed, this bias was so entrenched in the field that even in the mid-1990s cardiologists initially resisted using Astellas's Adenoscan product as a pharmacologic stress agent for fear of inducing AV block. (Klose 1516:7-1517:1.) 4. Drug Development Efforts in the 1970s Sought Analogs to Harness the Vasodilating Ability of Adenosine While Avoiding Its Adverse Effects on the Heart

43. The discussion of longer acting analogs in the context of PSVT treatment and the lack of any mention by Dr. Berne and his colleagues of using adenosine as a vasodilator reflected the general view in the art that adenosine itself was not a viable drug candidate for most applications because of its short half-life and adverse cardiac effects. (See, e.g., TX-214 at 415; Binkley 326:18-328:1; Strauss 769:8-770:20.) 44. Consequently, throughout the 1970s and early 1980s, many investigators had instead tried to develop adenosine analogs that would have the desirable effects of adenosine without its 10

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undesirable adverse side effects. (Binkley 326:18-328:1; Strauss 769:8-770:20.) As stated in a typical publication from the early 1970s: The use of adenosine in cardiovascular therapy has been precluded both by the transitory nature of its vasodilator effects and by its toxic actions on the heart. It would seem feasible however that certain analogs of adenosine may be found which have the coronary vasodilatory activity of adenosine, but which have greater duration of action in vivo and which lack the cardiac depressant action of the parent compound. (TX-214 at 415 (emphasis added); Binkley 326:23-328:1; Strauss 770:16-20.) 45. Many researchers were involved in the search for useful adenosine analogs. This unsuccessful search for viable analogs is exemplified by efforts to use an intravenous infusion of the analog ethyl-adenosine to dilate coronary arteries in conjunction with cardiac stress imaging. (See TX-176; TX-1184; TX-259.) 46. In the mid-1970s, Abbott Laboratories carried out and published animal studies on the adenosine analog ethyl adenosine 5-carboxylate hydrochloride ("ethyl-adenosine") demonstrating, in dogs, that the compound was a potent and selective coronary vasodilator with a prolonged duration of action as compared to natural adenosine. (TX-176 at 419; Strauss 771:6-772:17.) The studies also demonstrated that ethyl-adenosine, unlike adenosine, did not decrease systemic blood pressure or slow heart rate (i.e., cause bradycardia) in dogs. (TX-176 at 419; Strauss 771:6-772:17.) 47. Consequently, in the late 1970s, Sicor's expert, Dr. Strauss, and a colleague selected ethyl-adenosine for a series of pilot animal studies they were performing on the use of a pharmacologic agent instead of exercise to stress the heart in connection with myocardial perfusion imaging. (Strauss 767:19-768:9, 769:3-7; Binkley 328:7-329:5.) Although they too worked with dogs, their goal was to transfer the technique to humans. (Strauss 767:19-768:9.)

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48. Yet when researchers tested ethyl-adenosine in human patients with coronary artery disease, they found that the compound, in fact, caused ischemia and angina (chest-pain), which led them to abandon further studies on the compound. (Strauss 773:14-21, 775:17-776:4; TX-259 at 470, 472-73.) The article reporting this study described the failure, stating "[o]ur study demonstrates lack of clinical effectiveness as well as detrimental effects produced by an adenosine analogue thought, on the basis of animal investigations, to be potentially antianginal in its effect in man." (TX-259 at 472.) 49. The experience with ethyl-adenosine illustrates that even an analog that was designed to eliminate the negative effects of adenosine and which showed promise in animal studies turned out to be harmful, causing ischemia and angina in humans. 5. The Prior Art Suggested Infusion of Dipyridamole, Not Adenosine, as a Pharmacologic Stress Agent for Myocardial Perfusion Imaging

50. Other researchers continued efforts on myocardial perfusion imaging studies, but turned to dipyridamole rather than adenosine. (Binkley 328:22-329:17.) Despite the fact that dipyridamole was believed to act, at least in part, by raising endogenous adenosine levels (TX-93 at 758; Binkley 330:8-25), nobody even suggested that adenosine itself should be used instead. While Sicor contends that dipyridamole was chosen because pharmaceutical grade adenosine was not commercially available at the time, the evidence does not bear this out. (Compare Binkley 1377:18-1378:20 with 331:1-332:14.) 51. The evidence clearly shows that scientists, such as those at the University of Virginia and elsewhere, who were sufficiently interested in adenosine were able to obtain and prepare adenosine for human administration. (Binkley 331:1-332:14.) 52. Indeed, the record shows that it was a lack of interest and lack of recognition by those in the art that adenosine would be a safe or effective alternative to dipyridamole in human 12

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patients rather than a lack of availability of pharmaceutical-grade adenosine that prompted researchers to choose dipyridamole. (See Binkley 331:21-332:14; Klabunde 525:16-526:14.) 53. Also demonstrating that lack of commercial availability was no impediment to researchers in the field, a 1979 article authored by Sicor's expert, Dr. Strauss, recommended the use of dipyridamole or ethyl-adenosine, but not adenosine itself, as pharmacologic stress agents in humans even though neither was then commercially available. (See Strauss 774:19-776:4, 777:24-778:4; TX-232 at 247-48.) Indeed, a 1986 review article authored by Dr. Strauss did not even mention adenosine as part of the "State of the Art" of myocardial imaging, even though an adenosine infusion had been used in dogs for this purpose in 1981. (TX-373; Strauss 776:13-777:1,778:18-779:8.) 54. Also telling, Dr. Strauss himself did not begin using adenosine for myocardial imaging until 1991, and even then he used a "stepwise" protocol starting at doses far below the then recommended amount of 140 mcg/kg/min. (TX-314; Strauss 779:21-780:19.) At trial, Dr. Strauss testified that the decision to use the stepwise protocol had "nothing to do with the AV block." (Strauss 780:7-781:5.) But he was impeached by his flatly contradictory prior deposition testimony. He previously testified that he used the stepwise protocol "because adenosine had been used to treat arrhythmias where the onset of [AV] block is intentional that this could be a significant problem with infusion." (Strauss 780:20-781:5, 782:17-783:18.) He was concerned that adenosine at 140 mcg/kg/min would induce heart block. (Strauss 782:27-783:18.)

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6.

Adenosine Triphosphate (ATP) Was a Separate Molecule Whose Characteristics Were the Subject of Separate Laboratory and Clinical Studies a. ATP Was Known to Have Unique Properties and Its Own Receptors and Had Been Shown to Be a More Potent Vasodilator Than Adenosine

55. Sicor relies in part on prior art concerning administration of an intravenous infusion of ATP rather than adenosine in support of its validity challenge to the asserted claims. (See, e.g., Binkley 192:2-23; TX-42; TX-51.) 56. ATP (adenosine triphosphate) is a high energy molecule with a chemical structure that includes three "phosphate groups" (collections of phosphorous and oxygen atoms) not found in adenosine itself. (Klabunde 505:17-506:10.) 57. As is not uncommon with chemical molecules, the presence of these additional atoms of phosphorus and oxygen gives ATP important biological properties that adenosine lacks. (Klabunde 506:11-18.) For example, ATP is the primary energy source in all cells, and is particularly prevalent in the muscular tissue of the heart. (Klabunde 506:7-10; TX-113 at 317.) In contrast, adenosine does not serve as an energy source and is only generated transiently in the heart. (Klabunde 506:11-13;.) 58. By the mid-1980s, it was well known that ATP and adenosine worked through different receptors in the body, (the adenosine receptor was referred to as the P1 receptor, and the ATP receptor was referred to as the P2 receptor), and that those different receptors would lead to different biochemical actions within a cell. (Klabunde 510:8-513:24; TX-151.) 59. Despite knowledge of these receptors, it was still largely unknown what the effects of natural ATP and adenosine were in various tissues in the body, much less whether the two compounds would have the same or different effects when administered intravenously, or what the differences in their effects might be. (TX-151 at 110; Binkley 1455:15-24.) 14

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b.

Prior Art Studies Identified ATP as a Powerful Vasodilator in Its Own Right

60. The prior art described studies by various researchers on the vasodilating effects of ATP, as well as related purine molecules, including adenosine diphosphate ("ADP") and adenosine. (See, e.g., TX-126 at 610; TX-199.) While the specific role played by the various compounds was poorly understood, these studies demonstrated differences in the ability of each to act as an independent vasodilator. (Binkley 273:1-274:24; Klabunde 507:8-508:3, 1116:51117:4.) For example, Moir and Downs demonstrated in the early 1970s that ATP and ADP "were significantly more potent than AMP [adenosine monophosphate] or adenosine as coronary vasodilators." (TX-199 at 1386; Klabunde 551:3-552:10, 1117:5-1118:1.) 61. Further studies on the vasodilating effects of ATP included a 1982 abstract, published by Fukunaga and colleagues, in which ATP was administered by intravenous administration to induce hypotension in surgical patients. (TX-42 ("Fukunaga 1982"); Klabunde 506:23-507:7.) 62. The abstract discussed only ATP, not adenosine, noting that ATP-induced hypotension had "long been employed during clinical anesthesia in Japan," but that "the detailed pharmacological and circulatory effects" of such treatment had not been well documented. (TX-42.) The abstract further described ATP as a "physiological intracellular substance, which relaxes and dilates vascular smooth muscles, including coronary and cerebral arteries" and concluded that "ATP should potentially be considered for use among the vasoactive hypotensive drugs." (TX-42.) In other words, Fukunaga 1982 concluded that ATP itself was a vasodilator. (Klabunde 508:8-24.) 63. The abstract was notably silent as to adenosine, did not suggest that the effects of ATP were mediated by adenosine, and did not mention adenosine as a potential alternative to ATP as an experimental hypotensive agent. (TX-42; Klabunde 508:4-7.) Indeed, consistent with

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the earlier study by Moir and Downs, which showed ATP to be fifty times more potent than adenosine, adenosine would have been expected to be less potent than ATP itself in inducing hypotension in humans, suggesting higher doses of adenosine would need to be used. (Klabunde 1117:5-1118:4.) c. ATP Was Known to be Metabolized into Various Compounds, Including Adenosine, But Its Greater Potency as a Vasodilator Showed that it Also Worked Through Its Own Receptor

64. In addition to recognizing ATP as a direct acting vasodilator, prior art investigators knew that it could be broken down by enzymes in the bloodstream into more than six different metabolites, including adenosine. (TX-126 at 612; Binkley 272:15-274:9; DTX-2008.) But it would have been impossible to predict the specific amount of these various metabolites or separate their individual effects because they rapidly interconverted with each other and several, including ADP, AMP, and adenosine, caused vasodilation in their own right. (Klabunde 507:8508:3, 1116:5-1117:4, 1220:19-1221:10; Binkley 273:1-274:9.) 65. Furthermore, it was known that the "metabolic" pathways acting on ATP also operated in reverse, so that while ATP was being rapidly broken down into ADP, AMP, and adenosine, inosine, and other metabolites, a portion of those metabolites were being reformed into AMP, ADP, and even ATP itself. (Binkley 272:15-25; DTX-2008.) 66. Further complicating the picture, administration of exogenous ATP could cause release of intracellular stores of endogenous ATP, with the result that ATP administration would, in effect, "beget" more ATP. (Binkley 1445:5-1446:10; TX-126 at 615; TX-228 at 807.) 67. Finally, as ATP was broken down, the phosphate groups were removed at various steps along the metabolic pathway. These phosphate groups released during ATP metabolism themselves had some modest vasodilatory activity. (Binkley 274:10-275:6.)

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68. Consequently, the vasodilation observed upon administration of an intravenous ATP infusion in humans was the result of the combined activity of exogenous ATP, endogenous ATP, and all the various metabolites, including the released phosphate groups. (Klabunde 507:8-508:3, 1116:5-1117:4, 1220:19-1221:10; Binkley 273:1-275:6.) 69. Although the prior art recognized the possibility that certain effects of ATP might be indirect, resulting from metabolism of ATP to form adenosine rather than direct binding of ATP to its receptor, there was no reliable evidence that the vasodilatory effects of ATP following intravenous administration to humans were solely the result of conversion to adenosine. (TX-152 at 198; Klabunde 1044:5-25, 1116:5-1117:4; Binkley 1466:16-1467:23.) The primary hallmark of such an indirect effect, were it to be true, would be where ATP was observed to be less potent than adenosine. (TX-152 at 198; Binkley 1459:20-1460:14, 1470:9-1471:6.) 70. Logically, if ATP was working solely by being metabolized into adenosine, it would make no sense for ATP itself to be more potent than the purported direct acting molecule. However, Moir and Downs had shown ATP to be a more potent vasodilator than its metabolites AMP and adenosine. (TX-199 at 1386; Klabunde 551:20-552:3.) Moreover, as discussed in detail below, subsequent studies by Dr. Fukunaga and Dr. Sollevi, involving administration of ATP or adenosine in the presence of dipyridamole, also showed ATP to be the more potent vasodilator in humans, indicating a direct vasodilating effect of ATP rather than an indirect effect. (Compare TX-51 with TX-1170; TX-199 at 1386; TX-152 at 198; Klabunde 1044:5-25, 1116:5-1117:4, 1118:8-21; Binkley 259:3-260:8, 1459:20-1460:14.) Such a direct effect would further indicate that ATP's vasodilatory action was not solely due to the ATP's metabolism to adenosine.

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d.

The Effects of ATP and the Extent of Its Metabolism Into Adenosine Were Highly Species Dependent

71. Metabolism of ATP differed in prior art studies of different species. Consequently, prior art investigators knew that effects of ATP and its degree of metabolism would be different in different species. (See, e.g., Klabunde 1216:18-25; TX-126 at 613.) 72. For example, Sicor cited a study in dogs in which ATP apparently acted by being completely metabolized to adenosine. (TX-88; Binkley 396:4-397:17.) A different study by Fukunaga in rabbits, however, showed ATP to be the more potent vasodilator, demonstrating that, in rabbits, ATP was having a direct effect. (Binkley 267:9-269:6, 1465:5-1466:15; TX-87 at 275.) Indeed, Fukunaga commented in that rabbit study that "[a]lthough much information about the extracellular, especially cardiovascular, effects of the adenine nucleotides has been accumulated, clinical uses will require more information in different species and under a variety of conditions." (TX-87 at 277.) 73. Sicor's expert, Dr. Binkley, attempted to also rely on two dog studies that were not disclosed in his expert report and offered previously undisclosed opinions and testimony about them. (TX-88; TX-236; Binkley 1412:1-1421:19.) Yet the record shows very different levels of ATP metabolism and different effects of ATP in various animal species and in animals versus humans. (See, e.g., Binkley 1465:5-1466:15; TX-87 at 277; Klabunde 1215:2-1216:18; TX-126 at 613.) Most importantly, the available human data in the prior art showed ATP to be a more potent vasodilator than adenosine, contradicting the notion that ATP was working solely through metabolic formation of adenosine. (See, e.g., Klabunde 1044:5-25, 1116:5-1118:21.) 74. Other investigators also reported that the rate of ATP breakdown in humans was low in comparison to other species. (TX-126 at 613; Klabunde 1215:2-1216:3.)

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B.

Dr. Alf Sollevi Countered Conventional Wisdom and Pioneered the Use of Adenosine Infusion in Humans

75. It was against this backdrop -- the historical belief that adenosine itself was not a useful molecule, that ATP was, in any event, more potent, and that the only viable medical use for adenosine was as a rapid bolus for treatment of patients suffering from the arrhythmia PSVT -- that Dr. Alf Sollevi pioneered the administration of adenosine as an intravenous infusion in humans. (Sollevi 437:21-438:7.) 76. He performed his studies at the Karolinska Institute, one of Sweden's premier research hospitals. (Sollevi 427:18-22.) 77. Dr. Sollevi became interested in adenosine while still a medical student, when he performed basic science studies on adenosine's ability to regulate circulatory and nerve function in fat tissue. (Sollevi 429:2-12.) That interest grew into a life-long endeavor leading to numerous clinical studies in humans and close to a hundred peer-reviewed articles concerning adenosine. (Sollevi 429:13-18.) 78. Remarkably, Dr. Sollevi's work on adenosine in the early 1980s was directly contrary to the conventional wisdom that adenosine was not useful and was potentially dangerous in humans, outside of the narrow application of a rapid bolus injection for individuals suffering from PSVT. Dr. Sollevi, however, persevered despite the contrary teaching of the scientific literature. (See, e.g., TX-48 at 2229; TX-36 at 1254; TX-214 at 415; Klabunde 516:13-522:2, 523:24-524:20, 1052:4-1055:1; Binkley 326:18-328:1; Strauss 769:8-770:20.) 79. Dr. Sollevi was uniquely suited to make his own judgments about the safety and utility of adenosine, as he had spent nearly six years studying adenosine's effects in animals before attempting to administer it to humans. (Sollevi 434:12-18.)

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80. One application Dr. Sollevi envisioned as a result of his work was to use an intravenous infusion of adenosine as a vasodilator for controlled hypotension in patients undergoing neurosurgery for a cerebral aneurysm. (Sollevi 434:19-435:4.) A cerebral aneurysm is a serious condition involving a "bulb" or bubble on a blood vessel in the brain that could rupture and cause bleeding and death. (Sollevi 435:5-15.) 81. While surgery is required to repair the aneurysm, there is a high risk that manipulation of the weakened vessel during surgery could itself rupture the aneurysm and kill the patient. (Sollevi 435:9-19.) Consequently, neurosurgeons sought to drastically reduce the patient's blood pressure during surgery by inducing controlled hypotension to cause "slack" in the aneurysm. (Sollevi 435:20-436:24.) 82. The greater the drop in blood pressure during the controlled hypotension the less likely it would be that the aneurysm would rupture. However, allowing the blood pressure to fall too low could also kill the patient. (Sollevi 435:24-436:24.) Thus, to accommodate these competing concerns, surgical hypotension was typically induced to cause a fall of approximately 40 percent in the mean arterial blood pressure. (Sollevi 436:14-436:24.) 1. Dr. Sollevi's First Studies Used Low Dose Administration of Adenosine in Conjunction with Dipyridamole Pretreatment to Induce Surgical Hypotension

83. When planning his controlled hypotension studies in humans, Dr. Sollevi was concerned about the effects of adenosine on cardiac conduction, as well as its ability to cause ischemia. (Sollevi 438:8-15.) He was also concerned about the potential buildup of adenosine metabolites as a result of infusing adenosine, particularly uric acid, which could lead to kidney damage. (Sollevi 437:9-438:16, 438:8-15.) 84. To reduce the danger of side effects, Dr. Sollevi planned to monitor the patients' heart beat by electrocardiogram (ECG) and to administer the lowest possible dose of adenosine, 20

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carefully titrating the dose so patients received only the amount of adenosine required to achieve the desired blood pressure reduction. (Sollevi 438:17-439:8.) 85. Dr. Sollevi also decided to pretreat the patients with dipyridamole, a drug known to block the uptake of adenosine into cells, thus increasing the amount of endogenous adenosine in the circulatory system. Dr. Sollevi chose dipyridamole as a pretreatment, knowing that such pretreatment would inhibit the metabolism of adenosine (which occurred inside cells) and allow a much lower dose of adenosine to be used while also reducing the overall concentration gradient of adenosine in the body between the central circulation, where it was administered, and the more peripheral sites where it would cause vasodilation and reduce blood pressure. (Sollevi 438:17-439:23.) This reduction in the overall concentration gradient would occur because dipyridamole, by inhibiting the breakdown of adenosine, caused higher concentrations of adenosine to reach to periphery. (Binkley 250:5-251:19.) 86. When he began his studies, Dr. Sollevi did not know how much pretreatment with dipyridamole would reduce the necessary dose of adenosine in patients. (Sollevi 437:21-25, 439:24-440:17.) However, his animal studies had suggested that the dipyridamole might result in as much as a 20-fold reduction in the necessary dose of adenosine. (Sollevi 440:7-17.) 87. Even with such a reduced dose, Dr. Sollevi also took the precaution of sampling the patients' blood before, during, and after hypotension, to analyze the buildup of possibly harmful metabolites using methods established in his own laboratory. (Sollevi 440:18-441:15.) 88. To reduce concerns about causing ischemia in patients treated with adenosine, Dr. Sollevi excluded those with a history of heart disease from the study. (Sollevi 441:17-442:2.) 89. Results of Sollevi's initial studies were published in abstracts in 1983 and 1984. (TX-1170; TX-37; Sollevi 442:3-443:11.)

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90. These abstracts demonstrated that, in the presence of a dipyridamole pretreatment, an average dose of 140 mcg/kg/min of adenosine, infused intravenously, would reduce mean blood pressure by about 40 percent. (TX-1170; TX-37; Binkley 258:2-5, 258:10-13.) 91. While no serious side effects were reported in these abstracts, they involved less than a dozen patients. (TX-1170; TX-37.) 92. Importantly, these abstracts did not mention the possibility of eliminating the dosereducing dipyridamole pretreatment or provide any guidance about whether one could determine a safe and effective dose that would induce hypotension in the absence of that pretreatment. (TX-1170; TX-37.) To the contrary, a subsequent study by Biaggioni in April 1985 showed that administration of adenosine by intravenous infusion without dipyridamole pretreatment at doses up to 140 mcg/kg/min in five normal healthy volunteers did not cause hypotension. (TX-1187; Klabunde 555:3-556:14.) 2. Dr. Fukunaga Later Recommended Using Dipyridamole Pretreatment to Avoid Problems Associated with Administering ATP Infusions

93. Two years after his 1982 abstract concerning administration of an ATP infusion to induce controlled hypotension in surgical patients, and after the publication of Dr. Sollevi's studies on the use of adenosine with a dipyridamole pretreatment, Dr. Fukunaga published an abstract expressing concerns about the effects of administering high doses of ATP in surgical patients. (TX-51.) 94. In his second abstract, Dr. Fukunaga noted that adenosine could be responsible for many of the hemodynamic effects of ATP infusion, but that further metabolism of the adenosine formed by ATP breakdown could also lead to undesirably high levels of uric acid. (TX-51.) Consequently, Dr. Fukunaga recommended pretreating patients with dipyridamole to reduce the necessary dose of ATP required during controlled hypotension. (TX-51.) 22

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95. Specifically, the second Fukunaga abstract stated "[w]hen hypotension is needed for long periods, the large doses of ATP required may cause undesirably high levels of uric acid and phosphate. It was found that this problem can be greatly avoided if dipyridamole (Dp) is used simultaneously." (TX-51; Binkley 270:15-271:1; Klabunde 540:15-541:8.) 96. Dr. Fukunaga's study demonstrated that dipyridamole could reduce the required dose of ATP infusion by about twelve-fold on average or as much as fifty-fold, leading him to recommend the ATP-dipyridamole combination to enhance the hypotensive effect of ATP alone and allow use of a lower dose. (TX-51; Binkley 178:19-25, 270:15-271:1; Klabunde 541:17-542:6.) 97. Thus, despite his earlier abstract, Dr. Fukunaga later became concerned about the safety of administering ATP without affirmatively reducing the necessary dose by pretreating with dipyridamole. (See TX-51; Klabunde 540:15-541:8.) 98. The timing of his later publication strongly suggests that Dr. Fukunaga was motivated by Dr. Sollevi's published abstracts to add dipyridamole pretreatment to his earlier protocol for administering ATP, not to attempt administration of adenosine without dipyridamole. (TX-51; Klabunde 1045:2-1046:13.) 99. Dr. Fukunaga also determined that the mean dose of ATP required to reduce mean arterial blood pressure in human patients by 40% after dipyridamole pretreatment was only about 32 mcg/kg/min as compared to Dr. Sollevi's mean dose of 140 mcg/kg/min of adenosine to achieve a similar degree of hypotension under similar conditions. (Compare TX-51 with TX-1170; Klabunde 1044:5-18.) As mentioned above, this requirement for substantially less ATP than adenosine to achieve the same hypotensive effect was consistent with the observations

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of Moir and Downs that ATP was a more potent vasodilator than adenosine. (TX-199; Klabunde 550:4-14, 1044:19-25.) 100. Dr. Fukunaga's results thus provided additional evidence that ATP acted, at least

in part, as a direct vasodilator in humans, despite also being broken down into adenosine and other byproducts. (TX-51; Klabunde 1044:5-25, 1116:5-1117:4, 1220:19-1221:10.) 3. Animal and In Vitro Models Regarding Adenosine and Human Studies of ATP Infusion Suggested That Dipyridamole Pretreatment Greatly Reduced the Effective Dose of Adenosine

101.

A variety of studies in the early 1980s had demonstrated dipyridamole's powerful

ability to inhibit the metabolic breakdown of adenosine. (See, e.g., TX-101; TX-40; TX-51.) This potent effect of dipyridamole suggested that much higher amounts of adenosine would have had to be infused into patients to achieve the same degree of controlled hypotension that Dr. Sollevi had observed at a dose of 140 mcg/kg/min following dipyridamole pretreatment. (TX-101; see Klabunde 535:13-536:8, 1041:25-1042:22, 1050:7-1051:8.) 102. Indeed, Dr. Sollevi had concluded, based on his own studies that as much as

twenty times more adenosine would be required in the absence of dipyridamole than in its presence. (Sollevi 440:7-17.) 103. Plaintiffs' expert, Dr. Klabunde, performed studies in the early 1980s

demonstrating and quantifying the rapid breakdown of adenosine in human blood. (TX-101; Klabunde 501:16-503:20.) This rapid breakdown was expressed in terms of the half-life of adenosine, i.e., the time it took for half of an administered dose of adenosine to disappear, which Dr. Klabunde measured to be less than 10 seconds. (TX-101; Klabunde 501:16-503:20.) 104. Dr. Klabunde found that, by inhibiting adenosine metabolism, dipyridamole

dramatically increased adenosine's half-life in human blood, leading him to conclude in 1983

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that "the usual therapeutic concentrations of dipyridamole are sufficient to inhibit adenosine metabolism by more than 90% in whole blood." (TX-101 at 25; Klabunde 503:21-504:2.) 105. Studies in live animals also pointed to dipyridamole as dramatically reducing the

necessary dose of adenosine infusion required for controlled hypotension. (See, e.g., TX-40.) 106. For example, a 1983 publication by Kassell and colleagues involving induction of

controlled hypotension in dogs reported that dipyridamole pretreatment had reduced the necessary dose of adenosine by nearly 200-fold. (TX-40 at 73; Klabunde 532:7-534:25.) While the authors "speculated" that the dipyridamole pretreatment might be unnecessary in humans because dogs were "notoriously difficult" animals in which to induce hypotension, they offered no data to support their speculation. (TX-40 at 73; Klabunde 1046:14-1048:25.) Indeed, far from being difficult, the dogs in the Kassell study showed dramatic hypotension at a dose of only 50 mcg/kg/min in the presence of dipyridamole, compared to a dose of 10,000 mcg/kg/min without dipyridamole. (TX-40 at 73; Klabunde 1048:6-25.) 107. Dr. Fukunaga's 1984 study of ATP-induced hypotension following dipyridamole

pretreatment also evidenced a powerful dipyridamole effect in humans. (TX-51; Klabunde 541:17-542:3; DTX-2002.) Specifically, Dr. Fukunaga demonstrated that dipyridamole reduced the required human dose of ATP by approximately 12-fold on average to as much as 50-fold. (TX-51; Klabunde 541:17-542:3, 1050:24-1051:8.) 108. Taken together with the in vitro and animal studies, these human studies with

ATP would have further suggested that to achieve hypotension with adenosine in the absence of dipyridamole in the way Dr. Sollevi had at a dose of 140 mcg/kg/min in the presence of dipyridamole would require at least a 10-fold or greater increase in the dose of adenosine administered. (TX-51; TX-1170; Klabunde 543:12-544:7.) But administering such a large dose

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of adenosine (e.g., in excess of 1,400 mcg/kg/min) would have been out of the question given the likelihood of causing bradycardia, cardiac arrest, or AV block, as well as potential kidney toxicity due to accumulation of the adenosine metabolite uric acid. (TX-36; TX-51; TX-410; Klabunde 537:5-538:6, 1054:2-1055:1) . 109. Indeed, eliminating dipyridamole pretreatment would have been exactly the

opposite of the advice in the Fukunaga 1984 abstract. (TX-51.) 4. Dr. Sollevi Unexpectedly Discovered that Adenosine Could Selectively Vasodilate Arteries and Safely Induce Surgical Hypotension Without Dipyridamole Pretreatment

110.

Despite the studies suggesting the need for much higher doses of adenosine in the

absence of dipyridamole and very real concerns that administration of adenosine alone at a dose sufficient to induce controlled hypotension would cause serious cardiac side effects, Dr. Sollevi proceeded in the winter of 1983 to 1984 to perform studies in human patients intravenously infusing adenosine without an initial dipyridamole pretreatment. (TX-112; TX-1169; Sollevi 446:1-14, 447:13-449:18.) 111. Dr. Sollevi explained that his prior work with adenosine infusion in conjunction

with dipyridamole pretreatment had not answered his concerns about AV block, accumulation of uric acid, or possible ischemia because those same effects could well be observed at the higher doses he believed would be required in the absence of the dipyridamole pretreatment. (TX-112; Sollevi 448:2-8.) Dr. Sollevi's perspective was that he had "no information" on the amount of adenosine that would be required apart from his own animal studies suggesting that as much as 20-fold higher doses would be needed. (TX-112; Sollevi 448:2-449:8.) 112. Dr. Sollevi's ultimate goal, however, was to administer adenosine alone, in hopes

that it would be a fast-acting compound that would be easy to titrate and reverse when

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hypotension was no longer needed, so he proceeded in the face of uncertainty. (Sollevi 448:918.) 113. To his surprise, Dr. Sollevi found that only a small increase of approximately 50

percent (1.5-fold) in the adenosine dose was required in the absence of dipyridamole in humans. (TX-169; Sollevi 450:5-451:6.) Indeed, the mean dose increased f