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 ) KING PHARMACEUTICALS RESEARCH AND DEVELOPMENT, INC., ASTELLAS US LLC, and ) ) ASTELLAS PHARMA US, INC., ) ) Plaintiffs, ) ) v. ) ) SICOR INC. and SICOR PHARMACEUTICALS, ) INC., ) ) Defendants. )

Civil Action No. 05-337-SLR

PLAINTIFFS' POST-TRIAL PROPOSED FINDINGS OF FACT AND CONCLUSIONS OF LAW CONCERNING U.S. PATENT NO. 5,070,877

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 E. Crawford #493 Patricia Smink Rogowski #2632 CONNOLLY BOVE LODGE & HUTZ LLP 1007 North Orange Street Wilmington, DE 19801 (302) 658-9141 [email protected] F. Dominic Cerrito Brian Poissant JONES DAY 222 E. 41st Street New York, NY 10017 (212) 326-3939 Attorneys for Plaintiff King Pharmaceuticals Research and Development, Inc.

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TABLE OF CONTENTS

PLAINTIFFS' PROPOSED FINDINGS OF FACT........................................................................1 I. THE PARTIES.....................................................................................................................1 A. B. II. III. Plaintiffs...................................................................................................................1 Defendants ...............................................................................................................2

NATURE OF THE CASE ...................................................................................................2 FACTUAL BACKGROUND..............................................................................................4 A. B. C. D. Diagnosis of Coronary Artery Disease with Myocardial Perfusion Imaging ....................................................................................................................4 The Asserted Claims of the `877 Patent ..................................................................6 The Prior Art Taught Away from Use of Adenosine in Patients With Coronary Artery Disease..........................................................................................8 The Prior Art Taught Away from Use of Adenosine as a Pharmacologic Stress Agent ..................................................................................11 1. 2. Researchers Used Anything But Adenosine for Pharmacologic Stress Tests.................................................................................................11 The Actual Uses of Adenosine In Humans in the Early and Mid-1980s Would Have Discouraged Its Use for Myocardial Perfusion Imaging......................................................................................16 a. b. c. E. F. Limited Use of Bolus Doses of Adenosine to Treat Arrhythmias ...................................................................................16 Dr. Sollevi's Studies In Surgical Patients ......................................18 Conflicting Results of Studies of Adenosine in Normal Volunteers ......................................................................................21

Prior to the Invention of the `877 Patent Nobody In the MPI Medical Community Even Mentioned the Possibility of Using Adenosine ........................23 The Medical Community Greeted the Invention of the `877 Patent with Skepticism and Concern ........................................................................................25

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1. 2. 3. G. H.

Contemporaneous Documents Capture the Concern of the Medical Community ..................................................................................25 Sicor's Expert, Dr. Strauss, Admitted that He Was Reluctant to Administer Adenosine at 140 mcg/kg/min ................................................27 Unresolved Concerns Regarding Ischemia, AV Block, and Hypotension Kept Adenosine Out of the Clinic ........................................27

Adenosine Is Now Preferred as a Pharmacologic Stress Agent Because of Its Superior Safety and Speed............................................................................28 Adenoscan is a Highly Successful Commercial Product .......................................28 1. 2. Adenoscan Went From Newcomer To Market Leader..............................29 Sales of Adenoscan Were Driven by the Attributes of the Claimed Invention, Not Marketing and Promotion ...................................30

I.

Sicor Copied Every Aspect of Adenoscan and the Patented Invention in its Abbreviated New Drug Application and Subsequently Admitted Infringement of the Asserted Claims of the `877 Patent........................................31 Sicor's Contrary Contentions Are Unmeritorious .................................................32 1. 2. Contentions Regarding Availability of Adenosine ....................................32 Contentions Regarding the State of the Art ...............................................33 a. b. 3. Sicor's Characterization of the Sollevi Prior Art...........................33 Sicor's Untimely New Contentions ...............................................35

J.

Arguments Regarding Commercial Success..............................................36 a. b. Adenoscan's Promotion Was Typical In The Industry..................37 Sicor's Economic Expert Was Unreliable And His Theories Not Supported By The Record........................................38

K.

Dr. Sollevi's Proposals to Use Adenosine as a Pharmacologic Stress Agent Are Not Prior Art and Do Not Disclose the Dose of 140 mcg/kg/min ............................................................................................................41 1. 2. Example XIII Does Not Disclose or Suggest an Adenosine Infusion at About 140 mcg/kg/min ............................................................41 Example XIII Disclosed No More Than What the Inventors Had Previously Disclosed in the Inventors' Own Protocols......................42 ii

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3. 4. 5. 6. L.

The "Creighton Protocols" Set Forth a Titration Method for Determining the Appropriate Adenosine Dose for Imaging......................43 Balancing Tolerability and Reliability: the Unexpected Discovery of 140 mcg/kg/min ...................................................................45 The Inventors Displayed "Remarkable" Diligence....................................48 The Karolinska Request Proposed Using Adenosine at a Dose Well Below 140 mcg/kg/min .....................................................................49

Subsequent Experience Has Validated 140 mcg/kg/min as the Ideal Adenosine Infusion Rate for MPI ..........................................................................50

PLAINTIFFS' PROPOSED CONCLUSIONS OF LAW .............................................................52 I. II. CONTROLLING AUTHORITY.......................................................................................52 VALIDITY OF THE `877 PATENT.................................................................................52 A. B. C. Patent Claims .........................................................................................................52 Sicor Bears the Burden of Proving Invalidity by Clear and Convincing Evidence.................................................................................................................52 The Asserted Claims Are Not Invalid for Obviousness.........................................53 1. 2. 3. 4. 5. The Law of Obviousness and the Supreme Court's Decision in KSR ............................................................................................................53 The Qualifications of the Person of Ordinary Skill in the Art...................55 The Scope and Content of the Prior Art.....................................................56 Differences Between the Claimed Invention and the Prior Art .................57 The Use of Adenosine In Human MPI Was Not Obvious.........................57 a. b. 6. The Prior Art Taught Away from Administration of Adenosine to Patients with Coronary Artery Disease....................57 The Dose of about 140 mcg/kg/min in Claim 23(18) Was Unpredictable in View of the Prior Art .................................58

The Objective Evidence Further Establishes the Nonobviousness of the Asserted Claims....................................................59 a. The Claimed Invention Was Met with Skepticism and Surprise ..........................................................................................59

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b.

The Lack of Any Suggestion to Use Adenosine For Imaging for Nearly 10 Years After the Publication of the Use of Dipyridamole Evidences Nonobviousness ...................60 Sicor's Copying Demonstrates Nonobviousness ...........................61 Adenoscan's Outstanding Commercial Success is Strong Evidence of Nonobviousness .............................................62 (1) (2) Commercial Success Generally .........................................62 Dr. Leffler's Contrary Opinions Are Not Credible..............................................................................62 (a) (b) There is a Nexus Between the Sales of Adenoscan and the Claims of the Patent................63 Sicor Failed To Prove that Sales of Adenoscan Are Not Driven by the Attributes of the Claimed Method .........................65 Clinical Attributes Determine Success of Pharmacologic Stress Agents, Not Promotion...............................................................66 Dr. Leffler's Opinion Is Contrary To The Evidence .........................................................67

c. d.

(c)

(d) D.

Sicor Failed to Prove the Asserted Claims Are Invalid Based On Dr. Sollevi's MPI Proposals.........................................................................................68 1. Even If They Were Prior Art, Neither Example XIII Nor the Karolinska Request Anticipates Claim 23(18) of the `877 Patent..........................................................................................................68 Even If They Were Prior Art, Neither Example XIII Nor the Karolinska Request Renders Obvious the 140 mcg/kg/min Dose of Claim 23(18).................................................................................69 Neither Example XIII Nor the Karolinska Request Are Prior Art and Thus Cannot Anticipate or Render Obvious the Asserted Claims .........................................................................................69 a. b. Sicor Failed to Prove that Example XIII of the `296 Patent is Prior Art...........................................................................70 The Karolinska Request is Not a Printed Publication....................72

2.

3.

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III.

Evidentiary Objections.......................................................................................................73 A. B. Expert Testimony and Exhibits Not Disclosed In Expert Reports ........................73 The Karolinska Request.........................................................................................74

IV.

CONCLUSION..................................................................................................................75

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This matter was tried before the Court on February 20, 2007 through February 28, 2007. 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.) Both corporations 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. 133, Ex. 1, ¶ 1.) 2. Astellas was formed from a merger between two pharmaceutical

companies, Fujisawa Pharmaceutical Co., Ltd. and Yamanouchi Pharmaceutical Co., Ltd. (White 1227:15-17.) 3. Plaintiff King Pharmaceuticals Research and Development, Inc. ("King")

is a corporation organized and existing under the laws of the State of Delaware having a principal place of business at 7001 Weston Parkway, Suite 300, Cary, North Carolina 27513. (D.I. 133, Ex. 1, ¶ 2.)

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B.

Defendants 4. 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. 1 ¶ 13.) Both corporations are organized and existing under the laws of the State of Delaware having principal places of business at 19 Hughes, Irvine, California 92618. (D.I. 133, Ex. 1, ¶¶ 3-4, 14.) 5. (D.I. 133, Ex. 1, ¶ 5.) II. NATURE OF THE CASE 6. Plaintiffs Astellas and King brought this suit against (i) Sicor and (ii) Teva Sicor Pharmaceuticals Inc. is a wholly owned subsidiary of Sicor Inc.

Pharmaceuticals USA (a Delaware corporation) and Teva Pharmaceutical Industries, Ltd. (an Israeli corporation) (collectively "Teva") for infringement of King's United States Patent No. 5,070,877 ("the `877 patent"). (D.I. 1 ¶¶ 30-31.) 7. The `877 patent is entitled "Novel Method of Myocardial Imaging" and

lists Syed Mohiuddin and Daniel Hilleman as the inventors. (See TX-320.) The `877 patent issued in 1991 and was assigned on its face to Medco Research, Inc. ("Medco"). The `877 patent is now assigned to King. (D.I 133, Ex. 1, ¶¶ 6-7, 9.) The `877 patent claims generally, methods of using adenosine in connection with diagnostic coronary artery imaging. (See generally TX-320.) 8. Astellas is the exclusive licensee of certain rights under the `877 patent.

(D.I. 133, Ex. 1, ¶ 10.) Pursuant to those rights, Astellas markets a product known as Adenoscan®.1 (D.I. 133, Ex. 1, ¶ 12.)

1

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

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9.

Adenoscan was approved by the United States Food and Drug

Administration (the "FDA") in 1995. Adenoscan is an adenosine solution administered to patients undergoing cardiac stress tests who are unable to exercise adequately on a treadmill. (D.I. 133, Ex. 1, ¶ 12; TX-75.) As such, 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-2031.) 10. On December 6, 2004, Sicor filed Abbreviated New Drug Application No.

77-425 ("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 product after expiration of the `877 patent. (TX-4.) On April 16, 2005, Sicor amended its ANDA to allow it to market its product prior to expiration of the `877 patent and to include a certification that (i) its proposed product would not infringe the `877 patent and/or (ii) the `877 patent was invalid or unenforceable. (TX-7.) King and Astellas then filed suit against Sicor and Teva alleging infringement of the `877 patent under 35 U.S.C. § 271(e)(2)(A). (D.I. 1 ¶¶ 24-26, 28-29.)2 11. 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. 12. Plaintiffs seek an order (i) prohibiting FDA approval of the Defendants'

generic adenosine product for use in myocardial perfusion imaging prior to the expiration of the
2

Astellas is also exclusive licensee of rights under U.S. Patent No. 5,731,296 (the `296 patent), which is owned by Item Development AB. Item and Astellas also filed suit against Sicor in the parallel action copending in this Court. See CV No. 05-0336-SLR.

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`877 patent, in accordance with 35 U.S.C. § 271(e)(4)(A); and (ii) enjoining the defendants from the commercial manufacture, use, 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.) 13. 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.) 14. While Sicor initially contended that its product did not infringe the claims

of the `877 patent, Sicor later conceded infringement. (D.I. 137 ¶ 2.) Sicor admitted "that making, using, offering to sell, importing, or selling Sicor's Adenosine Injection USP in the United States would infringe asserted claim 23 as read through claim 17, claim 23 as read through claim 18, and claim 43 of the `877 patent." (D.I. 137.) III. FACTUAL BACKGROUND A. Diagnosis of Coronary Artery Disease with Myocardial Perfusion Imaging 15. Patients with coronary artery disease usually do not have symptoms when

resting because the coronary arteries, even when partially blocked, deliver sufficient blood flow to supply oxygen to the resting heart muscle. (TX-138 at 295; Wackers 882:4-883:15.) When such patients exercise or exert themselves, however, the workload on the heart increases and coronary blood flow has to increase to meet the increased oxygen demand. (Wackers 882:4883:15.) If the blocked arteries are unable to deliver enough blood to meet the heart's need for oxygen, the heart muscle becomes starved for oxygen, a condition called "ischemia," and the patient feels chest pain, commonly referred to as "angina." (TX-138 at 295; Wackers 882:4883:15, 890:1-14; DTX-2022.)

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16.

Chest pain or discomfort is the main reason patients are referred for the

cardiac diagnostic method termed "myocardial perfusion imaging" (MPI). (Wackers 883:9-15.) Typical MPI diagnostic protocols pair exercise (usually walking on a treadmill) with injection of a radioactive tracer that allows physicians to visualize blood flow in the heart and evaluate the presence and severity of coronary artery disease or other heart dysfunction. (TX-138 at 298-300; Wackers 883:9-886:8; DTX-2003; DTX-2023.) 17. The exercise stress usually begins at a low level and is increased slowly

because the physician does not know when the patient will "run into trouble." (Wackers 885:1418.) The patient typically continues to exercise until he or she experiences symptoms (such as chest pain, an abnormal electrocardiogram) or is too fatigued to continue. (Wackers 885:14886:3.) Obtaining a sufficient level of exercise and a corresponding increase in blood flow is critical to the diagnostic accuracy of the test. (Wackers 901:2-22; DTX-2018.) For instance, if there is not sufficient increase in blood flow, the patient's coronary artery disease may not be detected. (Wackers 901:2-22; DTX-2018.) 18. While exercise stress testing remains a preferred method for diagnosing

coronary artery disease, forty to fifty percent (40-50%) of patients referred for stress testing are unable to perform adequate physical exercise. (TX-138 at 300; Wackers 886:8-887:11.) These patients are usually older and manifest a variety of risk factors for heart disease, such as deconditioning, peripheral artery disease (claudication), diabetes, or obesity. (Wackers 887:25888:11.) 19. In patients referred for pharmacological stress testing, nearly half have

known coronary artery disease and one-quarter have already had a myocardial infarction (heart attack). (TX-103 at 386; Strauss 834:3-836:1.) Consequently, a need exists for stressors other

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than exercise for this sizeable "at risk" segment of the population. (TX-168 at 1344; see Wackers 887:25-888:11.) For such patients, "pharmacologic stress testing" is a way to increase blood flow in the heart to allow effective imaging without the need for exercise. (Wackers 889:7-891:12; DTX-2022.) 20. Sometimes referred to as a "lazy man's stress test," pharmacologic stress

testing allows a patient to lie prone while a pharmacologic stress agent is administered through an intravenous tube. (Wackers 888:12-889:6; DTX-2006.) The stress agent dilates the coronary resistance vessels (small arteries), causing an increase in blood flow of 3 to 5 times (300% to 500%) in the case of adenosine. (Wackers 890:15-891:12.) A radioactive tracer is then injected and pictures are taken of the blood flow in the heart muscle so that the presence and severity of coronary artery disease can be evaluated as in the exercise stress test. (Wackers 888:12-889:6; DTX-2006.) 21. In this regard, the pharmacologic stress causes "heterogeneity" in the

blood flow between healthy and diseased vessels, which allows effective myocardial perfusion imaging, and consequently accurate diagnosis of coronary artery disease. (Wackers 890:15891:12.) B. The Asserted Claims of the `877 Patent 22. The three claims asserted in this litigation, claims 23(17), 23(18), and 43,

concern cardiac diagnostic methods. (See TX-320.) In the claimed methods, adenosine is administered to cause vasodilation, a radioactive tracer is administered to allow imaging, and the heart is imaged by MPI to allow diagnosis of coronary artery disease. (See TX-320.) 23. Claim 23 is a multiply dependent claim dependent on any one of claims

17, 18, or 19. (TX-320, col. 9, ll. 34-35.) Thus, claim 23 is legally equivalent to three individual dependent claims, one dependent on claim 17, one dependent on claim 18, and one dependent on 6

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claim 19. Consequently, claim 23 must be read with respect to the particular claim "in relationship to which it is being considered."3 24. "Claim 23(18)," for example, refers to claim 23, as it depends from claim

18, and is read to narrow the terms set forth in claim 18 (which itself is a dependent claims based on claim 17) as follows: 23(18). A method of detecting the presence and assessing the severity of coronary artery disease in a human comprising the steps of: (a) administering by an intravenous route to said human about 140 mcg/kg/minute of adenosine sufficient to provide coronary artery dilation (b) administering a radiopharmaceutical agent into said human; and (c) performing radiopharmaceutical myocardial perfusion imaging on said human in order to detect the presence and assess the severity of coronary artery disease. (TX-320, col. 8, l. 53-col. 9, l. 35.) 25. Claim 23(18) recites use of an intravenous adenosine infusion at a dose of

140 mcg/kg/min. (TX-320; Wackers 896:25-897:7.) 26. Claim 23(17) is read as a narrowing of only claim 17 and therefore

specifies use of an effective amount of adenosine in the range of 20 to 200 mcg/kg/min, which is alternately written as 20-200 mcg/kg/min. (TX-320, col. 8, l. 53-col. 9, l. 35; Wackers 897:913.) As set forth in Proposed Conclusion of Law 2, infra, "[a] multiple dependent claim shall be construed to incorporate by reference the limitations of the particular claim in relation to which it is being considered." 35 U.S.C. § 112, ¶ 5 (2000); M.P.E.P. § 608.01(n) 600-86 (explaining that multiple dependent claims "must be considered in the same manner as a plurality of single dependent claims"); H.R. Rep. No. 94-592, at 1241 (1975) ("A multiple dependent claim, as such, does not contain all the limitations of all the claims to which it refers, but rather, contains at any one time only those limitations of the particular claim under consideration.").
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27.

Claim 43 similarly recites use of an effective amount of adenosine in the

range of 20-200 mcg/kg/min, and additionally specifies the radiopharmaceutical agent as thallium-201. (TX-320, col. 10, l. 66-col. 11, l. 9; Wackers 897:20-898:2.) C. The Prior Art Taught Away from Use of Adenosine in Patients With Coronary Artery Disease 28. Although recognized today as a safer and faster vasodilator than

dipyridamole, adenosine was long thought to be too dangerous and too short-lived to be useful as a coronary vasodilator in patients, particularly patients suffering from coronary artery disease. (See, e.g., TX-48 at 2229.) 29. Adenosine is a naturally-occurring compound that has been known since

at least the late 1920s. (See TX-35; Strauss 765:12-766:1.) Despite its early discovery and its natural presence in the body, adenosine was quickly recognized to be capable of severe negative effects on the beating heart. (See TX-36 at 1254; Strauss 765:17-766:1.) Specifically, in pharmacologic and animal studies, adenosine lowered heart rate and impeded the transmission of electrical signals that caused the heartbeat, a condition termed "AV block." (See generally TX-36; Strauss 765:17-766:1, 796:5-9.) 30. AV block is classified by degrees according to the severity of its effect.

First degree AV block is merely a "lengthening" of the propagation time of the electrical impulses of the heartbeat, although it presents a concern as a potential precursor to other problems. (Wackers 894:13-895:14.) By contrast, complete AV block results in a sudden "flat line" on the electrical cardiogram as the heartbeat ceases. (Wackers 895:2-14, 895:25-896:12.) Complete AV block was recognized as a serious side effect. According to Dr. Wackers, "when you see it [in a patient] for the first time, your own heart stops beating as well." (Wackers 895:21-896:12.)

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31.

In addition to its effects on electrical conduction, adenosine also had a

well-documented risk of systemic effects, particularly its capacity to cause hypotension (a major decrease in blood pressure) and myocardial "steal" (in which blood is "stolen" from one arterial pathway to another), which discouraged its use. (TX-217 at 430; Wackers 909:19-910:7.) These systemic effects were considered particularly risky for patients with coronary artery disease, as the dilation of relatively healthy arteries could "steal" blood away from partially blocked arteries, triggering myocardial ischemia similar to that resulting from inadequate blood flow during exercise. (TX-240 at 439; Wackers 910:8-17.) Even if initially mild, such ischemia presented a concern because it could lead to a worsening of conditions. As Dr. Wackers explained, "ischemia may beget ischemia," producing "a spiral that may be hard to get out of." (Wackers 955:10-956:16.) 32. Consequently, for many years adenosine was primarily considered a

laboratory tool without practical use in humans. This history is recounted in a variety of thirdparty scientific articles published during the 1980s and 1990s. (See, e.g., TX-46; TX-48.) 33. For example, a 1986 article by Biaggioni reported:

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; Strauss 797:22-798:9.) 34. Similarly, a 1990 publication by Wilson, a recognized authority in the

field, and his coworkers stated: Despite the widespread use of adenosine in animal studies, concern over adenosine induced hypotension and heart block have hampered its use in humans.

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(TX-46 at 1596; Strauss 803:11-804:8, 852:1-10.) 35. Therefore, "[d]espite [its] 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." (See TX-47 at 1854; Strauss 805:6-22.) 36. Even as of 1990, the "use of adenosine in humans has been limited mainly

because of side effects reported by patients and the AV node block produced." (TX-47 at 1855; Strauss 805:23-806:8.) This record of publications confirms that the short-acting nature of adenosine and its tendency to cause sharp decreases in blood pressure in animal studies also led away from its use in humans. (See TX-47 at 1854.) 37. Dr. Wackers explained that the short-acting nature of adenosine

complicates the question of how much adenosine should be administered. (Wackers 954:24955:9.) Adenosine has an ultrashort half-life in humans of about 2-10 seconds. (TX-240 at 1038.) As explained by Dr. Wackers, "if you consider that if you inject a drug in an arm vein, it takes at least 17, 20 seconds to arrive at the heart, which would mean if you inject a certain amount, when it gets to the heart, it's only half the dose." (Wackers 955:1-955:9.) 38. In an effort to avoid the long-running concerns about adenosine described

above, scientists worked to develop chemical analogs of adenosine that lacked its negative effects on the heart and blood pressure while extending the duration of its beneficial effects. (Strauss 769:18-770:20.) The medical literature of the time reflects the concerns that led to such efforts: 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

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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; see, e.g., Strauss 770:5-20.) 39. Ethyl adenosine 5-carboxylate hydrochloride ("ethyl-adenosine") was one

of the most promising of these synthetic chemical analogs of adenosine. (Strauss 771:6-772:10.) Studies in dogs showed that ethyl-adenosine was more potent and more selective in dilating coronary arteries than adenosine, and that ethyl-adenosine also had a prolonged duration of action. (See TX-176 at 419.) Unlike adenosine, however, intravenous administration of ethyl-adenosine to animals did not slow heart rate or decrease systemic arterial blood pressure. (See TX-176 at 419; Strauss 772:3-14.) 40. Highlighting the unpredictability of extrapolating animal testing to human

patients, subsequent human clinical trials showed that ethyl-adenosine induced ischemia and anginal pain in patients with coronary artery disease, leading to the cessation of further clinical studies. (See TX-259; Strauss 773:14-21.) D. The Prior Art Taught Away from Use of Adenosine as a Pharmacologic Stress Agent 1. 41. Researchers Used Anything But Adenosine for Pharmacologic Stress Tests By the late 1970s, researchers began to explore pharmacologic alternatives

to exercise stress for MPI. In the first article concerning tests in animals of such a pharmacologic alternative, Dr. Strauss, Sicor's technical expert in this case, and his colleague, Dr. Pitt, described administering a bolus injection of ethyl-adenosine, not a continuous infusion of adenosine, to dogs. (See TX-1184.) Strauss and Pitt used ethyl-adenosine, not adenosine, stating that they had selected ethyl-adenosine because it caused coronary vasodilation "with a relatively small change in systemic arterial pressure." (TX-1184 at 406; Strauss 772:19-773:5.)

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A large drop in systemic pressure was considered undesirable in the context of diagnostic cardiac imaging and could potentially lead to ischemia and other ill effects. (Wackers 910:8-17, 922:7-9.) 42. They also noted based on their earlier animal studies, that ethyl-adenosine

did not cause ischemia. (TX-1184 at 405; Strauss 773:6-13.) By contrast, they cautioned readers regarding the use of systemic vasodilators, stating that those drugs might result in a "`myocardial steal syndrome' and myocardial ischemia." (TX-1184 at 406.) 43. Of course, as discussed above, the hypothesis that ethyl-adenosine would

retain adenosine's vasodilating activity without causing ischemia in humans turned out to be false, and ethyl-adenosine was discarded as a potential pharmacologic stress agent for humans. (See TX-259 at 472; Strauss 773:14-21.) 44. Notably, neither Dr. Strauss nor anyone else suggested in the late 1970s

that adenosine should be used instead of ethyl-adenosine as a pharmacologic stress agent in humans. (Strauss 774:2-18.) 45. The perceived requirements for a pharmacologic stress agent were

reflected in the literature of the day. Dr. Lance Gould and colleagues, for example, stated in 1978 that an appropriate pharmacologic stress agent must be "selective for the coronary arteries," have "insignificant systemic effects," and have "an effect for at least 3 minutes until thallium201 is removed from the systemic circulation." (TX-391 at 275.) Adenosine did not fit this profile, as it was associated with systemic hypotension, was known to cause AV block, was associated with ischemia, and had an extremely short duration of effect. (See, e.g., TX-36 at 1254; TX-217 at 430; TX-259 at 470; Strauss 790:3-23; Wackers 909:9-910:17.)

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46.

Accordingly, when Dr. Gould and colleagues published a series of papers

following up on Dr. Strauss's preliminary studies on the use of ethyl-adenosine as a pharmacologic stress agent, they did not turn to adenosine but instead turned to a different drug, dipyridamole. (See TX-38 (Gould 1978); TX-93 (Albro); Wackers 902:25-903:16, 907:1-20.) Dipyridamole was known to act, at least in part, by preventing the breakdown of adenosine -- but dipyridamole was considered to be "quite nontoxic." (TX-39 at 822; Wackers 913:3-12, 907:25-908:24.) Unlike adenosine, dipyridamole was believed to selectively induce coronary vasodilation, i.e., its effects were expected to be limited to coronary arteries as opposed to the systemic vascular beds that regulate blood pressure. (See TX-391 at 275; Strauss 790:3-23.) Most importantly, dipyridamole had been used safely in patients with coronary artery disease, alleviating concerns about hypotension and ischemia. (TX-391 at 275; Wackers 913:3-12.) 47. Gould 1978 reported the use of intravenous dipyridamole as a

pharmacological stress agent in a group of patients also undergoing exercise stress testing for suspected coronary artery disease. (See TX-38.) The article reported that dipyridamole had a "potent, selective" effect on the coronary arteries, increasing coronary flow four hundred percent (400%) over baseline levels. (TX-38 at 279, 284; Wackers 924:3-6.) The diagnostic reliability of MPI images obtained with a 400% increase in blood flow was reported to compare favorably with the results of exercise stress tests. (See TX-38 at 279, 284.) Gould 1978 further stated that the sensitivity of the imaging technique could be improved by using other coronary vasodilators that were more potent than dipyridamole, but did not identify any specific compounds and noted that such vasodilators would also carry an increased risk of inducing ischemia or myocardial steal, depriving the heart of needed oxygen. (TX-38 at 285; Wackers 905:6-19.)

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48.

In a companion paper to Gould 1978, Albro and coworkers compared the

sensitivity of myocardial perfusion imaging using dipyridamole versus exercise. (See TX-93; Wackers 907:1-13.) Albro specifically stated that dipyridamole was thought to induce vasodilation by preventing the inactivation of adenosine, but nowhere taught, suggested, or even mentioned the possibility of direct administration of adenosine instead of dipyridamole. (See TX-93 at 758; Wackers 907:18-908:18.) 49. Following the publication of Gould 1978 and Albro, others became

interested in dipyridamole as a pharmacologic stress agent. (See, e.g., TX-229; TX-232; TX-258; TX-373.) Yet, no one tested or even suggested the possibility of using adenosine instead of dipyridamole for that purpose. As reported in 1982, when Dr. Strauss, Sicor's expert and the author of the ethyl-adenosine study described above, performed pharmacologic stress imaging in humans, he too reached for dipyridamole, not adenosine. (TX-258; Strauss 777:14778:1.) 50. No one considered adenosine as a realistic substitute for dipyridamole

because adenosine was viewed as too dangerous. (See, e.g., TX-46; TX-47; Strauss 803:11804:8, 805:23-806:8.) Dr. Melvin Marcus, acknowledged by Sicor as an expert in the field, wrote in a well-regarded treatise in 1983 that intravenous administration of adenosine into animals caused "marked systemic hypotension and reflex tachycardia [abnormally rapid heart beat]." (TX-217 at 430; Strauss 799:19-800:2; Wackers 909:9-910:25.) Dr. Marcus stressed that "[b]ecause of the hypotensive effects of adenosine, it is not utilized clinically to produce maximal coronary dilation." (TX-217 at 430; Wackers 909:19-910:7.) Even Sicor's technical expert acknowledged that hypotension was "undesirable" during MPI. (Strauss 799:9-13.)

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51.

In contrast to the potent hypotensive effects associated with adenosine, the

prior art described dipyridamole as a "relatively selective coronary dilator" with only "modest effects on systemic pressure." (TX-217 at 432.) The Marcus treatise chapter continued as follows: Dipyridamole has two specific advantages when used to produce maximal coronary dilation in human beings. First, the coronary dilation produced is reasonably well sustained (half-life = 33 min) [sic]. Therefore, maximal coronary flow in response to drug administration is sufficiently sustained to be measured with a washout technique [sic]. Second, the safety of intravenous dipyridamole in doses that produce intense coronary dilation is based on experience with hundreds of patients with heart disease. (TX-217 at 432; Wackers 911:15-913:12.) 52. The Marcus chapter underscores the perceptions of adenosine and

dipyridamole in the mid-1980s. (See TX-217.) Adenosine was perceived as a short-acting systemic vasodilator and barred from the clinic, capable of causing dangerous decreases in blood pressure and interfering with the electrical conduction of the beating heart. (See TX-217; Wackers 909:9-910:25.) In contrast, dipyridamole was viewed as a relatively selective coronary vasodilator, with sustained activity, proven safe through testing in numerous actual patients with heart disease.4 (See TX-258; TX-391; Wackers 911:15-913:12.) 53. The factors that taught away from the use of adenosine as a pharmacologic

stress agent persisted throughout the mid-1980s. Even ten years after Dr. Strauss's publication, a

On cross examination, Sicor raised the issue that the adenosine studies described in the Marcus chapter were based on animal data. (Wackers 1006:3-6.) Yet, the human adenosine publications relied on by Sicor also showed that adenosine was a powerful hypotensive agent capable of causing systemic vasodilation. See § III.D.2.b., infra. Moreover, to the extent publications described tests in healthy normal volunteers, they failed to establish the safety of adenosine in the relevant patient population. See § III.D.2.c., infra.

4

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February 1988 review article reiterated perceived requirements for a pharmacologic stress agent that adenosine simply did not meet: It appears that the specific type of coronary vasodilator does not appear to be of critical importance as long as the agent has a selective action on the coronary arteries, has an insignificant systemic effect, and has an effect that lasts for at least 3 minutes to permit thallium extraction from the systemic circulation. (TX-229 at 432; Strauss 813:3-24.) 54. Moreover, even after the Adenoscan product was introduced by the

predecessor of Astellas in the 1990s, cardiologists initially resisted using the product for pharmacologic stress testing for fear of inducing AV block. (Klose 1516:3-14.) 2. The Actual Uses of Adenosine In Humans in the Early and Mid-1980s Would Have Discouraged Its Use for Myocardial Perfusion Imaging a. 55. Limited Use of Bolus Doses of Adenosine to Treat Arrhythmias

In 1983, physician-scientists at the University of Virginia published

studies showing that, when administered in bolus doses (i.e., rapid injections), adenosine could be used to treat patients suffering from an abnormal heart rhythm known as PSVT (paroxysmal supraventricular tachycardia). (TX-36; Strauss 795:6-13.) PSVT is a condition where a patient experiences a very rapid, or abnormal, heartbeat that is perceived as very unpleasant, and may lead to other complications. (Wackers 914:3-14.) These studies took advantage of adenosine's potent ability to interrupt electrical conduction in the beating heart, as bolus doses of adenosine appeared to interrupt electrical conduction sufficiently to "reset" the normal rhythm of the heart. (See TX-45; Wackers 914:9-22.) 56. Thus, these University of Virginia clinicians discovered that in this unique

group of patients, the toxic effects of adenosine could be harnessed to beneficial effect. (See

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TX-45.) However, this clinical situation was very different from the situation of a patient undergoing myocardial imaging. As Dr. Wackers explained, "it's a completely different situation" when a patient is in need of an urgent cardiac therapeutic intervention, as compared to a patient who may need to undergo a stress test. The two groups of patients are "totally different." (Wackers 915:4-18.) 57. These researchers cautioned that clinical use specifically required a careful

consideration of adenosine's powerful and potentially harmful effects: Overdosage might lead to prolonged asystole [cessation of heart beat], hypotension [low blood pressure], or other tachyarrhythmias [abnormal heart beats]. Even though the direct effects of adenosine are quite brief, 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; Wackers 916:12-16; 917:10-22.) 58. In addition to expressing concern regarding serious adverse effects and the

consequences of overdosage, the authors noted a seven-fold variation in dosages required to achieve a therapeutic response, leading the authors to recommended that the physician should individualize the adenosine dosage for each patient. (TX-45 at 422; Wackers 916:17-917:9.) The authors emphasized that "the 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.) As Dr. Wackers recognized, no patient is the same and each may have different sensitivities regarding the electrical effects of adenosine on the heart. (Wackers 915:23-916:16.) 59. The University of Virginia physicians also commented on adenosine's

unsuitability for more extended treatments and the efforts to develop analogs lacking its negative effects: The development of longer-acting adenosine analogs might permit chronic therapy, but unless an analog specific for the AV nodal 17

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adenosine receptor is developed, the chronic adenosine-like activity of the analog in the many organs in which adenosine plays an important physiologic role would have to be considered. (TX-45 at 423.) 60. Thus, while the bolus injection of small amounts of adenosine proved

useful for treating PSVT, these studies reinforced concerns regarding adenosine's toxic effects, overdosage, systemic effects, and short-half life. (See TX-45; Wackers 918:17-919:3.) b. 61. Dr. Sollevi's Studies In Surgical Patients

Sicor relies on three publications by Dr. Sollevi from the mid-1980s to

suggest that an ordinary cardiologist would have believed adenosine appropriate for use in patients with coronary artery disease and likely to succeed as a pharmacologic stress agent. (See TX-112; TX-1169; TX-1171; Strauss 699:4-20, 708:10-709:20, 725:12-726:6.) In fact, these articles would have taught just the opposite. 62. Dr. Sollevi pioneered the development of continuous intravenous

infusions of adenosine in anesthetized patients undergoing surgery. Contrary to Sicor's allegations, Dr. Sollevi's publications do not teach or suggest the use of adenosine as a pharmaceutical stress agent for myocardial perfusion imaging. (See TX-112; TX-1169; TX-1171; Wackers 921:5-922:9.) 63. From 1984 to 1987, Dr. Sollevi published a series of scientific papers

characterizing the effects of various dosages of adenosine, including Sollevi 1984b (TX-112), Sollevi 1986 (TX-1171), and Owall 1987 (TX-1169).5 These publications contained several important common elements: (1) the publications disclosed adenosine's utility in producing profound systemic hypotension, a condition that both Plaintiffs' and Defendants' experts agree Sollevi I (TX-1170), while mentioned in Dr. Strauss's expert report, was not referenced by Dr. Strauss at trial in support of his opinion on obviousness.
5

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was sought to be avoided during MPI (see Strauss 768:22-769:2; Wackers 910:8-17), 922:7-9; (2) they lacked any systematic study of patients with coronary artery disease, generally excluding or expressly cautioning against the administration of adenosine infusions to such patients; (3) they did not explicitly or impliedly suggest the use of adenosine as a pharmacologic stress agent for MPI, particularly at a dose of 140 mcg/kg/min; and (4) they did not include any data regarding a safe and efficacious dose for producing maximal coronary vasodilation in patients with suspected coronary artery disease. (See, e.g., TX-112; TX-1169; TX-1171; Wackers 921:5931:6; see DTX-2027.) 64. In the Sollevi 1984b article, Dr. Sollevi described the use of intravenous

infusions of adenosine in ten patients to induce major reductions of blood pressure. (TX-112; Strauss 797:7-21.) The studies involved patients without any known history of cardiopulmonary disease. (TX-112 at 400; Wackers 922:10-15.) Sollevi 1984b reported that a continuous intravenous infusion of adenosine of 140 mcg/kg/min following dipyridamole pretreatment could be used to decrease blood pressure by forty percent (40%), a drop which Sicor's expert characterized as "quite significant," and which would have been highly undesirable in a patient undergoing a pharmacologic stress test. (See TX-112 at 400; Strauss 797:7-21, 768:22-769:2.) 65. The Sollevi 1986 review article entitled "Cardiovascular effects of

adenosine in man; possible clinical implications," reported that approximately 20,000 studies had been performed regarding the effects and formation of adenosine since Drury and Szent-Gyorgi first characterized the cardiovascular effects of adenosine in 1929. (TX-1171 at 319.) Despite this recognition of the enormous scientific experience with adenosine and the expressly stated purpose of the article to set forth "possible clinical implications" of adenosine administration,

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adenosine is nowhere suggested as a candidate pharmacologic stress agent for myocardial perfusion imaging. (See TX-1171; Strauss 774:13-18.) 66. Like Sollevi 1984b, Sollevi 1986 disclosed the hypotensive effect of

adenosine, describing the dramatic decreases in blood pressure that result from intravenous infusions of adenosine. (See TX-1171.) In particular, Sollevi 1986 stated that adenosine induced an "extremely rapid" fall in blood pressure, mediated by "a profound decrease in the systemic vascular resistance." (TX-1171 at 332.) 67. Particularly significant among these publications was Owall 1987, in

which two of the patients receiving adenosine to induce hypotension during brain surgery had a history of myocardial infarction 9 and 13 years before surgery. (TX-1169 at 229; Wackers 927:16-928:3.) Both of those patients experienced adverse side effects from the adenosine infusion. Indeed, one of these patients developed a potentially dangerous abnormal heart rhythm called ventricular tachycardia shortly after the induction of hypotension, requiring termination of the adenosine infusion and treatment with an intravenous injection of lidocaine. (TX-1169 at 231; Wackers 928:4-929:9.) The other developed atrial flutter, a type of supraventricular tachycardia, and required intravenous administration of a separate cardiac drug. (TX-1169 at 231; Wackers 929:10-17.) 68. In view of these side effects, the authors of Owall 1987 explicitly

cautioned against using adenosine in patients with a history of heart disease, stating that "[t]he use of adenosine hypotension should be carefully considered in patients with ischemic heart disease because in this clinical study, dysrhythmias occurred in the two subjects with earlier history of myocardial infarction." (TX-1169 at 233; Wackers 929:18-930:2.)

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c. 69.

Conflicting Results of Studies of Adenosine in Normal Volunteers

Subsequent to Dr. Sollevi's hypotension studies, several groups published

papers investigating the effects of adenosine infusions in normal, conscious volunteers. These papers included Biaggioni 1986 (TX-48), Conradson I (TX-1211), Conradson II (TX-220), Fuller 1987 (TX-1208), and Biaggioni 1987 (TX-226). (Wackers 933:4-18; DTX-2017.) None of these papers mentioned MPI. (Wackers 933:22-934:5.) These publications again contain a number of important common elements: (1) the studies dealt with normal, healthy subjects, not heart patients; (2) the number of subjects studied was small, usually no more than seven; (3) no measures of coronary blood flow were reported; (4) no mention was made of MPI; (5) no medical use for adenosine in humans was proposed; (6) dose-limiting negative side effects were reported; and (7) the dose at which side effects were reported to be intolerable was as low as 70 mcg/kg/min and varied widely. (See generally, TX-48; TX-220; TX-226; TX-1208; TX-1211; Strauss 826:24-831:6.) 70. These publications were scientific investigations of the molecular

mechanism by which adenosine exerted its effects combined with a description of certain physiological responses. (See TX-48; TX-220; TX-226; TX-1208; TX-1211.) 71. As detailed in DTX-2017, these publications disclosed tests of 35 normal,

healthy volunteers spread across 5 different studies. The subjects received adenosine infusions according to a variety of different protocols, and consequently the results are not directly comparable. (Wackers 933:4-934:8; see DTX-2017.) 72. The subjects that received adenosine infusions exhibited a wide range of

maximal tolerable dosages, with intolerable side effects occurring at doses as low as 70

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mcg/kg/min. (See TX-1211 at 527; TX-1208 at 311; Strauss 826:24-831:6; Wackers 936:5-937:2, 937:15-938:2; DTX-2017.) 73. None of these normal volunteer articles provided any suggestion to use

adenosine in MPI or sufficient information to determine what adenosine dose, if any, would be useful for that purpose. Nor did any of these articles indicate that the effect of adenosine on coronary blood flow was sufficient for diagnostically reliable MPI. (Strauss 826:24-831:6; Wackers 934:25-935:5, 937:14-939:1.) 74. Additionally, none of these studies taught a safe dose for administration to

patients with coronary artery disease, because the studies specifically excluded such patients. (Wackers 938:19-939:1.) This is an important omission, as the patient population requiring pharmacologic stress imaging was known to suffer from numerous adverse circulatory and coronary conditions. (TX-168 at 1344.) In fact, a subsequent publication reported that 50% of over 9,000 patients receiving pharmacologic stress testing had a history of coronary artery disease and nearly 25% of those patients had suffered a heart attack. (TX-103 at 300; Strauss 835:1-836:1.) 75. The normal volunteer studies also examined a patient population ranging

in age from 23-40.6 In contrast, more than half of the patients that are in need of pharmacological stress imaging are typically older with a mean age of 65. (TX-103 at 386; Strauss 835:1-11.) This age difference may be important, as age can influence the response to a given pharmaceutical. (Wackers 934:9-20.) 76. The normal volunteer studies produced conflicting results regarding

tolerable dosing, and provided no information about the safety of adenosine infusions in patients
6

Biaggioni 1986 (TX-48) did not report the age of the 7 subjects tested.

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with coronary artery disease. (Strauss 826:24-831:6; Wackers 934:21-935:5, 938:19-939:1.) Moreover, the normal volunteer studies nowhere proposed using adenosine as a pharmacologic stress agent, nor did they even suggest that adenosine satisfied the perceived requirements for a pharmacologic stress agent. None of these studies characterized adenosine as a more potent coronary vasodilator than dipyridamole. (See TX-48; TX-220; TX-226; TX-1208; TX-1211.) E. Prior to the Invention of the `877 Patent Nobody In the MPI Medical Community Even Mentioned the Possibility of Using Adenosine 77. While both sides agree that dipyridamole was known to carry out its

effects, at least in part, by modulating internal adenosine levels, the prior art was noticeably devoid of suggestions to substitute adenosine for dipyridamole in human patients. A series of articles reviewing developments in MPI, including publications by both Plaintiffs' expert, Dr. Wackers, and Sicor's expert, Dr. Strauss, were published in the late 1980s. (See, e.g., TX-168; TX-170; TX-373.) None of these articles discussed or even proposed adenosine as an alternative pharmacologic stressor. (See, e.g., TX-168; TX-170; TX-373.) 78. For example, Dr. Strauss published a review article in 1986 entitled

"Myocardial Perfusion Studies: Lessons from a Decade of Clinical Use" discussing dipyridamole imaging, but not mentioning adenosine. (TX-373 at 577, 581; Strauss 779:4-8.) Indeed, an inspection of Dr. Strauss's CV reveals that prior to 1988, Dr. Strauss had never used adenosine in humans. (See TX-246; Strauss 774:2-7.) Significantly, not withstanding that he was the developer of the pharmacologic MPI stress test technique, Dr. Strauss acknowledged that none of his publications explicitly mentioned using adenosine as a pharmacological stress agent, and that he was not aware of a single publication prior to 1988 that suggested using adenosine for MPI. (Strauss 774:2-18.)

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79.

Similarly, Dr. Wackers wrote a review article in 1987 entitled "Clinical

Assessment of Myocardial Perfusion with Thallium-201." Like Dr. Strauss's article, Dr. Wackers's included a section on MPI using dipyridamole, but nowhere mentioned even the possibility of using adenosine. (See TX-170 at 60, 70; Wackers 939:7-943:19.) Notably, the review article by Dr. Wackers included a description of cutting edge techniques that were not yet commercially available. (TX-170 at 72; Wackers 942:12-943:10.) When asked why he did not discuss adenosine in this section, Dr. Wackers stated, "Nobody talked about it. Nobody wrote about it." (Wackers 943:11-19.) 80. Dr. Wackers also stated that as of 1987, he had not thought of using

adenosine as a pharmacologic stress agent, and had never heard anyone discuss using adenosine for MPI in human patients. (Wackers 943:11-19.) 81. Dr. Wackers also authored a book chapter on MPI that was published in

1988. (TX-171; Wackers 943:22-944:11.) This chapter was included in a textbook that nuclear cardiology residents and fellows read as part of their training. (Wackers 944:12-19.) As with the Strauss and Wackers review articles, the book chapter discussed dipyridamole as a pharmacologic stress agent for MPI, noting that dipyridamole is a potent dilator of the coronary arteries. (TX-171 at 45; Wackers 944:20-945:18.) The book chapter did not mention adenosine. (See TX-171; Wackers 945:19-23.) 82. A 1989 review of "Alternatives to Exercise Stress Testing" by Stratmann

and Kennedy, published during the prosecution of the `877 patent, is particularly enlightening. (See TX-168.) After reviewing 210 recent publications in the field, the article included a list of alternatives to exercise stress for evaluating coronary artery disease. (TX-168 at 1345.) The list included 11 alternatives, including 5 different pharmacologic stress agents. (TX-168 at 1345;

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Strauss 814:14-815:9.) While this list included dipyridamole, it failed to include adenosine. Indeed, the article nowhere mentioned adenosine. (See TX-168; Strauss 815:6-18.) F. The Medical Community Greeted the Invention of the `877 Patent with Skepticism and Concern 83. Drs. Daniel Hilleman and Syed Mohiuddin, the inventors of the methods

claimed in the `877 patent, were researchers at Creighton University when they overturned conventional wisdom by conceiving and conducting experiments to determine if adenosine could be safely and effectively used as a pharmacologic stress agent for MPI. (See Mohiuddin 1855:21-1857:14; Hilleman 2106:3-21.) Dr. Mohiuddin was trained as a cardiologist, Dr. Hilleman as a pharmacologist. (Mohiuddin 1856:4-13; Hilleman 2106:19-2108:3.) In the mid1980s, both were participating in clinical trials funded by Medco, the predecessor in interest to Plaintiff King, relating to the treatment of tachycardia (PSVT) with small, bolus doses of adenosine. (Salzberg 1839:1-11; Mohiuddin 1857:17-24; Hilleman 2109:13-2110:7.) 84. In the summer of 1987, Gail Salzberg, an employee of Medco responsible

for coordinating the clinical trials on adenosine as a treatment for PSVT, met with Drs. Hilleman and Mohiuddin during a site visit at Creighton University. They told her about their idea to use adenosine as a pharmacologic stress agent for MPI. (Salzberg 1838:3-24.) Ms. Salzberg testified that prior to this meeting, she had never heard anyone discuss the possibility of using adenosine for MPI--despite having met with approximately 20 cardiology groups at many different sites who were also working with Medco's adenosine. (Salzberg 1839:12-1840:11.) 1. 85. Contemporaneous Documents Capture the Concern of the Medical Community The invention of the `877 patent was greeted with skepticism and concern

by the medical community. For example, upon hearing that Drs. Hilleman and Mohiuddin planned to test adenosine in myocardial perfusion imaging, the Director of Clinical Cardiology at 25

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the University of Minnesota wrote, "I am not certain how effective and safe adenosine would be as a coronary vasodilator for this purpose. . . ." (See TX-53; Salzberg 1844:11-23.) 86. After a 1989 presentation on the use of adenosine for myocardial

perfusion imaging, Dr. Marcus, an acknowledged leader in the field, stood up and cautioned that adenosine "was not a benign drug" and that you have to watch out for heart block. (Wackers 946:11-947:11.) 87. Letters to the editor, editorials, and scientific articles in contemporaneous

journals further reflected this concern. (See, e.g., TX-169.) 88. Following a 1989 publication of the inventors describing the use of

adenosine as a pharmacologic stress agent, the Journal of Radiology published a letter to the editor written by a cardiologist named Dr. Spiegler. (See TX-67; TX-169; Wackers 948:22-949:19.) Dr. Spiegler stated that he was "particularly disturbed by the electrocardiographic changes noted during the adenosine infusion," and observed that two patients developed asymptomatic transient second degree or complete heart block. (TX-169; Strauss 816:16-818:6; Wackers 947:24-948:21.) The letter concluded that "[o]nly further investigation will determine whether this will ultimately preclude routine use of adenosine as a pharmacological stress agent." (TX-169; Strauss 816:16-818:6; Wackers 947:24-948:21.) 89. A 1990 editorial published in Circulation, one of the premier journals in

the field of cardiology, explained that the safety of infusions of adenosine at 140 mcg/kg/min still needed to be established, as did the effectiveness and safety of infusing adenosine in people with a variety of heart conditions, including significant coronary obstructions, left ventricular dysfunction, ventricular hypertrophy, predisposition to arrhythmias, and SA or AV node disease. (TX-47 at 1856 (emphasis added); Strauss 818:19-819:3; Wackers 950:3-14.) In Circulation,

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such editorials were written by experts in the field by invitation of the Editor-in-Chief of the journal. (Wackers 950:15-951:6.) 2. 90. Sicor's Expert, Dr. Strauss, Admitted that He Was Reluctant to Administer Adenosine at 140 mcg/kg/min Sicor's Dr. Strauss did not begin using adenosine as a pharmacologic

stress agent until the early 1990s, well after the filing date of the `877 patent. When Dr. Strauss finally used adenosine, he initially administered the drug not at the manufacturer recommended dose of 140 mcg/kg/min, but at a much lower dose that he gradually titrated upwards. (See TX-314; Strauss 779:9-13; 779:21-780:19.) 91. 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 782:17-783:18.) He was concerned that adenosine at 140 mcg/kg/min would induce heart block. (Strauss 782:17-783:18.) 3. 92. Unresolved Concerns Regarding Ischemia, AV Block, and Hypotension Kept Adenosine Out of the Clinic Dr. Mario Verani, acknowledged by Dr. Strauss as a leader in the field of

pharmacologic stress imaging, wrote in 1995 that the long interval between animal experiments and clinical investigations using adenosine may have resulted from concern with the ultrashort half-life of exogenous adenosine (2-10 seconds), concerns regarding the safety of large intravenous doses of a drug that could trigger severe myocardial ischemia in patients with coronary artery disease, and the potential for slowing antrioventricular conduction (i.e., AV

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block). (See TX-240 at 1038-39; see also TX-47 at 1855 (stating that fear of AV block and hypotension had limited adenosine use in patients); Strauss 805:23-809:14.) G. Adenosine Is Now Preferred as a Pharmacologic Stress Agent Because of Its Superior Safety and Speed 93. Today, both adenosine and dipyridamole are used as clinical alternatives

to physical exercise in connection with myocardial perfusion imaging. (See TX-138 at 300; Wackers 891:13-892:1.) While both drugs are considered acceptable vasodilators, adenosine has proven to have clear clinical advantages in terms of its rapid onset of action and short half-life, which makes it safer, particularly in high risk patients. (TX-138 at 300; Wackers 892:2-13, 893:13-894:3.) 94. Sicor's expert, Dr. William Strauss, admitted that he uses adenosine

because of the rapidity and safety of the