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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 REDACTED ­ PUBLIC VERSION

DEFENDANTS SICOR INC. AND SICOR PHARMACEUTICALS, INC.'S PROPOSED FINDINGS OF FACT AND CONCLUSIONS OF LAW

Josy W. Ingersoll (No. 1088) John W. Shaw (No. 3362) Karen E. Keller (No. 4489) YOUNG CONAWAY STARGATT & TAYLOR, LLP The Brandywine Building 1000 West Street, 17th Floor Wilmington, DE 19801 (302) 571-6600 [email protected] Of Counsel: David M. Hashmall, P.C. Annemarie Hassett GOODWIN PROCTER LLP 599 Lexington Avenue New York, NY 10022 (212) 813-8800 Dated: May 9, 2007 Attorneys for Defendants Sicor Inc. and Sicor Pharmaceuticals, Inc.

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TABLE OF CONTENTS I. PROPOSED FINDINGS OF FACT................................................................................. 1 A. The Parties .................................................................................................................... 1 B. The `296 Patent ............................................................................................................. 2 C. Background ................................................................................................................... 4 1. The State of the Art ................................................................................................... 4 2. Level of Ordinary Skill in the Art .............................................................................. 4 3. The Circulatory System............................................................................................. 5 4. Vasolidators Generally .............................................................................................. 5 5. Hemodynamic Parameters Relevant to Vasodilation.................................................. 6 a. Pressure (P) ......................................................................................................... 7 b. Blood Flow (F).................................................................................................... 8 c. Resistance (R) ..................................................................................................... 8 6. Adenosine ................................................................................................................. 9 7. ATP ........................................................................................................................ 13 8. Dipyridamole .......................................................................................................... 16 D. The Claimed Inventions of the `296 Patent Would Have Been Obvious in View of the Prior Art................................................................................................................ 19 1. The Scope and Content of the Prior Art ................................................................... 19 a. Sollevi I............................................................................................................. 19 b. Sollevi II ........................................................................................................... 25 c. Fukunaga Abstract............................................................................................. 28 2. A Person of Ordinary Skill Would Have Been Motivated to Find Additional Medical Uses for Adenosine .................................................................. 32 3. A Person Skilled in the Art Would Have Been Motivated to Administer Adenosine Without Dipyridamole Pretreatment....................................................... 34 4. No Secondary Factors Support Non-Obviousness.................................................... 35 a. "Side Effects" Upon Which Plaintiffs Rely........................................................ 35 (i) AV Block .................................................................................................. 36 (ii) Uric Acid Build-Up ................................................................................... 38 (iii) Excessive Fluid Load................................................................................. 38 b. There is No Evidence of Skepticism of Experts ................................................. 39 c. Adenosine Does Not Exhibit Any Unexpected Results as Compared with Dipyridamole............................................................................ 39 d. The Commercial Success of Adenoscan is Not Due to Any Alleged Superiority of the Claimed Invention................................................................. 41 (i) There was Only One Other FDA-Approved Competitor in the Pharmacological Stress-Testing Market at the Time of Adenoscan® Entry...................................................................................... 42

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(ii) Adenoscan® Became the Only Promoted Product in the Pharmacological Stress Testing Market Shortly After Its Entry.......................................................................................................... 43 (iii) Extensive Marketing and Promotion of Adenoscan® by Fujisawa .................................................................................................... 43 (1) A Concentrated Market .................................................................... 44 (2) Substantial Detailing Efforts ............................................................ 45 (3) Support of the ASNC ........................................................................ 45 (4) Physician Advocacy Program........................................................... 46 (5) Financial Incentives: Trial Support and Pumps................................ 47 (6) Educational Initiatives: The Chest Pain Initiative and the Her Heart Initiative .................................................................... 47 (7) Combining Adenosine with Exercise................................................. 48 (8) Fujisawa's Marketing and Promotion Was Extensive ....................... 49 (iv) Growth in Demand for Pharmacological Stress Testing Unrelated to the Asserted Inventions.......................................................... 50 (v) The Four Economic Factors Explain the Sales Levels Achieved by Adenoscan®, Irrespective of Any Claimed Superiority of the Product .......................................................................... 54 E. The Claimed Inventions of the `296 Patent Were Anticipated By the Prior Art...... 55 II. PROPOSED CONCLUSIONS OF LAW....................................................................... 56 A. Claims 1, 3, 7, and 9 of the `296 Patent Are Invalid As Obvious............................... 56 1. Legal Standard ........................................................................................................ 56 2. The Scope and Content of the Prior Art ................................................................... 59 3. Differences Between The Claimed Invention Of The `296 Patent And The Prior Art.................................................................................................................. 60 a. Sollevi Prior Art ................................................................................................ 60 b. Fukunaga Abstract............................................................................................. 61 4. The Sollevi Prior Art, In Combination with the Knowledge of a Person of Ordinary Skill in the Art, Renders the Asserted Claims Obvious ............................. 61 a. Element No. 1 ................................................................................................... 61 b. Element No. 2 ................................................................................................... 62 c. Element No. 3 ................................................................................................... 62 d. Element No. 4 ................................................................................................... 63 e. Element No. 5 ................................................................................................... 63 5. The Fukunaga Abstract, In Combination with the Knowledge of a Person of Ordinary Skill in the Art, Renders the Asserted Claims Obvious ......................... 64 a. Element No. 1 ................................................................................................... 64 b. Element No. 2 ................................................................................................... 65 c. Element No. 3 ................................................................................................... 65 d. Element No. 4 ................................................................................................... 65 e. Element No. 5 ................................................................................................... 66 6. No Secondary Factors Support Non-Obviousness.................................................... 66 ii

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B. Claims 1, 3, 7, and 9 of the `296 Patent Are Invalid As Inherently Anticipated....... 69 1. Legal Standard ........................................................................................................ 69 2. The Asserted Claims are Inherently Anticipated by the Fukunaga Abstract ............. 69 a. Element No. 1 ................................................................................................... 70 b. Element No. 2 ................................................................................................... 70 c. Element No. 3 ................................................................................................... 70 d. Element No. 4 ................................................................................................... 70 e. Element No. 5 ................................................................................................... 71 III. CONCLUSION ............................................................................................................... 72

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TABLE OF AUTHORITIES CASES Abbott Labs. v. Baxter Pharm. Prods., Inc., 471 F.3d 1363 (Fed. Cir. 2006) ......................................................................................69, 71 Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286 (Fed. Cir. 2006) ...................................................................................... 57-58 Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001) ........................................................................................... 69 Brown & Williamson Tobacco Corp. v. Philip Morris Inc., 229 F.3d 1120 (Fed. Cir. 2000) ................................................................................58, 59, 67 Dystar Textilefarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006) .......................................................................... 56, 57, 58, 60 Ecolochem, Inc. v. Southern Cal. Edison Co., 227 F.3d 1361 (Fed. Cir. 2000) ........................................................................................... 66 Eli Lilly & Co. v. Barr Labs, Inc., 251 F.3d 955 (Fed. Cir. 2001)........................................................................................69, 71 Graham et al. v. John Deere Co. of Kansas City et al., 383 U.S. 1 (1966) ............................................................................................................... 67 In re Bigio, 381 F.3d 1320 (Fed. Cir. 2004) ......................................................................................59, 60 In re O'Farrell, 853 F.2d 894 (Fed. Cir. 1988)............................................................................................. 58 In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) ......................................................................................58, 64 In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ........................................................................................... 59 J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563 (Fed. Cir. 1997) ........................................................................................... 67 KSR Int'l Co. v. Teleflex Inc., No. 04-1350, 2007 WL 1237837 (U.S. Apr. 30, 2007) ................................................. Passim Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) ......................................................................................56, 58 iv

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Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804 (Fed Cir. 1989).............................................................................................. 67 Newell Cos., Inc. v. Kenney Mfg. Inc., 864 F.2d 757 (Fed. Cir. 1988)..................................................................................66, 67, 68 Novo Nordisk Pharm., Inc. v. Bio-Technology Gen. Corp., 424 F.3d 1347 (Fed. Cir. 2005) ........................................................................................... 69 Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299 (Fed. Cir. 2006) .................................................................................... Passim Pentec, Inc. v. Graphic Controls Corp., 776 F.2d 309 (Fed. Cir. 1985)............................................................................................. 67 Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 58, 59, 64, 67 Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476 (Fed. Cir. 1997) ......................................................................................59, 67 Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373 (Fed. Cir. 2003) ......................................................................................69, 71 Sibia Neurosciences, Inc., v. Cadmus Pharm. Corp., 225 F.3d 1349 (Fed. Cir. 2000) ........................................................................................... 59 Tec Air, Inc. v. Denso Mfg. Michigan Inc., 192 F.3d 1353 (Fed. Cir. 1999) ........................................................................................... 67 STATUTES 21 U.S.C. § 355(b)(1) ................................................................................................................. 3 21 U.S.C. § 355(j) ...................................................................................................................... 2 21 U.S.C. § 355(j)(2)(A)(vii)(IV) ............................................................................................... 2 35 U.S.C. § 102 ........................................................................................................................ 69 35 U.S.C. § 102(b).........................................................................................................20, 25, 29 35 U.S.C. § 103(a).................................................................................................................... 56

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I. PROPOSED FINDINGS OF FACT A. The Parties 1. Plaintiff Item Development AB ("Item") is a Swedish corporation having an

office and principal place of business at Svanholmsvagen 2A, Stocksund, 18207, Sweden. (Joint Statement of Admitted Facts No. 2, Docket Index ("D.I.") 127, Ex. 1.) 2. Plaintiffs Astellas US LLC and Astellas Pharma US, Inc. (collectively "Astellas")

are both corporations organized and existing under the laws of the State of Delaware, having their principal places of business at Three Parkway North, Deerfield, Illinois 60015-2548. (Joint Statement of Admitted Facts No. 1, D.I. 127, Ex. 1.) 3. Defendants Sicor Inc. and Sicor Pharmaceuticals, Inc. (collectively "Sicor") are

both corporations organized and existing under the laws of the State of Delaware, having their principal places of business at 19 Hughes, Irvine, California 92618. (Joint Statement of Admitted Facts Nos. 3-4, D.I. 127, Ex. 1.) 4. Sicor Pharmaceuticals, Inc. is a wholly-owned subsidiary of Sicor Inc. (Joint

Statement of Admitted Facts No. 5, D.I. 127, Ex. 1.) 5. Adenoscan® (Adenosine Injection, USP) is an adenosine-based product. (Joint

Statement of Admitted Facts No. 12, D.I. 127, Ex. 1.) 6. Astellas manufactures Adenoscan® (Adenosine Injection, USP), pursuant to NDA

No. 20-059. (Joint Statement of Admitted Facts No. 11, D.I. 127, Ex. 1.) 7. Astellas sells Adenoscan® (Adenosine Injection, USP) for use as an adjunct to

thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately. (Joint Statement of Admitted Facts No. 12, D.I. 127, Ex. 1.) 8. Item is the assignee of all title, right, and interest in U.S. Patent No. 5,731,296

("the `296 patent"). (Joint Statement of Admitted Facts No. 9, D.I. 127, Ex. 1.) 1

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9.

Astellas is the exclusive licensee of certain rights under the `296 patent ( Joint

Statement of Admitted Facts No. 10, D.I. 127, Ex. 1.) 10. Pursuant to the Hatch-Waxman Act, on December 6, 2004, Sicor filed

Abbreviated New Drug Application No. 77-425 ("ANDA No. 77-425") with the U.S. Food and Drug Administration ("FDA"), seeking approval to market generic adenosine for use with myocardial perfusion imaging. ( Joint Statement of Admitted Facts Nos. 14-15, D.I. 127, Ex. 1.) 11. Sicor later amended its ANDA to incorporate a certification pursuant to 21 U.S.C.

§ 355(j)(2)(A)(vii)(IV) ("Paragraph IV certification"), asserting that the `296 patent is invalid, unenforceable or would not be infringed by Sicor's generic product. (D.I. 127.) 12. On April 16, 2005, Sicor provided a notice of its Paragraph IV certification to

Item and Astellas (collectively "Plaintiffs") in accordance with 21 U.S.C. § 355(j). (D.I. 127.) 13. 2005. (D.I. 1.) B. The `296 Patent 14. The `296 patent issued on March 24, 1998 from U.S. Patent Application No. Plaintiffs brought suit for infringement of the `296 patent in this Court on May 26,

08/031,666 ("the '666 application"), filed March 15, 1993. (TX 275.) 15. The patent is entitled "Selective Vasodilation By Continuous Adenosine

Infusion." (TX 275.) 16. 17. The named inventor on the face of the `296 patent is Alf Sollevi. (TX 275.) The `666 application is a division of U.S. Patent Application No. 07/821,395,

filed January 14, 1992, which is a continuation of U.S. Patent Application No. 07/630, 413, filed December 19, 1990, which is a continuation of U.S. Patent Application No. 07/138,306, filed December 28, 1987, which is a continuation-in-part of U.S. Patent Application No. 07/030,245,

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filed March 24, 1987, which is a continuation-in-part of U.S. Patent Application No. 06/779,516, filed September 24, 1985 (the "original Sollevi application"). (TX 275.) 18. The `296 patent has a priority date of September 24, 1985, and therefore the

relevant time for prior art is on or before September 24, 1985. (Binkley, Tr. 192:2-193:2; TX 275; DTX 3063.) 19. Pursuant to 21 U.S.C. § 355(b)(1) and the FDA regulations promulgated pursuant

thereto, the `296 patent is listed with respect to Adenoscan® in "Approved Drug Products with Therapeutic Equivalence Evaluations" ("the Orange Book"), 24th Edition, published by the FDA. (D.I. 127, Ex. 1.) The `296 patent relates to the use of adenosine to dilate arteries with little or no venous dilation. (TX 275 at col. 2, ll. 39-42.) 20. 21. 22. The `296 patent recites nine claims. (TX 275, col. 22, ll. 10-61.) At trial, Plaintiffs asserted four claims: claims 1, 3, 7, and 9. (D.I. 127, Ex. 10.) Claim 1 of the `296 patent reads as follows: A method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation and without pretreatment with dipyridamole, comprising continuously administering into the blood stream of said patient adenosine at a rate of administration of 0.35 milligrams of adenosine per kilogram body weight per minute, or less. (TX 275, col. 22, ll. 11-17; DTX 3046.) 23. Claim 3 of the `296 patent reads as follows: A method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation and without pretreatment with dipyridamole, comprising continuously administering into the blood stream of said patient by intravenous administration about 0.05 milligrams to about 0.30 milligrams of adenosine per kilogram body weight per minute. (TX 275, col. 22, ll. 20-26; DTX 3047.)

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24.

Claim 7 of the `296 patent reads as follows: A method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation and without pretreatment with dipyridamole, comprising continuously administering into the blood stream of said patient by intravenous administration about 0.01 milligrams to about 0.15 milligrams of adenosine per kilogram body weight per minute.

(TX 275, col. 22, ll. 41-47; DTX 3048.) 25. Claim 9 of the `296 patent reads as follows: A method for inducing a reduced afterload in the vascular system of a human without reducing the preload and without pretreatment with dipyridamole, the method comprising continuously administering into the blood stream of said patient adenosine at a rate of administration of 0.35 milligrams of adenosine per kilogram body weight per minute, or less. (TX 275, col. 22, ll. 55-61; DTX 3049.) 26. The specification of the `296 patent uses the term "preload" as equivalent to

dilating veins and the term "afterload" as equivalent to dilating arteries. (TX 275, col. 2, ll. 3942.) C. Background 1. The State of the Art 27. The field of art relevant to the `296 patent can be described broadly as the field of

vasodilators and the related hemodynamic parameters, with a focus on the medical uses of vasodilators. (Binkley, Tr. 95:9-24.) 2. Level of Ordinary Skill in the Art 28. The person of ordinary skill in the art to which the `296 patent pertains is a

cardiologist with a residency in internal medicine and two years of a cardiology fellowship, whose experience could also include nuclear cardiology imaging. (Binkley, Tr. 95:25-96:7.) 29. There is no real dispute between the parties concerning the definition of a

hypothetical person of ordinary skill in the art in 1985. (Klabunde, Tr. 515:15-25.)

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3. The Circulatory System 30. The circulatory system consists of the heart, the blood vessels, and the lungs.

(Binkley, Tr. 80:3-7.) It transports oxygenated blood to the organs of the body and brings poorly oxygenated blood back to the heart. (Binkley, Tr. 80:3-81:7.) 31. The function of the heart in the circulatory system is to contract rhythmically to

pump blood to the rest of the body. (Binkley, Tr. 81:11-14.) 32. Arteries are blood vessels that take oxygen-rich blood away from the heart and

transport it to the rest of the body. (Binkley, Tr. 81:15-21; DTX 3002.) 33. Veins are blood vessels that transport oxygen-poor blood back to the heart and

lungs. (Binkley, Tr. 81:22-82:2; DTX 3002.) 34. Arteries and veins are tubular structures. (Binkley, Tr. 82:4-7; DTX 3004-B.)

The inner open space in the middle of an artery or vein is called the lumen. (Binkley, Tr. 83:212; DTX 3004-B-C.) 35. Arteries and veins can change in shape in response to certain chemical

compounds in the body. (Binkley, Tr. 82:8-10.) Their lumens can expand in response to drugs called vasodilators, and contract in response to other drugs called vasoconstrictors. (Binkley, Tr. 82:8-12, 83:13-16; DTX 3004-B-C.) 4. Vasolidators Generally 36. A vasodilator causes the muscles lining the wall of an artery or vein relax,

causing the lumen to expand. (Binkley, Tr. 83:13-22; DTX 3004-B-C.) This process is called vasodilation or vasodilatation. (Binkley, Tr. 83:13-22.) 37. Vasodilators can be grouped into three classes, defined by the blood vessels on

which they act. (Binkley, Tr. 84:5-7.) Some vasodilators act predominantly to dilate veins,

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some vasodilators act predominantly to dilate arteries, and some vasodilators act equally to dilate both arteries and veins. (Binkley, Tr. 84:5-11.) 38. Vasodilators that act primarily to dilate arteries include adenosine, dipyridamole,

and hydralazine. (Binkley, Tr. 85:10-15; DTX 3004-I.) 39. Vasodilators that act primarily to dilate veins include nitrogen compounds.

(Binkley, Tr. 85:10-86:4; DTX 3004-I.) These vasodilators are also called venodilators. (Binkley, Tr. 85:13-15.) 40. Vasodilators that act equally on arteries and veins to cause vasodilation include

nitroprusside. (Binkley, Tr. 86:5-13; DTX 3004-I.) 41. Vasodilators have been used in medicine since the early 1950s, when they were

used in medication to treat hypertension (i.e., high blood pressure) by "relaxing" the blood vessels. (Binkley, Tr. 86:17-21.) For example, a vasodilator like hydralazine would be used to relax the arteries, and therefore reduce the patient's blood pressure. (Binkley, Tr. 86:17-87:12.) 42. Later, in the 1970s and early 1980s, vasodilators were also used in the treatment

of congestive heart failure and to lower blood pressure during surgical procedures. (Binkley, Tr. 87:13-24.) In the case of congestive heart failure, doctors began using vasodilators to reduce blood pressure in order to allow the weakened heart muscle to function more efficiently. (Binkley, Tr. 87:16-21.) Doctors also began using vasodilators to reduce blood pressure during surgery in order to reduce the risk of bleeding. (Binkley, Tr. 87:22-24.) 5. Hemodynamic Parameters Relevant to Vasodilation 43. A person of ordinary skill in the art at the relevant time considers certain

hemodynamic parameters to determine whether vasodilation has occurred in response to the administration of a drug. (Binkley, Tr. 88:5-22.) The relationship between these parameters can be summarized by the following equation: 6

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Pressure (P) = Blood Flow (F) * Resistance (R). (Binkley, Tr. 88:1-16; DTX 3006-A.)

a. Pressure (P) 44. Pressure (P) may be defined as the pressure that blood is exerting against the

walls of the arteries. (Binkley, Tr. 89:4-8.) Differences in this pressure at different points in a given artery are responsible for pushing blood through that artery. (Binkley, Tr. 89:9-13; DTX 3006-B.) 45. Pressure is usually described in terms of "blood pressure" or "mean arterial blood

pressure" ("MABP"), which is the average blood pressure in a vessel during one complete cardiac cycle. (Binkley, Tr. 91:5-17; DTX 3008-F.)

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46.

The "cardiac cycle" is defined as the time period beginning from the time that the

heart begins to contract and pump blood to the rest of the body to the time it is fully relaxed, filled with blood, and ready to contract again. (Binkley, Tr. 91:18-23.) b. Blood Flow (F) 47. Blood flow (F) may be defined as the volume of blood that passes a given point in

an artery per unit time (e.g., mL/min) and is usually described in terms of "cardiac output" ("CO"). (Binkley, Tr. 89:14-90:1; DTX 3009-C.) 48. Cardiac output can be calculated by multiplying a patient's "stroke volume" by

his or her "heart rate." (Binkley, Tr. 92:18-93:5; DTX 3009-C.) 49. "Stroke volume" is the amount of blood that the heart pumps out each time it

contracts, and it is measured in milliliters or liters per heartbeat. (Binkley, Tr. 92:20-93:1; DTX 3009-C.) 50. The "heart rate" is the number of times the heart beats each minute. (Binkley, Tr.

93:2-4; DTX 3009-C.) 51. As the product of the stroke volume and the heart rate, cardiac output is measured

in either milliliters or liters per minute. (Binkley, Tr. 93:4-8; DTX 3009-C.) c. Resistance (R) 52. Resistance (R) may be defined as the resistance by the artery against blood flow,

and is often described in terms of systemic vascular resistance ("SVR"). (Binkley, Tr. 90:6-11, 94:6-10; DTX 3006-D; DTX 3011-A-C.) 53. Vasodilation is essentially a decrease in resistance because it occurs when blood

vessels relax, allowing the lumen to widen and the blood to flow more freely. (Binkley, Tr. 83:13-22; 88:5-11; 93:11-94:5; 94:11-16.)

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54.

Vasodilation can be detected through changes in the hemodynamic parameters.

(Binkley, Tr. 88:5-16; 90:12-19; DTX 3011-A-C.) In other words, measurements of MABP and cardiac output can be used to determine changes in arterial and venous resistance. (Binkley, Tr. 88:5-16.) 55. For example, if MABP (i.e., pressure) decreases and CO (i.e., flow) increases or

remains the same, then resistance in the arteries, i.e., SVR, must have also decreased. (Binkley, Tr. 94:17-95:7; DTX 3011-B-C.) This relationship between the hemodynamic parameters is summarized by the following equation: Pressure (P) ·= Blood Flow (F) · * Resistance (R) ·. (Binkley, Tr. 94:6-95:7; DTX 3011-B.) From such information, i.e., if MABP decreases and CO increases or remains the same, a person of ordinary skill in the art would conclude that arterial vasodilation had occurred. (Binkley, Tr. 94:17-95:13.) 56. In the same example as the one described in paragraph 55, since CO did not

decrease, a person of ordinary skill would conclude that there was little or no venous dilation. (Binkley, Tr. 95:5-13.) If venous dilation had occurred, a decrease in flow would be expected. (Binkley, Tr. 95:11-13.) 57. All of the facts recited supra in paragraphs 30-56 would have been known to a

person of ordinary skill in the art at the beginning of September 1985. (Binkley, Tr. 96:14-18.) 6. Adenosine 58. Adenosine is a naturally-occurring compound that contributes to a variety of

physiological processes in nearly every cell of the human body. (TX 275, col. 1, ll. 22-28; Binkley, Tr. 96:23-97:7; DTX 3013-C; DTX 3014-A-C.) Adenosine that is produced naturally in the body is called "endogenous adenosine." (Binkley, Tr. 97:12-18.)

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59.

Adenosine can also be administered from outside the body. (Binkley, Tr. 96:23-

97:7.) Adenosine that is supplied from outside the body is called "exogenous adenosine." (Binkley, Tr. 97:19-21.) 60. Endogenous adenosine has an important auto-regulatory function and behaves as

a vasodilator, dilating coronary arteries in response to circumstances that require increased levels of oxygen in the body (e.g., physical exertion). (Binkley, Tr. 97:22-98:4, 98:15-21; DTX 3014C-E.) 61. Molecules of adenosine in the bloodstream can either be metabolized, i.e.,

eliminated through a process of converting adenosine to another substance, or bound to receptors in the artery wall through which the adenosine will act. (Binkley, Tr. 102:4-103:24; DTX 3014A-C, see white "cones.")

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62.

When adenosine is metabolized, it is taken up by the red blood cell or certain sites

on the artery wall and acted on by an enzyme called adenosine deaminase, which breaks the adenosine down into molecules such as hypoxanthine and inosine. (Binkley, Tr. 103:7-18; DTX 3014-A-C, see green "pacmen.") 63. When adenosine binds to receptors in the artery wall, the smooth muscle cells in

the artery relax, causing the artery to dilate. (Binkley, Tr. 103:19-24; DTX 3014-A-C, see blue "pacmen.") 64. When the body is at rest, there is a certain amount of endogenous adenosine that

regulates the resting tone of the artery. (Binkley, Tr. 104:5-6.) When the body increases its

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demand for oxygen (e.g., during exercise), the body increases its production of adenosine. (Binkley, Tr. 105:13-106:13; DTX 3014-C.) 65. The increase in adenosine in the bloodstream necessarily results in an increase of

the amount of adenosine binding to the receptors in the arterial wall; the effect is an increase in the relative degree of arterial vasodilation. (Binkley, Tr. 105:13-106:13; DTX 3014-C-E.) The more adenosine that is produced, the greater the magnitude of arterial vasodilation. (Binkley, Tr. 103:25-104:13.) 66. All of the facts recited supra in paragraphs 58-65 would have been known to a

person of ordinary skill in the art at the beginning of September 1985. (Binkley, Tr. 99:4-7, 106:23-107:4.) 67. Adenosine's potent vasodilator effects were recognized in the art as early as 1929,

when Drs. A.N. Drury and A. Szent-Gyorgy published an article in the Journal of Physiology entitled "Physiological Activity of Adenine Compounds with Especial Reference to their Action Upon the Mammalian Heart." (Binkley, Tr. 99:4-22; TX 35.) In this foundation article, Drs. Drury and Szent-Gyorgy observed that adenosine and adenosine nucleotides "lower general arterial pressure. This is due in part to the cardiac slowing and in part to a general arterial dilation." (Binkley, Tr. 99:23-101:17; TX 35 at 236; DTX 3055.) 68. As discussed supra in paragraph 42, during the time period from the early 1970s

to the 1980s, there was an increasing focus on the use of selective arterial vasodilators (like adenosine) to treat a number of cardiovascular conditions, including congestive heart failure and hypertension. (Binkley, Tr. 86:17-87:24.)

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69.

A seminal publication in Circulation Research by Dr. Robert Berne in 1980, "The

Role of Adenosine in the Regulation of Coronary Blood Flow," observed that "adenosine is a very active vasodilator." (Binkley, Tr. 110:21-111:3; TX 228 at 807; DTX 3056.) 70. Dr. Berne's article resulted in numerous animal and clinical studies to explore

adenosine's medical uses. (See, e.g., TX 36, TX 37, TX 40, TX 45, TX 88, TX 236, TX 1170, TX 1187, TX 5000.) 7. ATP 71. Adenosine triphosphate ("ATP") is a substance that is found in the human body

and is composed of an adenosine molecule bound to a "tail" composed of three phosphate molecules. (Binkley, Tr. 106:14-18, 107:22-108:24; TX 228; DTX 3016-A, see blue triangles.) 72. Within the body, ATP is constantly converted to adenosine by a reaction that is

fundamental to human metabolism. (Binkley, Tr. 108:1-109:9; DTX 3016-A-H.) An enzyme called 5'-nucleotidase sequentially clips each of the phosphates off of the "tail," first converting the adenosine triphosphate to adenosine diphosphate, then to adenosine monophosphate, and then ultimately to adenosine. (Binkley Tr. 108:1-109:9, 113:17-114:3; Klabunde, Tr. 1083:9-16, 1107:3-7; DTX 3016-A-H.) 73. This conversion is nearly immediate, as noted in several references published in

the early 1980s, including one co-authored in 1984 by Dr. Sollevi. (Binkley, Tr. 109:10-15, 111:8-112:17, 1418:21-1419:5; TX 228 at 807-08; TX 236 at 547; TX 5000 at 1196.) In 1980, Dr. Berne observed that "it is virtually impossible to make accurate measurements of ATP in venous blood since the nucleotide is rapidly degraded in blood and also can be released from the cellular elements of the blood." (TX 228 at 807 (emphasis added); see also Binkley, Tr. 111:23112:17.) In 1984, Dr. Sollevi wrote that ATP was nearly immediately converted to adenosine following administration: 13

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Using a quantitative HPLC method for purine determination, we recently have demonstrated that ATP given by the iv route is degraded entirely to adenosine and its breakdown products during the transpulmonary passage. (TX 236 at 547; see also Binkley, Tr. 109:10-15, 111:8-112:17, 1418:21-1419:5; TX 228 at 80708; TX 5000 at 1196.) 74. The reaction that causes ATP to be constantly converted to adenosine would have

been known to a person of ordinary skill in the art in 1985. (Binkley, Tr. 107:22-109:20, 109:25110:10, 111:8-22; Klabunde, Tr. 1043:21-23.) 75. The conversion of ATP to adenosine is equimolar. (Binkley, Tr. 1415:19-1416:9;

TX 88 at 174.) "Equimolar" means that a certain number of ATP molecules are converted to the same number of molecules of adenosine. (Binkley, Tr. 1416:4-9.) 76. A number of references disclosed that exogenous ATP is converted rapidly and

completely to adenosine following the administration of ATP. In 1984, Dr. Sollevi wrote as follows: The arterial plasma adenosine concentration during ATP infusions was similar to that found during an equimolar infusion of adenosine. Moreover, similar arterial plasma concentrations of adenosine were found at similar hypotensive levels, whether adenosine or ATP was given . . . (TX 88 at 173-175; see also Binkley, Tr. 1409:15-19, 1411:17-1414:6; Klabunde, Tr. 1125:231126:13; TX 36 at 1262; TX 236 at 547.) 77. Like adenosine, ATP causes selective arterial vasodilation when administered

intravenously. (Binkley, Tr. 396:20-24, 397:3-17.) This property led to the use of ATP to induce controlled hypotension in surgical patients. (Binkley, Tr. 161:24-162:9; TX 42.) 78. By the early 1980s, it was known that the vasodilative effects of ATP are due to

its breakdown to adenosine ­ not the actions of the ATP itself. In June 1984, Dr. Berne wrote:

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In the guinea pig heart the AV conduction delay and block caused by adenosine triphosphate is due to its degradative product, adenosine. Thus, it is probable that in humans, as in the case of the guinea pig, adenosine triphosphate must be hydrolyzed to adenosine to exert its effect. Hence, it is adenosine that is the active agent. (TX 5000 at 1196 (emphasis added); see also Binkley, Tr. 112:22-113:16, 115:2-116:3, 166:12167:1, 179:13-180:6, 396:16-397:17, 1410:2-21, 1412:17-1413:11, 1414:23-1416:22, 1420:61421:10; Klabunde, Tr. 1107:3-12; TX 51 at A39; TX 88 at 174-175; TX 228 at 807; TX 236 at 547 n.6.) 79. In September 1984, Dr. A.F. Fukunaga wrote: ATP, a purine nucleotide, when administered parenterally is rapidly hydrolyzed to Ad[enosine] . . . Most of the hemodynamic effects of ATP, however, are attributed to Ad[enosine] because of the speed of this hydrolysis in the blood. (TX 51 at A39; see Klabunde, Tr. 1107:3-12; DTX 3061.) Dr. Fukunaga's 1984 article teaches a person of ordinary skill in the art in 1985 that ATP causes vasodilation through its conversion to adenosine. (Binkley, Tr. 178:14-18; TX 51 at A39.) 80. Dr. Sollevi also published several papers in the early 1980s plainly stating that the

vascular effects of ATP were due to its conversion to adenosine. (TX 88 at 174-75; TX 236 at 547.) In one paper, Dr. Sollevi expressly recommended the use of adenosine instead of ATP to induce controlled hypotension: We therefore consider it more appropriate to use adenosine instead of ATP to induce controlled hypotension. (TX 236 at 547; see Klabunde, Tr. 1164:5-22.) 81. to adenosine: Hence the vascular effects of parenterally administered ATP are due mainly to adenosine. In another paper, Dr. Sollevi stated several times that the effects of ATP were due

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[T]he present data suggest that adenosine mediates the vasodilatory effects of exogenously administered ATP. In conclusion, the present experiments demonstrate that intravenously administered ATP is eliminated from plasma before reaching the arterial vascular bed where it may cause hypotension. Furthermore, the vasodilatory effect of ATP and adenosine was directly proportional to the arterial adenosine level. (TX 88 at 174-175; see Binkley, Tr. 396:4-23; Klabunde, Tr. 1128:15-17.) 82. The view that the vasodilative effects of ATP are due to its breakdown to

adenosine was widely-held in the early 1980s, and would have been understood by a person of ordinary skill in the art in 1985. (Binkley, Tr. 112:22-113:16, 115:2-116:3, 166:12-167:1, 178:14-19, 179:13-180:6, 181:17-22, 396:16-397:17, 1410:2-21, 1412:17-1413:11, 1414:231416:22, 1420:6-1421:10; Klabunde, Tr. 1043:21-23, 1107:3-12, 1124:18-1126:13, 1127:181128:1, 1164:5-22, 1174:16-20; TX 51 at A39; TX 88 at 174-175; TX 151 at 107-111; TX 228 at 807; TX 236 at 547 n.6.) 83. A person of ordinary skill in the art in 1985 would know that this is because the

receptors in the blood vessel walls that are responsible for vasodilation were known to bind primarily to adenosine, not ATP. (Binkley, Tr. 1434:4-1435:6, 1435:12-1438:2; Klabunde, Tr. 1169:8-1174:20; TX 151 at 110-111; TX 152 at 195, 196.) 8. Dipyridamole 84. In the late 1970s, dipyridamole was being studied for new uses. (Binkley, Tr.

354:24-355:15; TX 93.) 85. Dipyridamole had long been used as a vasodilator, and its mechanism of action

has been understood since at least the 1970s. (Binkley, Tr. 355:16-356:8; TX 101 at 21; TX 228 at 809.)

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86.

A person of ordinary skill in the art in 1985 would have known that the

administration of dipyridamole and the administration of adenosine have the same net result ­ an increase of adenosine in the bloodstream. (Binkley, Tr. 117:16-118:13, 119:15-22, 131:1-14, 181:9-13, 355:16-356:8; Klabunde, Tr. 1092:22-1094:1, 1095:11-21, 1165:2-15; TX 101 at 21; TX 228 at 809.) 87. Dipyridamole functions as a "middle man" by blocking adenosine deaminase, an

enzyme responsible for adenosine uptake and metabolism. (Binkley, Tr. 117:16-118:13, 119:1522, 131:1-14, 181:9-13, 355:16-356:8; Klabunde, Tr. 1092:22-1094:1, 1095:11-21, 1165:2-15; TX 101 at 21; TX 228 at 809; DTX 3020-A-D.) 88. As described supra in paragraphs 61-63, adenosine can either be taken up and

metabolized or it can bind to receptor sites in the artery wall to cause vasodilation. 89. When dipyridamole is administered, endogenous adenosine is still able to bind to

the receptor sites, but the dipyridamole blocks the uptake of any adenosine and its subsequent metabolism. (Binkley, Tr. 131:16-132:13; DTX 3020-A-B, see purple semicircles.) As a result, endogenous adenosine builds up within the body because it is no longer being rapidly eliminated from the bloodstream. (Binkley, Tr. 117:16-118:13, 119:15-22, 131:1-14, 132:15-16, 136:18-22, 181:9-13, 356:1-8; Klabunde, Tr. 1095:11-21, 1165:2-15; DTX 3020-B.)

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90.

The build-up of endogenous adenosine following the administration of the

dipyridamole leads to vasodilation, since the increase in the amount of adenosine that is binding to the receptor sites causes the walls of the arteries to relax. (Binkley, Tr. 132:14-133:1; DTX 3020-B-D.) 91. While the net effect of the administration of adenosine and dipyridamole is the

same, i.e., the increase of adenosine in the bloodstream, a person of ordinary skill in the art in 1985 would have known that the effects of dipyridamole lasted much longer than the effects of adenosine, due to the much longer "half life" of dipyridamole. (Binkley, Tr. 133:2-16.) 92. The term "half life" refers to the amount of time that will elapse before half of the

concentration of a given compound will break down. (Klabunde, Tr. 503:12-16.)

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93.

The half life of dipyridamole is 30 to 40 minutes. (Binkley, Tr. 133:2-12,

1381:18-22, 1400:6-1402:14; TX 1173 at 167; TX 1177 at 1080.) 94. The half life of adenosine is about 10 to 30 seconds. (Binkley, Tr. 107:11-21;

Klabunde, Tr. 502:17-22.) 95. Another difference between the action of dipyridamole and that of adenosine is

that the onset of the effects of dipyridamole occurs later than the onset of the effects of adenosine. (Binkley, 134:3-9; DTX 3022.) Since dipyridamole acts by increasing the concentration of adenosine already present in the body, the accumulation of adenosine and its resultant effects occur gradually over time. (Binkley, Tr. 133:21-136:6; DTX 3022.) D. The Claimed Inventions of the `296 Patent Would Have Been Obvious in View of the Prior Art 1. The Scope and Content of the Prior Art 96. Claims 1, 3, 7, and 9 of the `296 patent are invalid as obvious in view of each of

the following three references in combination with the general knowledge of a person of ordinary skill in the art in 1985: (1) A. Sollevi et al., Cardiovascular effects of adenosine during controlled hypotension in cerebral artery aneurysm surgery, Anesthesiology (Circulation II) 59(3): A9 (Sept. 1983) ("Sollevi I"); (2) A. Sollevi et al., Cardiovascular effects of adenosine in man, Acta Physiol. Scan. 120(2): 11A (Feb. 1984) ("Sollevi II"); and (3) A.F. Fukunaga et al., ATP-induced hypotensive anesthesia during surgery, Anesth. & Anesthesiology, 57(3): A65 (1982) ("Fukunaga Abstract"). (Binkley, Tr. 119:23-121:2; TX 275; TX 1170; TX 37; TX 42.) a. Sollevi I 97. In September 1983, an abstract was published in the journal Anesthesiology

entitled "Cardiovascular Effects of Adenosine During Controlled Hypotension in Cerebral

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Aneurysm Surgery" ("Sollevi I"). (Binkley, Tr. 123:10-13, 123:19-22; TX 1170.) Dr. Sollevi, the inventor named on the face of the `296 patent, was listed as the first-named author. (Binkley, Tr. 123:14-18; TX 275; TX 1170.) 98. Sollevi I is prior art to the `296 patent under 35 U.S.C. § 102(b) because it was

published more than one year before the priority date of the `296 patent (i.e., September 24, 1985). (Binkley, Tr. 123:10-13; TX 275; TX 1170; DTX 3059.) 99. Sollevi I describes an investigation of the cardiovascular effects of adenosine on

nine patients who were anesthetized and undergoing surgery for cerebral aneurysms. (Binkley, Tr. 123:23-124:5, 125:9-12; TX 1170 at A9.) The term "controlled hypotension" refers to maintaining a reduction in blood pressure at a target level. (Binkley, Tr. 124:6-12.) The investigators monitored the hemodynamic effects associated with controlled hypotension following the administration of adenosine following a dipyridamole pretreatment. (Binkley, Tr. 123:23-124:5; TX 1170 at A9.) 100. A person of ordinary skill in the art in 1985 would understand that Sollevi I

teaches the administration of a continuous intravenous infusion of adenosine at a mean dose of 140 µg/kg/min, following pretreatment with dipyridamole, to induce controlled hypotension in nine anesthetized patients undergoing surgery for cerebral aneurysms. (Binkley, Tr. 124:25125:22, 126:24-127:9; TX 1170 at A9; DTX 3025; DTX 3026.) 101. Dipyridamole was administered 10 to 30 minutes prior to the administration of

adenosine "to inhibit cellular adenosine uptake" and to reduce the total required dose of adenosine. (Binkley, Tr. 130:2-9, 136:10-22, 1374:8-16; TX 1170 at A9.) Adenosine was subsequently administered to induce controlled hypotension at the desired level. (Binkley, Tr. 130:6-9, 137:20-138:9; TX 1170 at A9.) The duration of the controlled hypotension depended

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upon the length of time that the adenosine was administered. (Binkley, Tr. 130:6-9; TX 1170 at A9.) 102. Following administration of adenosine, Sollevi I reported a mean reduction in

mean arterial blood pressure ("MABP") of 43%. (Binkley, Tr. 127:10-128:15, 129:17-19; Sollevi, Tr. 483:11-16; TX 1170 at A9; DTX 3027.) Sollevi I teaches a person of ordinary skill in the art in 1985 that the significant decrease in MABP shows that the administration of adenosine resulted in selective arterial vasodilation, since arteries reduce pressure by dilating. (Binkley, Tr. 128:3-12.) 103. Following administration of adenosine, Sollevi I reported a relatively large mean

decrease in systemic vascular resistance ("SVR") of 61%. (Binkley, Tr. 128:16-129:7, 129:2022; TX 1170 at A9; DTX 3028.) Sollevi I teaches a person of ordinary skill in the art in 1985 that the significant drop in SVR suggests that the administration of adenosine resulted in selective arterial vasodilation, since arteries reduce resistance by dilating. (Binkley, Tr. 128:24129:7.) 104. Following administration of adenosine, Sollevi I reported a large increase in

cardiac output of 43%. (Binkley, Tr. 129:8-16; TX 1170 at A9; DTX 3029.) Sollevi I teaches a person of ordinary skill in the art in 1985 that the large increase in CO shows that the administration of adenosine resulted in selective arterial vasodilation, since the increase in CO indicates that there was no venodilation. (Binkley, Tr. 130:10-22.) 105. Based on the disclosed changes in MABP, SVR, and CO, Sollevi I would teach a

person of ordinary skill in the art at the relevant time that the intravenous administration of 140 µg/kg/min of adenosine would selectively dilate the arteries of a human patient without inducing significant venous dilation. (Binkley, Tr. 128:3-10, 130:10-22, 146:10-21; DTX 3030.) As

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described supra in paragraphs 56-57, a decrease in SVR coupled with a decrease in MABP and an increase in cardiac output a is a strong indication that dilation of arteries occurred. (Binkley, Tr. 94:17-95:7.) An increase in cardiac output would also indicate that little or no venous dilation occurred. (Binkley, Tr. 94:22-95:13.) 106. Almost one half-life of dipyridamole (30-40 minutes) elapsed by the time the

adenosine was administered (33 minutes into the treatment), yet the drop in blood pressure was observed in the Sollevi I study within two minutes after the adenosine administration began. (Binkley, Tr. 145:4-20; TX 1170 at A9; DTX 3064.) The timing of this drop in blood pressure indicates that the potency of the blocking action of dipyridamole described supra in paragraphs 88-91 would have decreased significantly by the time the adenosine administration began. (Binkley, Tr. 143:25-145:3, 145:21-146:7; DTX 3064.) 107. The decrease in MABP was sustained at the same level throughout the continuous

adenosine administration ­ regardless of the varying level of dipyridamole present. (Binkley, Tr. 142:24-143:4, 143:25-146:8; DTX 3064.) Based on the teachings of the prior art, a person of ordinary skill in the art in 1985 would understand that the administration of adenosine alone would cause some degree of selective arterial vasodilation. (Binkley, Tr. 139:17 141:7, 160:121.) This understanding would be supported by the maintenance of controlled hypotension for each patient despite the different intervals between the dipyridamole and adenosine treatments and the different lengths of the overall treatment with adenosine. (Binkley, Tr. 139:17 141:7, 160:1-21.) 108. A person of ordinary skill in the art in 1985 would understand that dipyridamole

alone did not cause the "profound" hypotension reported in Sollevi I. (Klabunde, Tr. 1166:4-9.) Therefore, a person of ordinary skill in the art in 1985 would conclude that the hemodynamic

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parameters observed in Sollevi I were mainly due to the action of exogenous adenosine, and not the action of dipyridamole. (Binkley, Tr. 143:25-145:3, 145:21-146:7; DTX 3064.) 109. Sollevi I reported that blood pressure rapidly returned to its baseline value after

the adenosine administration was stopped. (Binkley, Tr. 143:17-24; TX 1170 at A9.) This rapid return to baseline would suggest to a person of ordinary skill in the art in 1985 that there was very little dipyridamole remaining by the end of the adenosine administration, and would motivate such a person to conclude that the dipyridamole pretreatment could be omitted given that exogenous adenosine alone appeared to sustain the reduction in blood pressure. (Binkley, Tr. 146:25-147:21.) 110. Sollevi I concludes by referring to the intravenous administration of adenosine

without dipyridamole pretreatment and states: ADO in low molar concentrations rapidly induced a remarkably stable and easy reversible CH in man (see Fig 1), by a profound reduction in SVR concomitant with increased CO . . . It is concluded that the hemodynamic and metabolic properties of adenosine make it a suitable agent for CH in man. (Binkley, Tr. 136:23-137:8, 146:25-147:21; TX 1170 at A9; DTX 3030; DTX 3059; DTX 3064.) Sollevi I defines "ADO" as adenosine and "CH" as controlled hypotension. (TX 1170 at A9.)

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111.

There is no reference to the need for dipyridamole pretreatment in the conclusion

in Sollevi I. (TX 1170 at A9.) A person of ordinary skill in the art in 1985 would understand, based on the conclusion set forth in Sollevi I, that adenosine could be administered without dipyridamole to cause selective dilation of the arteries of a human patient without inducing significant venous dilation. (Binkley, Tr. 136:23-138:9, 139:17-140:8, 143:25-146:7, 146:25147:21.) 112. A person of ordinary skill in the art in 1985 would understand that the

investigators in the Sollevi I study had achieved a substantial amount of selective arterial vasodilation through the combination of the administration of dipyridamole and adenosine, and that eliminating dipyridamole and administering the same or a higher dose of adenosine would

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enable a physician to achieve selective arterial vasodilation, even if not to the same great (and often unnecessary) magnitude. (Sollevi, Tr. 486:9-12; Binkley, Tr. 139:17-141:7.) b. Sollevi II 113. In February 1984, an abstract was published in the journal Acta Physiologica

Scandinavica entitled "Cardiovascular Effects of Adenosine in Man" ("Sollevi II"). (Binkley, Tr. 147:23-148:7, 148:13-15; TX 37.) Dr. Sollevi, the inventor named on the face of the `296 patent, was listed as the first-named author. (Binkley, Tr. 148:8-12; TX 275; TX 37.) 114. Sollevi I is prior art to the `296 patent under 35 U.S.C. § 102(b) because it was

published more than one year before the priority date of the `296 patent (i.e., September 24, 1985). (Binkley, Tr. 148:4-7; TX 37; TX 275; DTX 3060.) 115. Sollevi II discloses, in part, the same results from the same clinical study reported

in Sollevi I, and further includes data from a tenth patient and information on the observed levels of certain adenosine metabolites. (Binkley, Tr. 148:16-22, 150:4-7; Sollevi, Tr. 482:20-483:16; compare TX 1170, TX 37.) 116. Sollevi II teaches the administration of a continuous intravenous infusion of

adenosine at a molar dose that is equivalent to 140 µg/kg/min to induce controlled hypotension in ten anesthetized patients undergoing surgery for cerebral aneurysms. (Binkley, Tr. 148:16-22; TX 37 at 11A:C16; DTX 3032; DTX 3033.) A dose of 0.5 µmol is equivalent to a dose of 138.62 µg (approximately 140 µg), based upon the molecular weight of adenosine provided in the Adenoscan package insert (267.24). (Binkley, Tr. 149:1-14; TX 75 at 1; DTX 3032.) A person of ordinary skill in the art in 1985 would have been able to perform this straightforward conversion calculation. (Binkley, Tr. 149:3-14.)

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117.

It is explained in Sollevi II that the "adenosine uptake inhibitor" dipyridamole

was administered prior to the administration of adenosine. (Binkley, Tr. 148:16-22, 149:9-16, 151:25-152:9, 159:2-4; TX 37 at 11A:C16.) 118. Sollevi II reported a mean reduction in MABP of 43% and a relatively large mean

decrease in SVR of 61%. (Binkley, Tr. 149:17-150:3; TX 37 at 11A:C16; DTX 3034; DTX 3035.) Sollevi II teaches a person of ordinary skill in the art in 1985 that the significant decrease in MABP and the large drop in SVR suggest that the administration of adenosine resulted in selective arterial vasodilation, since arteries reduce pressure by dilating. (Binkley, Tr. 150:8-19.) 119. Sollevi II also reported a large increase in cardiac output of 40%. (Binkley, Tr.

149:17-150:3; TX 37 at 11A:C16; DTX 3036.) Sollevi II teaches a person of ordinary skill in the art in 1985 that the large increase in CO suggests that the administration of adenosine resulted in selective arterial vasodilation, since one would expect a decrease in CO if there was any venodilation. (Binkley, Tr. 150:8-19.) 120. Based on these results, Sollevi II would teach a person of ordinary skill in the art

at the relevant time that the intravenous administration of 140 µg/kg/min of adenosine would selectively dilate the arteries of a human patient without inducing significant venous dilation. (Binkley, Tr. 150:8-151:24; DTX 3037.) As described supra in paragraphs 55-56, a decrease in SVR coupled with a decrease in MABP and an increase in cardiac output is a strong suggestion that dilation of arteries occurred. (Binkley, Tr. 94:17-95:7.) An increase in cardiac output would also indicate that little or no venous dilation occurred. (Binkley, Tr. 94:22-95:13.) 121. Sollevi II reports that the adenosine concentration in the plasma returned to

baseline levels within three to nine minutes of discontinuing the adenosine infusion. (Binkley, Tr. 152:10-153:25; TX 37 at 11A:C16.) Sollevi II also reports that after the adenosine

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administration was stopped, mean arterial blood pressure returned to its baseline values within one to two minutes. (Binkley, Tr. 154:18-22; TX 37 at 11A:C16.) This data would suggest to a person of ordinary skill in the art in 1985 that the blocking action of dipyridamole described supra in paragraphs 87-90 would have decreased significantly by the time the adenosine administration began, such that the changes in the hemodynamic parameters observed in Sollevi II were due to the action of exogenous adenosine, not the action of dipyridamole. (Binkley, Tr. 154:1-17, 154:23-155:14.) 122. Sollevi II concludes by referring to the administration of adenosine without the

use of a dipyridamole pretreatment: These results indicate that adenosine may be used to achieve controlled hypotension in man since it acts as a rather pure arteriolar vasodilator with rapid onset, sustained action and rapid elimination. (TX 37 at 11A:C16; see also Binkley, Tr. 158:22-160:21; DTX 3037; DTX 3060.)

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123.

There is no reference to the need for dipyridamole pretreatment in the conclusion

in Sollevi II. (Binkley, Tr. 159:8-18; TX 37 at 11A:C16.) Therefore, a person of ordinary skill in the art in 1985 would understand, based on the conclusion set forth in Sollevi II, that adenosine could be administered without dipyridamole to cause selective dilation of the arteries of a human patient without inducing significant venous dilation. (Binkley, Tr. 154:1-155:14, 158:5-160:21.) c. Fukunaga Abstract 124. In September 1982, an abstract was published in the journal Anesthesiology

entitled "ATP-Induced Hypotensive Anesthesia During Surgery" ("the Fukunaga Abstract").

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(Binkley, Tr. 161:24-162:4; TX 42.) Dr. Fukunaga was listed as the first-named author. (Binkley, Tr. 162:4-5; TX 42.) 125. The Fukunaga Abstract is prior art to the `296 patent under 35 U.S.C. § 102(b)

because it was published more than one year before the priority date of the `296 patent (i.e., September 24, 1985). (Binkley, Tr. 162:2-3; TX 275; TX 42; DTX 3058.) 126. The Fukunaga Abstract discloses the intravenous administration of ATP at a dose

of 200 to 600 µg/kg/min to induce controlled hypotension. (Binkley, Tr. 162:6-13; TX 42 at A65.) Blood pressure was reduced to a target value of a 40 percent reduction in 27 anesthetized patients undergoing surgery. (Binkley, Tr. 162:6-13, 163:19-165:11, 169:18-170:14; TX 42 at A65; DTX 3039-A; DTX 3040.) 127. The term "controlled hypotension" as used in the Fukunaga Abstract is defined in

the same manner as it is defined in Sollevi I and II--a reduction in blood pressure to some established target value. (Binkley, Tr. 162:21-163:2.) Here, that value is a 40 percent reduction in the baseline blood pressure value. (Binkley, Tr. 162:21-163:2.) 128. Dipyridamole was not administered in the study reported in the Fukunaga

Abstract. (Binkley, Tr. 170:15-17; TX 42 at A65.) 129. As discussed supra in paragraphs 71-83, since exogenous ATP rapidly and

completely breaks down to adenosine shortly after its administration, a person of ordinary skill in the art in 1985 would have known to use a simple molar conversion calculation to calculate that 200 to 600 µg/kg/min of ATP is equivalent to doses of between 97 and 290 µg/kg/min of adenosine. (Binkley, Tr. 167:6-168:18; DTX 3039-A-B.) This calculation is based upon the known molecular weights of those molecules. (Binkley, Tr. 167:20-169:7; DTX 3039-A-B.) To

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perform this calculation, a person of ordinary skill would have multiplied the ratio of the molecular weights of adenosine (261) and ATP (551) by the dose of ATP that was administered: 261/551 * Dose of ATP = Dose of Adenosine. (Binkley, Tr. 167:22-168:7; DTX 3039-B.) This range overlaps each of the ranges recited in the asserted claims of the `296 patent. (Binkley, Tr. 171:6-15; TX 275.) 130. The Fukunaga Abstract teaches a person of ordinary skill in the art in 1985 that

MABP decreased significantly, by 40 percent. (Binkley, Tr. 164:13-25; TX 42 at A65; DTX 3041.) 131. The Fukunaga Abstract teaches a person of ordinary skill in the art in 1985 that

SVR decreased significantly. (Binkley, Tr. 165:16-18; TX 42 at A65; DTX 3042.) 132. The Fukunaga Abstract teaches a person of ordinary skill in the art in 1985 that

cardiac output was "well maintained" or increased. (Binkley, Tr. 165:16-21; TX 42 at A65; DTX 3043.) 133. The teachings of the Fukunaga Abstract would lead a person of ordinary skill in

the art in 1985 to conclude that selective arterial dilation without significant venous dilation had occurred. (Binkley, Tr. 163:9-18; 165:22-166:7; DTX 3058.) As described supra in paragraphs 55-56, a decrease in SVR coupled with a decrease in MABP and an increase in cardiac output is a strong indication that dilation of arteries occurred. (Binkley, Tr. 94:17-95:7.) Since cardiac output is maintained and is not decreasing, a person of ordinary skill would conclude that little or no venous dilation occurred. (Binkley, Tr. 166:3-7.)

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134.

A person of ordinary skill in the art in 1985 would understand that the active

agent causing the selective arterial vasodilation in the Fukunaga Abstract was adenosine. (Binkley, Tr. 166:12-17.) Such a person would understand, as discussed supra in paragraphs 7183, that ATP is rapidly and completely degraded to adenosine and that adenosine would be the mediator of arterial vasodilation. (Binkley, Tr. 166:12-167:1.) 135. The Fukunaga Abstract does not report the occurrence of any serious side effects

following administration of ATP. (Binkley, Tr. 202:8, 202:11-203:1, 225:20-24; TX 42 at A65.) 136. A subsequent publication by Fukunaga concerned the administration of ATP

following a pretreatment with dipyridamole. (TX 51, referred to herein as "Fukunaga 1984.") Fukunaga 1984 would teach a person of ordinary skill in the art that dipyridamole could be a

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"potentially useful added agent," and is not a requirement for safe and effective selective arterial vasodilation. (Binkley, Tr. 182:20-183:4.) 137. The fact that administration of dipyridamole with ATP reduced the amount of

ATP that was required to induce controlled hypotension, as reported in Fukunaga 1984, would confirm to a person of ordinary skill in the art that adenosine ­ not ATP ­ was responsible for the vasodilation. (TX 51 at A39.) A person of ordinary skill would understand that dipyridamole does not block ATP uptake in the blood, but dipyridamole does block adenosine. (Klabunde, Tr. 1167:15-20.) A person of ordinary skill would therefore understand that the ATP concentration would not be increased by dipyridamole, but the adenosine concentration would be. (Klabunde, Tr. 1167:21-1168:1.) 138. Common sense would tell a person of ordinary skill in the art that the reduction in

the amount of ATP needed to induce controlled hypotension when a dipyridamole pretreatment was used would only be possible if adenosine was the active agent and played a substantial role in vasodilation following the administration of ATP. (Binkley, Tr. 179:13-24; 181:17-22.) 2. A Person of Ordinary Skill Would Have Been Motivated to Find Additional Medical