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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 REDACTED ­ PUBLIC VERSION

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

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

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TABLE OF CONTENTS Page I. PROPOSED FINDINGS OF FACT ................................................................................ 1 A. The Parties .......................................................................................................... 1 B. The `877 Patent ................................................................................................... 2 C. The Asserted Claims Would Have Been Obvious In Light Of The Prior Art....................................................................................................................... 5 1. Level Of Ordinary Skill In The Art .......................................................... 5 2. Scope And Content Of The Prior Art ....................................................... 5 a. Myocardial Perfusion Imaging ..................................................... 6 b. Pharmacologic Stress With MPI Was Known In The Art.............. 7 c. That Dipyridamole Acts Through Adenosine Was Known In The Art .................................................................................... 8 d. Safe Doses For Continuous Intravenous Infusion Of Adenosine To Humans Were Known In The Art ........................ 10 i. Sollevi 1986.................................................................... 11 ii. Sollevi 1984.................................................................... 12 iii. Owall.............................................................................. 13 iv. Biaggioni 1986 ............................................................... 14 v. Conradson ...................................................................... 15 vi. Fuller .............................................................................. 16 vii. Biaggioni 1987 ............................................................... 16 viii. The `296 Patent............................................................... 17 e. The Use Of Adenosine For MPI Was Known In The Art ............ 17 3. There Was Ample Reason To Use Adenosine In Place of Dipyridamole As A Pharmacologic Stress Agent For MPI ..................... 19 4. A Person Of Ordinary Skill In The Art Would Have Had A Reasonable Expectation That Adenosine Would Work For MPI............. 21 5. The Difference Between The Asserted Claims And The Prior Art.......... 23 6. No Secondary Indicia Weigh Against the Strong Showing of Obviousness........................................................................................... 24 a. No Unexpected Results .............................................................. 24 b. No Long Felt Need..................................................................... 25 c. No Skepticism or Teaching Away .............................................. 25 d. Any Commercial Success Of Adenoscan® Is Not Due To Any Alleged Superiority Of The Claimed Invention ................... 25 i. There Was Only One Other FDA-Approved Competitor In The Pharmacological Stress-Testing Market At The Time Of Adenoscan® Entry.................... 26 ii. Adenoscan® Became The Only Promoted Product In The Pharmacological Stress Testing Market Shortly After Its Entry .................................................... 27 iii. Extensive Marketing And Promotion of Adenoscan® By Fujisawa............................................... 28 (1) A Concentrated Market ....................................... 28 -iDB01:2085107.1 058956.1016

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D.

Substantial Detailing Efforts................................ 29 Support Of The ASNC ........................................ 29 Physician Advocacy Program.............................. 30 Financial Incentives: Trial Support And Pumps ................................................................. 31 (6) Educational Initiatives: The Chest Pain Initiative And The Her Heart Initiative ................ 31 (7) Combining Adenosine With Exercise .................. 32 (8) Fujisawa's Marketing And Promotion Was Extensive ............................................................ 33 iv. Growth In Demand For Pharmacological Stress Testing Unrelated To The Asserted Inventions................ 34 v. The Four Economic Factors Explain The Sales Levels Achieved By Adenoscan®, Irrespective Of Any Claimed Superiority Of The Product ....................... 38 The `296 Patent And/Or The Karolinska Request Disclose The Elements Of The Asserted Claims .................................................................................... 39 1. The `296 Patent And The Karolinska Request Are Prior Art................... 39 a. Priority Date Of The `877 Patent Claims .................................... 39 b. The Priority Date Of Example XIII Of The `296 Patent .............. 40 c. The Priority Date Of The Karolinska Request............................. 40 2. Every Element Of The Asserted Claims Is Disclosed In The `296 Patent..................................................................................................... 41 3. Every Element Of Claims 23(17) and 43 Is Disclosed In The Karolinska Request ................................................................................ 42

(2) (3) (4) (5)

II.

PROPOSED CONCLUSIONS OF LAW ...................................................................... 42 A. Claims 23(17), 23(18) and 43 of the `877 Patent Are Invalid As Obvious .......... 42 1. The Law Of Obviousness....................................................................... 42 2. Scope Of The Prior Art .......................................................................... 45 3. The Combination Of Either Gould 1978 Or Albro And Sollevi 1986 Renders The Asserted Claims Obvious.......................................... 46 4. The Combination Of Either Gould 1978 Or Albro And Biaggioni 1986 Renders The Asserted Claims Obvious.......................................... 48 5. Either Gould 1978 Or Albro In Light Of Knowledge In Art Concerning Adenosine Infusion Renders The Asserted Claims Obvious ................................................................................................. 49 6. Plaintiffs Present No Persuasive Secondary Indicia ................................ 50 B. Claims 23(17), 23(18) and 43 of the `877 Patent Are Invalid As Anticipated........................................................................................................ 51 1. Legal Standard....................................................................................... 51 2. The `296 Patent Anticipates And/Or Renders Obvious The Asserted Claims ..................................................................................... 52 3. The Karolinska Request ......................................................................... 53 CONCLUSION............................................................................................................. 53

III.

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TABLE OF AUTHORITIES Page CASES Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286 (Fed. Cir. 2006) ........................................................................................... 43 Amazon.com, Inc. v. Barnesandnoble.com, Inc., 239 F.3d 1343 (Fed. Cir. 2001) ........................................................................................... 45 Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313 (Fed. Cir. 2003) ................................................................................ 45, 51-52 Atofina v. Great Lakes Chemical Corp., 441 F.3d 991 (Fed. Cir. 2006)........................................................................................ 52-53 Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001) ........................................................................................... 51 Brown & Williamson Tobacco Corp. v. Philip Morris, Inc., 229 F.3d 1120 (Fed. Cir. 2000) ................................................................................ 44-45, 51 Dystar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006) ...................................................................................... 42-44 Graham v. John Deere Co., 383 U.S. 1 (1966) ............................................................................................................... 42 In re Bigio, 381 F.3d 1320 (Fed. Cir. 2004) ........................................................................................... 46 In re Huang, 100 F.3d 135 (Fed. Cir. 1996)............................................................................................. 45 In re O'Farrell, 853 F.2d 894 (Fed. Cir. 1988)............................................................................................. 44 In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ........................................................................................... 45 KSR Int'l Co. v. Teleflex Inc., 550 U.S. -- (2007)........................................................................................................ Passim Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) ................................................................................42, 47, 53

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Newell Cos., Inc. v. Kenney Manuf. Co., 864 F.2d 757 (Fed. Cir. 1989)........................................................................................44, 51 Novo Nordisk Pharm, Inc. v. Bio-Technology Gen. Corp., 424 F.3d 1347 (Fed. Cir. 2005) ........................................................................................... 51 Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299 (Fed. Cir. 2006) .................................................................................... Passim Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) .................................................................................... Passim Richardson-Vicks Inc. v. UpJohn Co., 122 F.3d 1476 (Fed. Cir. 1997) ......................................................................................44, 51 Sibia Neurosciences, Inc. v. Cadus Pharm. Corp., 225 F.3d 1349 (Fed. Cir. 2000) ........................................................................................... 45 Symbol Techs., Inc. v. Opticon, Inc., 935 F.2d 1569 (Fed. Cir. 1991) ........................................................................................... 45 Tec Air, Inc. v. Denso Mfg. Michigan Inc., 192 F.3d 1353 (Fed. Cir. 1999) ........................................................................................... 51 STATUTES 21 U.S.C. § 355 .......................................................................................................................... 2 35 U.S.C. § 102 .............................................................................................................51, 52, 53 35 U.S.C. § 103(a).................................................................................................................... 42

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I.

PROPOSED FINDINGS OF FACT A. 1. The Parties Plaintiff King Pharmaceuticals Research and Development, Inc. ("King") is a

Delaware corporation having a principal place of business in Cary, NC. (Joint Statement of Admitted Facts No. 2, D.I. 133.) 2. Plaintiff Astellas US LLC is a limited liability Delaware corporation having a

principal place of business in Deerfield, IL. Plaintiff Astellas Pharma US, Inc. is a Delaware corporation having a principal place of business in Deerfield, IL. (Collectively, "Astellas"). (Joint Statement of Admitted Facts No. 1, D.I. 133.) 3. Defendant Sicor Inc. is a Delaware corporation having a principal place of

business in Irvine, CA. Defendant Sicor Pharmaceuticals, Inc. is a Delaware corporation having a principal place of business in Irvine, CA. (Collectively, "Sicor"). (Joint Statement of Admitted Facts Nos. 3-4, D.I. 133.) 4. Sicor Pharmaceuticals, Inc. is a wholly-owned subsidiary of Sicor Inc. (Joint

Statement of Admitted Facts No. 5, D.I. 133.) 5. Adenoscan® (Adenosine Injection, USP) is an adenosine-based product. (Joint

Statement of Admitted Facts No. 12, D.I. 133.) 6. Astellas manufactures Adenoscan® (Adenosine Injection, USP) pursuant to NDA

No. 20-059. (Joint Statement of Admitted Facts No. 11, D.I. 133.) 7. Astellas markets Adenoscan®, as a pharmacologic stress agent for use with

myocardial perfusion imaging ("MPI"). (Joint Statement of Admitted Facts Nos. 11-12, D.I. 133.)

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8.

The United States Patent 5,070,877 (the "`877 patent") is assigned on its face to

MedCo Research, Inc. (Joint Statement of Admitted Facts Nos. 6-7, D.I. 133.) King is the current assignee of the `877 patent. (Joint Statement of Admitted Facts No. 9, D.I. 133.). 9. Astellas is the exclusive licensee of certain rights under the `877 patent. (Joint

Statement of Admitted Facts No. 10, D.I. 133.) 10. Pursuant to the Hatch-Waxman Act, Sicor filed an Abbreviated New Drug

Application with the U.S. Food and Drug Administration ("FDA") seeking approval to market generic adenosine for use with MPI on December 6, 2004. (Joint Statement of Admitted Facts No. 14, D.I. 133.) 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 `877 patent is invalid, unenforceable or would not be infringed by Sicor's generic product. (D.I. 1.) 12. On April 16, 2005, Sicor provided a notice of its Paragraph IV certification to

King and Astellas (collectively "Plaintiffs") in accordance with 21 U.S.C. § 355 (j). (D.I. 1.) 13. 2005. (D.I. 1.) B. 14. (TX 320.) 15. The original application leading to issuance of the `877 patent was filed on The `877 Patent U.S. Patent 5,070,877 ("the `877 patent") issued on December 10, 1991. Plaintiffs brought suit for infringement of the `877 patent in this Court on May 26,

August 11, 1988. (TX 320 at col.1, ll.4-6.) A continuation-in-part application, number 330,156, was filed on March 29, 1989, and the `877 issued from from application number 330,156 on Dec. 10, 1991. (TX 320.)

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16.

The `877 patent relates to use of the adenosine, and adenosine derivatives and

analogues, as pharmacologic stress agents in connection with MPI. (Strauss, Tr.642:17-643:2; TX 320.) 17. The named inventors on the face of the `877 patent are Syed M. Mohiuddin and

Daniel E. Hilleman. (TX 320.) 18. The `877 patent includes 47 claims. (TX 320.) At trial, Plaintiffs asserted three

claims: claim 23 as read through claim 17 ("claim 23(17)"); claim 23 as read through claim 18 ("claim 23(18)"); and claim 43. (Tr. 600:7-13.) 19. Claim 17 states: 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 20 mcg/kg/minute to about 200 mcg/kg/minute of an adenosine receptor agonist 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 at col.8, ll.53-65.) 20. Claim 18 states: The method of claim 17 wherein said adenosine receptor agonist is administered by intravenous infusion in a dosage of about 140 mcg/kg/minute. (TX 320 at col.8, ll.66-68.) 21. Claim 23 states: The method of claim 17, 19 or 18, wherein said adenosine receptor agonist is adenosine.

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(TX 320 at col.9, ll.34-35.) 22. Claim 43 states: A method of detecting the presence and assessing the severity of coronary artery disease in a human comprising the steps of: (a) administering to said human by intravenous infusion about 20 mcg/kg/minute to about 200 mcg/kg/minute of adenosine in order to provide coronary artery dilation; (b) administering thallium-201 to said human ; and (c) performing scintigraphy on said human in order to detect the presence and assess the severity of coronary artery disease. (TX 320 at col.10, l.66-col.11, l.9.) 23. Asserted claims 23(17) and 43 recite doses of adenosine in the range of about 20-

200 mcg/kg/minute. (TX 320 at claims 17, 43.) 24. Asserted claim 23(18) recites a dose of adenosine of about 140 mcg/kg/minute.

(TX 320 at claim 18.) 25. On its face, the priority date of the `877 patent is August 11, 1988. The priority

date of the `877 patent is no earlier than March 14, 1988. (Wackers, Tr. 1010:12-23, 1012:2-5, 1013:1-12, 1015:23-1016:1.) 26. The named inventors had not conceived of using a dose of adenosine in the range

of 20-200 mcg/kg/minute prior until at least March 14, 1988. (Wackers, Tr. 1010:12-15, 1013:112, 1015:23-1016:1; see also TX 57.) 27. The named inventors had not conceived of using a dose of 140 mcg/kg/minute

until at least March 14, 1988. (Wackers, Tr. 1010:16-18, 1012:2-5, 1015:23-1016:1; see also TX 57.)

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C.

The Asserted Claims Would Have Been Obvious In Light Of The Prior Art 1. Level Of Ordinary Skill In The Art

28.

The fields of art relevant to the `877 patent include cardiology, nuclear

cardiology, and nuclear medicine. (Strauss, Tr. 644:12-21; Wackers, Tr. 898:12-14.) 29. A person of ordinary skill in the art at the relevant time would have been a

practicing physician who either was trained in cardiology, with additional training in nuclear cardiology, or was trained in nuclear medicine, with additional training in cardiology. (Strauss, Tr. 646:4-14; Wackers, Tr. 898:15-20.) 2. 30. Scope And Content Of The Prior Art

The relevant prior art includes references within the fields of cardiology, nuclear

cardiology and/or nuclear medicine, or that are otherwise pertinent to the question of using a pharmacologic stress agent for MPI. (Strauss, Tr. 644:12-21; Wackers, Tr. 898:12-14.) 31. Dr. Wackers testified that the 1986 article titled Cardiovascular Effects of

Adenosine in Man; Possible Clinical Implications, by A. Sollevi ("Sollevi 1986," TX 1171) was "pertinent." (Wackers, Tr. 927:11-15.) 32. Dr. Wackers did not dispute the relevance of any of the other references on which

Dr. Strauss relied in his obviousness analysis. (Wackers, Tr. 900:21-24.) 33. Several of the references on which Dr. Strauss relied in his analysis, such as the

1984 Sollevi reference, Controlled Hypotension with Adenosine in Cerebral Aneurysm Surgery ("Sollevi 1984," TX 112); the 1987 Owall reference, Clinical Experience with Adenosine for Controlled Hypotension during Cerebral Aneurysm Surgery ("Owall," TX 1169); and the 1987 Fuller reference, Circulatory and respiratory effects of infused adenosine in conscious man ("Fuller," TX 1208), were identified by the inventors in the references section of their own study Protocol. (TX 57 at 9-10.) 5
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34.

Named inventor Dr. Hilleman testified that his general practice was to cite articles

that are relevant to the research being conducted, and he assumed that he followed his general practice in connection with the Protocol. (Hilleman, Tr. 2128:15-19, 2129:9-23.) 35. Several of the references cited by the inventors in the reference section of their

Protocol (TX 57 at 9-10) were not cited during prosecution of the `877 patent (TX 320). These include Albro et al., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilatation, ("Albro", TX 93); Gould et al., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilatation, ("Gould 1978", TX 38); Sollevi 1984 (TX 112); Fuller (TX 1208); and Owall (TX 1169) (compare TX 57 at 9-10 with TX 320). a. 36. Myocardial Perfusion Imaging

MPI is an imaging technique that provides images of the distribution of blood

flow to the heart. (Strauss, Tr. 647:12-17.) MPI is performed by injecting a tracer (also referred to as a radiotracer or radionuclide) into a patient at conditions of rest and stress then comparing the images to identify any areas of reduced blood flow. (Strauss, Tr. 635:13-22, 647:12-17.) 37. MPI requires the patient to experience "stress" because it creates a disparity in

blood flow between healthy vessels, which are able to dilate, and stenosed or blocked vessels, which cannot dilate or expand to accommodate greater demand for blood. (Strauss, Tr. 648:10649:2.) 38. The radioactive tracer is injected into the patient in order to capture an image of

the differential in flow between the vessels. (Strauss, Tr. 649:16-651:6; DTX3068-70.) 39. MPI is used to identify the presence and severity of coronary artery disease in

humans by comparison of the difference in flow between conditions of rest and stress. (Strauss, Tr. 635:10-22.) 6
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b. 40.

Pharmacologic Stress With MPI Was Known In The Art

In February 1978, K. Lance Gould, M.D., et al., published a seminal work

entitled, Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilation ("Gould 1978"), describing MPI during pharmacologic coronary vasodilatation. (Strauss, Tr. 662:2-663:6; TX 38.) 41. Gould 1978 describes the clinical feasability and methodology of performing MPI

by continuous infusion of a pharmacological stress agent. (Strauss, Tr. 663:10-664:4; TX 38 at 279.) 42. Gould 1978 uses dipyridamole as the pharmacological stress agent. (Strauss, Tr.

664:13-18; TX 38 at 279.) 43. The method described in Gould 1978 includes a continuous infusion of

dipyridamole to human patients for a period of four minutes to dilate the coronary vessels and increasing coronary blood flow to aid in detecting coronary artery disease. (Strauss, Tr. 662:23663:5, 663:10-20, 665:3-666:7; TX 38 at 280-81.) 44. Gould 1978 further describes injection of thallium-201 after completion of the

dipyridamole infusion, and the use of a gamma camera to obtain scintigraphic images. (Strauss 662:17-22, 664:23-665:2; TX 38 at 280-81.) 45. Gould 1978 describes the expected increase in coronary blood flow caused by the

dipyridamole infusion. (Strauss, Tr. 665:3-13; TX 38 at 284.) 46. Gould 1978 discusses an earlier study that reported changes in coronary blood

flow from dipyridamole infusion in 28 patients. According to Gould 1978, the average increase in coronary flow shown in the study was four times baseline control values. However, there was a "wide standard deviation" because three of the 28 patients showed an increase of less than three times baseline blood flow. (TX 38 at 284; see also Strauss, Tr. 663:10-20.) 7
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47.

Gould 1978 describes the safe and effective continuous intravenous infusion of a

pharmacologic stress agent to patients, in order to cause vasodilatation and the resultant increased blood flow, for purposes of using MPI as a diagnostic tool. (Strauss, Tr. 663:10-20, 664:5-12, 665:21-666:7; TX 38 at 279.) 48. In 1978 a publication entitled, Noninvasive Assessment of Coronary Stenoses by

Myocardial Imaging During Pharmacologic Coronary Vasodilation, by Albro et al. ("Albro") describes the continuous intravenous infusion of dipyridamole as a pharmacologic stress agent for use with MPI in humans. (Strauss, Tr. 667:15-22; TX 93 at 752.) 49. 752.) 50. Albro demonstrated that pharmacologic coronary vasodilatation is as effective as The radio tracer used in Albro is thallium-201. (Strauss, Tr. 667:15-22; TX 93 at

treadmill exercise in creating myocardial perfusion abnormalities detectable with thallium-201 imaging in humans. (Strauss, Tr. 667:15-22; TX 93 at 751.) Albro states: However, sensitivity and specificity in identifying significant coronary stenoses were identical for dipyridamole and exercise images. (TX 93 at 759.) c. 51. That Dipyridamole Acts Through Adenosine Was Known In The Art

Prior to 1987, the mechanism of dipyridamole was known in the art. (Wackers,

Tr. 908:19-24.) 52. Albro describes the mechanism of dipyridamole as preventing the inactivation of

adenosine by adenosine deaminase in the red blood cells and the lung and myocardial tissues, leading to an increase in endogenous adenosine. (Strauss, Tr. 669:10-670:1; TX 93 at 758-59.) 53. Specifically, Albro states that:

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Dipyridamole may induce coronary vasodilatation by several mechanisms. Adenosine, a product of adenine nucleotide utilization in myocardial tissue, has vasodilator activity and has been proposed as a coronary vasoregulator. Dipyridamole prevents inactivation of adenosine by adenosine deaminase in the red blood cells and lung and myocardial tissues, either by inhibiting adenosine deaminase or by preventing the uptake of adenosine into these tissues. (TX 93 at 758.) 54. A person of ordinary skill in the art at the time would understand from this

portion of Albro that "if dipyridamole is selected as the vasodilator, that the effector drug, if you will, is adenosine . . . ." (Strauss, Tr. 670:12-18.) 55. The 1985 edition the textbook of pharmacology commonly used by students and

physicians in 1985, Goodman and Gilman, states that dipyridamole acts, at least in part, through the metabolism and transport of adenosine and adenosine nucleotides. In particular, dipyridamole inhibits the uptake of adenosine by erythrocytes and other cells. (Strauss, Tr. 679:16-680:7; TX 39 at 822.) 56. Goodman and Gilman states of dipyridamole: The actions of dipyridamole seem to be linked, at least in part, to the metabolism and transport of adenosine and adenine nucleotides; in particular, dipyridamole inhibits the uptake of adenosine by erythrocytes and other cells. Adenosine, which is released from the hypoxic myocardium, is a coronary vasodilator and appears to be an important signal for the autoregulation of coronary blood flow. (TX 39 at 822.) 57. Based on this portion of Goodman & Gilman, a person of skill in the art at the

time would understand that when dipyridamole is infused, it is acting through adenosine to cause vasodilation. (Strauss, Tr. 680:8-22.) 58. A March 1987 article entitled, Cardiovascular effects of infused adenosine in

man: potentiation by dipyridamole, by Conradson et al. ("Conradson"), describes how the 9
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cardiovascular effects of dipyridamole in man, at least in part, are mediated by the the potentiation of the cardiovascular actions of the increased endogenous adenosine. (Strauss, Tr. 682:17-24, 683:8-13; TX 220 at 387.) 59. Conradson states that:

Dipyridamole inhibits the cellular update of adenosine which results in a potentiation of the cardiovascular actions of adenosine ... [t]here is also evidence that the cardiovascular effects of dipyridamole in man, at least in part, are mediated by endogenous adenosine. (TX 220 at 387 (internal citations omitted).) 60. A person of skill in the art would understand from Conradson that dipyridamole

acts through adenosine. (Strauss, Tr. 683:8-13.) 61. United States Patent No. 5,731,296 (the "`296 patent") states that, "[m]ost data

concerning the mechanism of action of dipyridamole's vasodilatory effect in fact support the view that it is solely due to adenosine vasodilation." (TX 275, col.21, ll.49-51; see Strauss, Tr. 684:12-685:2.) 62. The statement concerning dipyridamole's mechanism of action, as set forth in the

`296 patent, reflects the state of knowledge in the art in 1987. (Strauss, Tr. 684:12-685:6.) 63. A 1987 "Patient's Informed Consent" form to be used by Dr. Mario Verani and

his group at Baylor College of Medicine in connection with use of adenosine for MPI states that "[a]lthough the drug dipyridamole is used to dilate the coronary vessels, the ultimate substance that effectively causes the vasodilation is called adenosine, which is made available in higher amounts by dipyridamole administration." (TX 52 at AST0009469.) d. 64. Safe Doses For Continuous Intravenous Infusion Of Adenosine To Humans Were Known In The Art

By mid-1987, safe doses of adenosine that could be administered by continuous

infusion and that would result in vasodilation were known in the art. 10
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65.

In 1987, pharmaceutical grade adenosine for intravenous administration to

humans had only recently become available. TX52 at AST009465; Tr. 1023:22-1024:4.) Medco, the original assignee of the `877 patent, was the only source of pharmaceutical grade adenosine at the time. Tr. 1854:22-1855:16; see also Tr., 2119:13-2120:10.) 66. The ability to obtain adenosine in pharmaceutical grade from Medco was

sufficiently valuable that it was the only consideration either named inventor received for assigning all rights to the `877 patent to Medco. Tr. 1896:9-18; 1897:9-14; Hilleman, Tr. 2148:5-23.) 67. Absent a source of pharmaceutical grade adenosine, anyone wishing to use

intravenous adenosine in humans would have to purify chemical grade adenosine and qualify it as suitable for intravenous infusion to humans. See Strauss, Tr. 671:6-672:16.) i. 68. Sollevi 1986

A November1986 publication entitled, Cardioavascular Effects of Adenosine in

Man; Possible Clinical Implications, by Dr. A. Sollevi ("Sollevi 1986") describes infusing adenosine at a rate of 80 mcg/kg/minute. (TX 1171 at 335.) Sollevi 1986 further states that this infusion rate was associated with a "doubling of the myocardial blood flow." (Strauss, Tr. 702:21-703:14, 704:3-9; TX 1171 at 335, Fig.11.) Sollevi 1986 also states that "[t]his study is additional evidence for adenosine being an extremely effective coronary vasodilator in man." (TX 1171 at 335). 69. Sollevi 1986 states that a dose of 30-50 mcg/kg/minute caused a 100 percent

increase in graft flow. (Strauss, Tr. 704:22-705:5; TX 1171 at 335.) Sollevi 1986 further states that the "data demonstrate that intravenously administered adenosine can produce preferential coronary vasodilation in man." (TX 1171 at 335; see also Strauss, Tr. 704:22-705:5.)

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70.

Sollevi 1986 describes adenosine infusion doses greater than 200 mcg/kg/minute

as inducing controlled hypotension in anesthetized patients. (Strauss, Tr. 701:4-9; TX 1171 at 333.) 71. Sollevi 1986 did not report any instances of AV block in connection to the doses

required to produce controlled hypotension. (Strauss, Tr. 702:2-6; TX 1171.) 72. The summary chart at the conclusion of Sollevi 1986 states that a property of the

"low dose" of 20-50 mcg/kg/minute of adenosine is "preferential myocardial vasodilation." (TX 1171 at 345, Table 6.) 73. The summary chart at the conclusion of Sollevi 1986 also describes a "mean

dose" of 50-150 mcg/kg/minute and a "high dose" of 150-350 mcg/kg/min. (TX 1171 at 345, Table 6.) 74. Sollevi 1986 states that "adenosine may be used in many clinical situations as a

vasodilator, antiaggregatory compound as well as an antiarrythmic agent. Its effect is easy to control due to the extremely short plasma half-life." (TX 1171 at 345.) 75. A person of ordinary skill in the art would have understood from Sollevi 1986 that

there was a range of doses of adenosine from about 20 mcg/kg/min at the low end to about 200 mcg/kg/min at the high end that would cause vasodilation and the related increased blood flow, but would not result in hypotension. (Strauss, Tr. 708:10-709:12; 705:19-707:2; 747:10-748:13; 748:22-749:20.) ii. 76. Sollevi 1984

A 1984 article entitled, Controlled Hypotension with Adenosine in Cerebral

Aneurysm Surgery, by Dr. A. Sollevi ("Sollevi 1984") describes continuous intravenous infusion of adenosine for the purpose of inducing controlled hypotension in anesthetized patients undergoing cerebral aneurysm surgery. (Strauss, Tr. 692:12-23; TX 112.) 12
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77.

Sollevi 1984 describes adenosine doses of 200-300 mcg/kg/minute as causing

hypotension in anesthetized patients without an initial dose of dipyridamole. (Strauss, Tr. 695:616; TX 112 at 403, n.tt.) 78. Sollevi 1984 describes several advantagous features of adenosine. Specifically,

Sollevi 1984 states that "[t]he rapidity of onset and termination, stability of action, maintenance of cardiac output, and decrease in oxygen demand differentiate adenosine from other antihypotensive agents. These excellent properties justify further clinical investigation." (TX 112 at 404.) 79. Sollevi 1984 did not report any instances of AV block. (Strauss, Tr. 696:2-

697:11, 698:13-15.) 80. A person of skill in the art would have understood from Sollevi 1984 that

continuous intravenous infusion of adenosine would result in a stable state of coronary vasodilatation. (Strauss, Tr. 699:4-17.) 81. A person of skill in the art would have understood from Sollevi 1984 that

continuous intravenous infusion of adenosine is relatively safe, even at doses exceeding 200 mcg/kg/min. (Strauss, Tr. 699:4-17.) iii. 82. Owall

An article by Dr. Owall et al. ("Owall") published in March 1987 entitled,

Clinical Experience with Adenosine for Controlled Hypotension during Cerebral Aneurysm Surgery, describes results from adenosine infusion in a series of 47 anesthetized patients without pretreatment with dipyridamole. (Strauss, Tr. 721:8-22; TX 1169.) 83. Owall describes infusion rates from 88-530 mcg/kg/minute, with a mean dose

required to produce hypotension of about 210 mcg/kg/minute. (Strauss, Tr. 723:3-7, 724:20725:5; TX 1169 at 230, 232.) 13
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84.

Owall concludes that "adenosine induces a stable and easily controlled

hypotension without negative effects on cardiac output or acid-base balance in patients undergoing cerebral aneurysm surgery during neurolept anesthesia." (TX 1169 at 233; see also Strauss, Tr. 724:20-725:11.) 85. A person of skill in the art would have understood from Owall that one would

need an infusion dose of adenosine of about 200 mcg/kg/minute or more to achieve hypotension and, once the desired result was achieved, one could maintain it for a prolonged period of time. (Strauss, Tr. 724:20-725:11; TX 1169.) iv. 86. Biaggioni 1986

A 1986 publication entitled, Cardiovascular effects of adenosine infusion in man

and their modulation by dipyridamole, by Biaggioni et al. ("Biaggioni 1986"), describes continuous intravenous infusion of adenosine to seven conscious healthy volunteers at rates of 10, 20, 40, 60, 80, 100 and 140 mcg/kg/min. (Strauss, Tr. 711:1-14, 712:14-16; TX 48 at 2230.) Each infusion rate was maintained for 15 minutes. (Strauss, Tr. 711:9-14; TX 48 at 2230.) 87. The duration of infusion of each dose is significant. Only a few minutes are

needed for MPI, so even the 15 minute duration of one of the doses is longer than would be necessary to perform MPI. (Strauss, Tr. 711:20-712:13) 88. Biaggioni 1986 described total adenosine infusions of either 1-1/2 or 1-3/4 hours.

(Strauss, Tr. 711:22-712:13, 717:10-15; see TX 48 at 2230.) 89. Of the seven patients described in Biaggioni 1986, five tolerated a dose of 140

mcg/kg/minute and all patients tolerated a dose of 100 mcg/kg/minute. (Strauss, Tr. 712:14713:1; TX 48 at 2231.) 90. According to Biaggioni 1986, the study shows "that adenosine administered by

infusion over the range of 60 to 140 µg/kg/min to healthy conscious human subjects, lowers 14
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diastolic blood pressure but raises heart rate, systolic blood pressure and levels of plasma norepinephrine." (TX 48 at 2234; see Strauss, Tr. 718:6-16.) 91. The increase in systolic blood pressure coupled with the decrease in diastolic

blood pressure reported in Biaggioni 1986 indicates that the subjects had a "very significant vasodilation response to the adenosine infusion." (Strauss, Tr. 718:4-719:2.) 92. Biaggioni 1986 also describes the side effects experienced by the conscious

subjects at the highest tolerated infusion rates. The side effects included headache, subjective flushing in the head and neck, nervousness and an urge to breathe deeply, and they "disappeared immediately after discontinuation of the infusion." (TX 48 at 2233; see Strauss, Tr. 715:4-8.) 93. A person of ordinary skill in the art would understand from Biaggioni 1986 that

adenosine could be safely, continuously infused to conscious humans for extended periods of time at rates up to 140 mcg/kg/min and that the adenosine infusion would cause vasodilation. (Strauss, Tr. 719:3-18.) v. 94. Conradson

Conradson, published in March 1987, describes stepwise infusion rates in

conscious human subjects of 20 mcg/kg/min to a maximum of 100 mcg/kg/min in eight normal volunteers. Each dose was administered for six minutes. (Strauss, Tr. 726:23-727:15; TX 220 at 388.) 95. All eight subjects described in Conradson tolerated 70 mcg/kg/min; six of eight

tolerated 90 mcg/kg/min; and three of the eight tolerated 100 mcg/kg/min. (Strauss, Tr. 726:19727:5; TX 220 at 388.) 96. The duration of the adenosine infusions in Conradson exceeds the time necessary

for MPI. (Strauss, Tr. 727:13-15.)

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97.

Conradson reported side effects such as headache, backache, neck ache, pain in

arms and legs, jaw ache, abdominal pain, chest cramp, blocked noce and dry mouth. (TX 220 at 389.) These side effects disappeared within 2 minutes after cessation of the adenosine infusion. (Strauss, Tr. 728:22-5; TX 220 at 388-89.) 98. A person of ordinary skill in the art would understand from Conradson that

adenosine could be safely, continuously infused to conscious humans at rates up to 100 mcg/kg/min. (Strauss, Tr. 728:19-729:3.) vi. 99. Fuller

An article by Dr. Fuller, et al., ("Fuller") published in September 1987 and

entitled, Circulatory and Respiratory Effects of Infused Adenosine in Conscious Man, describes adenosine infusion beginning at 12 mcg/kg/min and increasing to 25, 50, and 100. (Strauss, Tr. 729:13-730-9; TX 1208 at 310.) 100. Each dose of adenosine was infused for 6 to 7 minutes. (Strauss, Tr. 729:19-730-

4; TX 1208 at 310.) 101. Two of the six subjects described in Fuller tolerated 200 mcg/kg/min for 1 and 2

minutes, respectively. (Strauss, Tr. 730:16-22; TX 1208 at 311.) 102. A person of skill in the art would understand from Fuller that adenosine could be

safely, continously infused to conscious humans at a rate of at least 100 mcg/kg/min and up to 200 mcg/kg/min. (Strauss, Tr. 731:1-12.) vii. 103. Biaggioni 1987

An article published in December1987 by Biaggioni et al. ("Biaggioni 1987")

entitled, Cardiovascular and Respiratory Effects of Adenosine in Conscious Man, describes adenosine infusion at rates of 80-180 mcg/kg/minute to healthy male volunteers. (Strauss, Tr. 732:6-733:6; TX 226.) 16
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104.

Eight subjects are discussed in connection with the continuous intravenous

infusion of adenosine described in Biaggioni 1987. Each of the eight subjects tolerated an infusion rate of 140 mcg/kg/minute. (Strauss, Tr. 732:17-22; TX 226 at 781-82, Fig.3, 784-86.) 105. Biaggioni 1987 states that the adenosine infusions produced dose-dependent

increases in heart rate and systolic blood pressure and decreases in diastolic blood pressure. (TX 226 at 781, Fig.3, see also Strauss, Tr. 736:8-13.) 106. A person of ordinary skill in the art would understand from Biaggioni 1987 that

adenosine can be safely, continuously infused for extended periods of time, that doses up to 140 mcg/kg/min are tolerable in conscious humans, and that adenosine has a predictable vasodilatory action. (Strauss, Tr. 735:4-19.) viii. 107. The `296 Patent

The `296 patent describes use of adenosine as a pharmacologic stress agent for

MPI. (TX 275 at col. 21.) 108. The `296 patent states that "a safer and more reliable test can be expected if

adenosine is used" instead of dipyridamole. (TX 275 at col.21, ll.57-58.) 109. The `296 patent further states that "[t]he exact dose will normally have to be

titrated individually but should lie in the range of 10 to 150 micrograms per kilogram per minute." (TX 275 at col. 21, ll. 59-61). 110. A person of ordinary skill in the art would understand from the `296 patent that

doses within the range of 10-150 mcg/kg/min would likely be both safe and effective for MPI. (Strauss, Tr. 752:7-19.) e. 111. The Use Of Adenosine For MPI Was Known In The Art

The `296 patent describes, inter alia, the use of adenosine as a pharmacologic

stress agent for MPI. (TX 275 at col. 21). 17
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112.

The `296 patent issued from U.S. Patent Application No. 08/031,666 (the "'666

application"), filed March 15, 1993. (TX 275.) 113. Example XIII was added in a continuation-in-part application filed on Dec. 28,

1987. (TX 275; Joint Statement of Admitted Facts No. 17, D.I. 133.) 114. Example XIII discloses "adenosine in the diagnosis of coronary heart disease by

radionucleide (sic) scintigraphy." (TX 275 at col.21, ll.25-61.) 115. Example XIII describes the use of dipyridamole in connection with MPI using

thallium 201. (TX 275 at col.21, ll.25-61.) Example XIII then explains the relationship of dipyridamole's action with adenosine's vasodilatory properties and teaches that adenosine can be used in place of dipyridamole as a pharmacologic stress agent for MPI. (TX 275 at col.21, ll.2561.) 116. Example XIII of the `296 patent teaches a dose range of 10 to 150 mcg/kg/min of

adenosine for MPI. (TX 275 at col.21, ll.59-61; see also Strauss, Tr. 750:2-22.) 117. The use of adenosine as a pharmacologic stress agent for MPI is also taught in a

proposal that was submitted to the Karolinska Institute in Sweden in or around February of 1988 (the "Karolinska Request"). (TX 1193 at SIC010940.) 118. The Karolinska Request discloses that adenosine could be used to replace

dipyridamole as the pharmacologic stress agent for MPI. (Strauss, Tr. 754:9-22; TX 1193 at SIC010943.) 119. The dose described in the Karolinska Request is 60 mcg/kg/min. (Strauss, Tr.

755:6-14; TX 1193 at SIC010944.)

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3. 120. adenosine. 121.

There Was Ample Reason To Use Adenosine In Place of Dipyridamole As A Pharmacologic Stress Agent For MPI

It was well known in the art by mid-1987 that dipyridamole acts through

A person of ordinary skill in the art in 1987 would have known that dipyridamole

acts indirectly, and that adenosine is the direct acting agent. (See, e.g., Strauss, Tr. 670:12-18; TX 93; TX 275.) 122. Albro, Goodman and Gilman, Conradson and the `296 patent all demonstrate that

it was well known in the art that dipyridamole works, at least in part, because of the increase in endogenous adenosine caused by dipyridamole's adenosine uptake inhibition. (Strauss, Tr. 670:12-671:12, 680:17-22, 683:8-13, 684:12-685-6; TX 93 at 758-59; TX 39 at 822; TX 220 at 387; TX 275, col.21, ll.49-51.) 123. A person of ordinary skill in the art would have reason to substitute adenosine for

dipyridamole in connection with MPI because that person would have known that the actual agent causing the vasodilation was adenosine. (Strauss, Tr. 670:12-671:12.) 124. Common sense would provide ample reason to substitute the direct acting agent

for the indirect agent in a known procedure. 125. The prior art further provides various additional suggestions and/or reasons to use

adenosine as a pharmacologic stress agent for MPI. 126. Gould 1978 teaches that coronary vasodilators other than dipyridamole could be

used for MPI. (Strauss, Tr. 664:13-18, 686:1-6.) 127. Gould 1978 states that:

Any other coronary vasodilator that was more potent than dipyridamole would further increase the sensitivity of imaging techniques for identifying coronary disease.

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(TX 38 at 285; see Strauss, Tr. 686:7-687:3.) 128. Gould 1978 discusses imaging methods using a "coronary vasodilator" generally,

further suggesting that coronary vasodilators other than dipyridamole could be used for MPI. (Strauss, Tr. 665:9-666:7; TX 38 at 285.) 129. A person of skill in the art would have had reason to use adenosine for MPI based

on the teachings of Gould 1978. (Strauss, Tr. 686:7:687:18.) 130. A person of ordinary skill in the art would have had further reason to substitute

adenosine for dipyridamole for MPI because of knoweldge of the duration of action of the two agents. 131. Dipyridamole was known to have a relatively long duration of action. (Strauss,

Tr. 673:17-674:11.) 132. Because of the long duration of dipyridamole, it is not possible to turn off

negative side effect by simply turning off the infusion. (Strauss, Tr. 673:17-674:11, 674:18675:12.) Instead, use of a reversal agent may be necessary. (Strauss, Tr. 673:17-674:11, 674:1217; see also TX 38 at 283.) 133. Adenosine has a very short duration of action. (Strauss, Tr. 673:17-674:11.) A

person of ordinary skill in the art at the time would have known of adenosine's short duration, and would have expected the effects of adenosine to be far more easily controlled than dipyridamole. (Strauss, Tr. 672:17-673:2; 673:17-674:11; 675:13-21; 742:2-18; see also TX 1171 at 345.) 134. It was generally known prior by mid-1987 that a drug with a shorter duration of

action would be preferable in terms of side effects. (Hilleman, Tr. 2137:22-2139:7.)

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135.

A person of ordinary skill in the art would have known that adenosine could be

continuously infused to maintain a stable effect for the duration of time needed to perform the MPI, but that the effects could then be turned off almost immediately upon termination of the infusion. (Strauss, Tr. 676:9-678:2; 692:12-694:7.) 136. A person of ordinary skill in the art would have recognized at least two

advantages of adenosine over dipyridamole: (1) it would allow almost immediate termination of negative side effects, and (2) it would eliminate the extended effect of the drug past its usefulness for the procedure. (Strauss, Tr. 673:17-674:11; 674:18-675:12; 676:9-677:8; 687:11688:2.) 137. Knowledge in the art regarding safety and vasodilation activity of adenosine when

administered to humans via continuous intravenous infusion would provide yet another reason to use adenosine infusion in place of dipyridamole infusion for MPI. (Strauss, Tr. 741:19-742:18; 749:7-9.) 4. 138. A Person Of Ordinary Skill In The Art Would Have Had A Reasonable Expectation That Adenosine Would Work For MPI

A person of ordinary skill in the art in 1987 would have reasonably expected

adenosine to work for MPI based on the strong suggestion in Gould 1978 that any other more potent coronary vasodilators could be used for MPI. (Strauss, Tr. 664:15-18; TX 38 at 285.) 139. A person of skill in the art in 1987 would have known that adenosine was already

working as a pharmacologic stress agent for MPI, through the intermediary action of dipyridamole in the method described in Gould 1978 and Albro. (Strauss Tr. 670:12-671:21; 687:11-688:2; TX 93 at 285.) A person of ordinary skill in the art in 1987 would have reasonably expected adenosine to work directly for the same purpose for which it was already being used indirectly by the mechanism of action of dipyridamole. (Strauss, Tr. 670:12-671:12.)

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140.

It was known in the art that adenosine was a potent vasodilator. (Strauss, Tr.

705:19-706:4; see also Mohiuddin, Tr. 1858:5-12; Hilleman, Tr. 2131:4-8.) A person of ordinary skill in the art would have reasonably expected adenosine to work for the same purpose ­ as a vasodilator ­ for pharmacologic stress MPI. (Strauss, Tr. 670:12-671:12.) 141. The prior art disclosed a range of doses of adenosine that would cause

vasodilation without causing hypotension or other severe side effects. A person of ordinary skill in the art would have known from the teachings in the art that certain continuous infusion rates were both safe and sufficient to cause vasodilation. (Strauss, Tr. 742:2-18, 748:2-13; 749:3-20, 750:2-22.) 142. Based on Sollevi 1986, a person of skill in the art would have understood that a

dose of about 20-30 mcg/kg/min would cause vasodilation. (Strauss, Tr. 704:22-705:15; TX 1171 at 335, 345.) Sollevi 1986 further taught that a dose of 30-50 mcg/kg/min caused a doubling of graft flow, and a dose of 80 mcg/kg/min caused a near doubling of myocardial blood flow. (Strauss, Tr. 704:22-705:15; 702:21-703:14; TX 1171 at 335.) 143. A person of skill in the art would have expected, based on Sollevi 1986 alone, that

doses beginning as low as 30 mcg/kg/min would likely be effective to cause vasodilation. (Strauss, Tr. 704:22-705:15, 739:2-15.)\ 144. A person of ordinary skill in the art would have also expected the upper range of

useful doses for MPI to be around 200 mcg/kg/min because each of Sollevi 1984, Sollevi 1986 and Owall teach that continuous infusion of adenosine at levels greater than 200 mcg/kg/min result in hypotension. (Strauss, Tr. 695:6-16; 700:19-701:9; 723:3-7; TX 112; 1169; 1171.)

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145.

A person of ordinary skill in the art would have reasonably expected adenosine

infusion rates between 20 and 200 mcg/kg/minute to be adequate for performing MPI. (Strauss, Tr. 749:3-20, 750:2-23.) 146. In light of the teachings of Biaggioni 1986, Conradson, Fuller and/or Biaggioni

1987, a person of skill in the art would have expected that most conscious patients would be able to tolerate doses somewhere between 90 and 140 mcg/kg/min. (Strauss, Tr. 719:3-18; 728:15729:3; 731:1-13: 735:4-12; TX 220; 226; 1169; 1208). 147. A person of ordinary skill in the art would have reasonably expected that doses in

the range of 20-200 mcg/kg/min, and more likely doses above 50 mcg/kg/min but less than 200 mcg/kg/min, would be very likely to work for MPI. (Strauss, Tr. 738:12-740:18.) 5. 148. The Difference Between The Asserted Claims And The Prior Art

There is only one difference between the Gould 1978 reference and the asserted

claims of the `877 patent ­ substituting the direct infusion of adenosine within the specified dosage ranges for the infusion of dipyridamole. 149. There is only one difference between the Albro reference and the asserted claims

of the `877 patent ­ substituting the direct infusion of adenosine within the specified dosage ranges for the infusion of dipyridamole. 150. Everything in the asserted claims of the `877 patent, except the direct infusion of

adenosine within the claimed dosage ranges, is disclosed in Gould 1978 and Albro. 151. Gould 1978 and Albro each disclose a method for detecting and assessing

coronary artery disease. (Strauss, Tr. 663:10-20; 665:9-20; 667:15-22; TX 38, TX 93.) 152. Both Gould 1978 and Albro disclose administering a pharmacologic stress agent

by intravenous route, and administering enough of the stress agent to cause vasodilation. (Strauss, Tr. 663:10-20; 667:15-22; 668:18-669:1; TX 38; TX 93.) 23
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153.

Both Gould 1978 and Albro disclose administering a radiopharmaceutical agent,

specifically thallium-201, into the human. (Strauss, Tr. 667:15-22; TX 38; TX 93.) 154. Both Gould 1978 and Albro disclose performing MPI (scintigraphy) to detect and

assess the severity of coronary artery disease. (Strauss, Tr. 664:23-665:20; 667:15-22; TX 38; TX 93.) 155. Gould 1978 suggests use of other more potent coronary vasodilators in place of

dipyridamole. (Strauss, Tr. 664:13-18; TX 38 at 285) 156. Albro states that dipyridamole acts through adenosine. (Strauss, Tr. 669:2-

670:11; TX 93 at 758.) 157. The sole difference between either of the prior art references Gould 1978 or Albro

and the asserted claims is the direct infusion of adenosine within the claimed dosage ranges in place of reliance on dipyridamole infusion to increase endogenous adenosine for the same effect. 6. No Secondary Indicia Weigh Against the Strong Showing of Obviousness a. 158. No Unexpected Results

Plaintiffs have not demonstrated any unexpected results for the methods in the

asserted claims. 159. A person of skill in the art at the relevant time would have expected adenosine to

work as a vasodilator and to cause sufficient vasodilation for MPI in humans. (Strauss, Tr. 735:4-12, 748:2-13; 749:10-21, 750:12-23.) 160. A person of skill in the art would have expected adenosine infusion in the range

of 20-200 mcg/kg/minute to be safe. (See, e.g., Strauss, Tr. 699:4-17, 747:18-748:1, 710:2-11.) 161. A person of skill in the art would have expected any side effects from adenosine

infusion to dissipate quickly upon termination of the infusion. (Strauss, Tr. 674:4-12, 742:2-18; TX 112 at 404; TX 48 at 2233; TX 220 at 388-89; TX 226 at 780.) A person of skill in the art 24
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would have expected the advantages of safety and controllability that are associated with a short duration of action. (Tr. 672:17-673:2; 673:17-674:11; 687:11-688:2.) b. 162. No Long Felt Need

Plaintiffs have not demonstrated any long felt need. (Wackers, Tr. 997:4-14,

1001:16-1002:9.) 163. Plaintiff's own expert Dr. Wackers explained that there was no particular need for

a pharmacologic stress agent at the time of Gould 1978. (Wackers, Tr. 905:20-906:14.) 164. Dr. Wackers further explained that interest in pharmacologic stress agents did not

become widespread until at least 1985. (Wackers, Tr. 997:10-14.) c. 165. 166. No Skepticism or Teaching Away

Plaintiffs have not shown skepticism or teaching away in the prior art. The prior art demonstrates interest in and willingness to use adenosine at the

infusion doses claimed in the `877 patent, as well as at doses much higher than needed for MPI. (Strauss, Tr. 717:2-15, 727:9-15, 730:5-9; TX 48, 220, 1208.) 167. A person of ordinary skill in the art would not have been discouraged by earlier

references discussing adenosine in other contexts. (Strauss, Tr. 759:4-761:13). d. 168. Any Commercial Success Of Adenoscan® Is Not Due To Any Alleged Superiority Of The Claimed Invention

The sales levels achieved by Adenoscan® do not provide evidence of any

superiority of this drug. (Leffler; Tr. 1631:12-1632:22.) Rather, the sales levels achieved by Adenoscan® are explained by the confluence and interaction of four economic factors: (1) There was only one other FDA-approved competitor in the pharmacological stress-testing market at the time of Adenoscan® entry; (2) Adenoscan® became the only promoted product in the pharmacological stress testing market shortly after its entry;

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(3) Extensive marketing and promotion of Adenoscan® by Fujisawa; and (4) Growth in demand for pharmacological stress testing unrelated to the asserted inventions. (Leffler, Tr. 1579:3-1582:13; DTX 3133.) i. There Was Only One Other FDA-Approved Competitor In The Pharmacological Stress-Testing Market At The Time Of Adenoscan® Entry

169.

Adenoscan® entered the market and began generating sales in August 1995.

(Leffler, Tr. 1572:6-8.) It was originally marketed by Fujisawa Pharmaceutical Co., Ltd. ("Fujisawa"), now Astellas. (White, Tr. 1228:8-17.) 170. In August 1995, when Adenoscan® entered the market, there was just one

competing product, Persantine®, marketed by DuPont. (Leffler, Tr. 1577:10-16, 1580:4-7; White, Tr. 1307:14-16; DTX 3133.) Persantine® is the brand name for the drug dipyridamole. (Leffler, Tr. 1577:13-16.) 171. The fact that there was only direct competitor to Adenoscan® made the

pharmacological stressor market unique as compared to most pharmaceutical markets, which generally have many competitors engaged in promotional activity. (Leffler, Tr. 1580:4-6.) 172. In most pharmaceutical markets, the real difficulty is capturing the attention of the

prescribers, who typically face numerous therapeutic alternatives and must filter through a lot of promotional "noise" in the marketplace. (Leffler, Tr. 1602:11-21.) 173. Unlike most pharmaceutical markets, the pharmacological stressor market was

uncluttered. (Leffler, Tr. 1602:22.) It was "ripe for the picking" for a new player to enter and launch a competitive challenge against the available product. (Leffler, Tr. 1602:22-25.) 174. As a result, Adenoscan® was able to succeed in capturing the ears and the minds

of doctors relatively quickly. (Leffler, Tr. 1602:22-1603:2.) There was just one other serious

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competitor ­ Persantine® ­ with which Adenoscan® vied briefly for the attention of prescribers. (Leffler, Tr. 1602:2-4, 1603:12-14.) 175. For this reason, the pharmacological stressor market was an "ideal" market for a

new entrant such as Fujisawa, seeking to achieve sales. (Leffler, Tr. 1602:11-1603:4.) ii. Adenoscan® Became The Only Promoted Product In The Pharmacological Stress Testing Market Shortly After Its Entry

176.

The second economic factor explaining the sales levels of Adenoscan® is that it

became the only promoted product in the pharmacological stress testing market shortly after its entry. (Leffler, Tr. 1580:14-21; DTX 3133.) 177. In anticipation of the 1997 expiration of the patent on Persantine®, DuPont

launched an authorized generic product in November 1996 in an advance attempt to capture generic dipyridamole sales. (Leffler, Tr. 1603:17-21.) 178. DuPont ceased its promotion of Persantine® approximately 16 months after the

entry of Adenoscan®. (Leffler, Tr. 1580:16-1581:7, 1603:14-16; White, Tr. 1307:17-1308:5.) 179. DuPont ceased its promotion of Persantine® when generic dipyridamole was

launched because promotion was no longer in DuPont's economic interest. (Leffler, Tr. 1603:211604:2.) First, the effects of such promotion would be most likely to benefit the competing generic dipyridamole products. (Leffler, Tr. 1604:2-4.) Second, the accompanying reduction in the price of the branded dipyridamole product in the face of generic competition made the promotion is no longer worth the expenditure. (Leffler, Tr. 1604:4-6.) 180. As a result, by late 1996, Adenoscan® found itself in the fortunate situation of

being the only product advertising itself to the prescribers of pharmacological stress tests. (Leffler, Tr. 1604:7-11.) This advantage has continued to the present day. (Leffler, Tr. 1604:1222; White, Tr. 1308:1-11.) 27
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iii. 181.

Extensive Marketing And Promotion of Adenoscan® By Fujisawa

The third economic factor explaining the sales levels of Adenoscan® is Fujisawa's

extensive and effective marketing and promotion of the product. (Leffler, Tr. 1581:11-15; DTX 3133.) (1) 182. A Concentrated Market

Typically, the pharmaceutical industry is very promotion-driven because

companies compete to capture the attention of very busy prescribers, who act as agents for patients. (Leffler, Tr, 1605:2-9.) Many articles in the economic literature have demonstrated the significance and importance of marketing and promotion to the success of a pharmaceutical product. (Leffler, Tr. 1605:9-12, 1606:15-25.) 183. One characteristic of the pharmacological stressor market in particular is that it is

very concentrated, i.e., in that the majority of procedures using pharmacologic stress agents are performed in a relatively low number of institutions. (Leffler, Tr. 1608:10-1609:3; TX 1226 at AST0065741.) This market characteristic was recognized in Fujisawa's "Launch Plan for Adenoscan." (White, Tr. 1294:4-21; TX 1226 at AST0065741.) 184. Since Adenoscan® is not prescribed by hundreds of thousands of office-based

physicians ­ as is the case with consumer-oriented products ­ Fujisawa could focus its promotion in a direct way on the relatively small number of clinics and hospitals comprising the market for its product. (Leffler, Tr. 1607:1-25.) 185. Fujisawa, a smaller company that did not have the resources for a vast marketing

apparatus, recognized this market characteristic as advantageous. (Leffler, Tr. 1607:1-25, 1608:5-9; White, Tr. 1292:22-1294:21; TX 1226 at AST0065741.) The search for opportunities to manufacture products in specialty markets, i.e., niche areas such as cardiology, was at the

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heart of Fujisawa's, and now Astellas's, business strategy. (White, Tr. 1227:5-1228:3; Leffler, Tr. 1607:1-25.) 186. Fujisawa engaged in traditional and non-traditional promotion in its efforts to

capture this narrow pharmacological stressor market. (Leffler, Tr. 1620:12-20; White, Tr. 1263:1-10, 1283:7-14.) Fujisawa's traditional marketing activities included, e.g., detailing, or informational visits to doctors by pharmaceutical sales representatives; advertising; and sampling. (Leffler, Tr. 1605:13-1606:14, 1610:19-20; White, Tr. 1263:1-10.) (2) 187. Substantial Detailing Efforts

The level of market concentration dictates how many human resources a company

would need to get a marketing message out to the target audience; the higher the concentration of a market, the fewer the number of sales representatives that would be needed. (White, Tr. 1294:4-21.) 188. The concentration of the pharmacological stress test market notwithstanding,

Fujisawa devoted a substantial sales force for the purpose of detailing prescribers regarding the Adenoscan® product. (Leffler, Tr. 1609:20-22.) The sales force employed by Fujisawa (86 sales representatives) was more than twice the size of the sales force DuPont had dedicated to the detailing of Persantine® to the same set of institutions and service providers (42 sales representatives). (Leffler, Tr. 1609:4-1610:3; White, Tr. 1294:22-25, 1303:22-1305:17; TX 1226 at AST0065741; TX 1242 at AST0185350.) (3) 189. Support Of The ASNC

Fujisawa also engaged in non-traditional marketing activities that were not in the

bailiwick of detailing, advertising, and sampling in its efforts to capture the pharmacological stressor market. (Leffler, Tr. 1610:15-20.; White, Tr. 1283:7-14, 1290:12-23.)

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190.

The first of the promotional activities that was not within the traditional set of

promotional activities was Fujisawa's sponsorship of the American Society of Nuclear Cardiology ("ASNC"), a medical society that advised doctors about which pharmacological stress agents to prescribe. (Leffler, Tr. 1611:5-8, 1611:13-15, 1613:5-1614:13; TX 1045 at AST0083228; TX 1078 at AST0066744; TX 1128 at AST0043954; DTX 3148.) 191. The ASNC was perceived to be a "major strategic partner" and engaged in several

marketing programs sponsored