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

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

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

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Civil Action No. 05-337 SLR

DEFENDANTS SICOR INC. AND SICOR PHARMACEUTICALS INC.'S RESPONSIVE 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 Attorneys for Defendants SICOR INC. and SICOR PHARMACEUTICALS, INC. Dated: June 19, 2007

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TABLE OF CONTENTS Page I. PROPOSED ADDITIONAL FINDINGS OF FACT ....................................................... 1 A. ADDITIONAL FACTUAL BACKGROUND ..................................................... 1 B. THE ASSERTED CLAIMS OF THE `877 PATENT .......................................... 3 C. THE PRIOR ART DID NOT TEACH AWAY FROM THE USE OF ADENOSINE FOR MPI...................................................................................... 4 1. Adenosine Was Known In The Art As A Potent Coronary Vasodilator .............................................................................................. 4 2. The Prior Art Taught Doses Of Adenosine That Were Likely To Work For MPI ......................................................................................... 4 3. In Arguing That The Prior Art Taught Away Or Was Inconsistent, Plaintiffs Ignore The Significance Of Differences In Doses And Methods of Administration ...................................................................... 5 4. Plaintiffs Ignore The Knowledge Of Ischemia In The Prior Art................ 6 5. None Of The References On Which Plaintiffs Rely Taught Away ­ Either Alone or In Combination With Other Teachings In the Art ............ 7 D. PLAINTIFFS PRESENT NO SECONDARY CONSIDERATIONS THAT REBUT THE STRONG CASE OF OBVIOUSNESS ............................. 12 1. No Unexpected Results .......................................................................... 12 2. No Skepticism or Teaching Away.......................................................... 15 3. Sicor Has Shown That Any Alleged Commercial Success Is Due To Economic Factors, Not To The Claimed Invention............................ 17 a. There Is No Nexus Between Any Alleged Commercial Success of Adenoscan® And Any Alleged Superiority Of The Subject Matter Of The Asserted Claim ................................ 17 i. Adenoscan® Entered the Pharmaceutical Stress Market at a Fortuitous Time............................................ 18 ii. Fujisawa's Extensive Marketing and Promotion Drove Adenoscan®'s Market Share Growth ................... 18 iii. Adenoscan's Increasing Sales Were Also Due to the General Growth of the Pharmacologic Stress Market ............................................................................ 20 b. Dr. Hay's Analysis Is Unsound and His Testimony Unreliable .................................................................................. 21 c. Dr. Leffler Is A Highly Qualified Expert .................................... 22 E. THE `296 PATENT AND/OR THE KAROLINSKA REQUEST DISCLOSE MORE THAN THE NAMED INVENTORS' PROTOCOL DISCLOSED AND ARE PRIOR ART.............................................................. 25 1. Example XIII Of The `296 Patent .......................................................... 26 2. The Karolinska Request ......................................................................... 26

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II.

PROPOSED CONCLUSIONS OF LAW ...................................................................... 27 A. CLAIMS 23(17), 23(18) AND 43 OF THE `877 PATENT ARE INVALID AS OBVIOUS.................................................................................. 27 1. Sicor Has Shown Obviousness By Clear And Convincing Evidence ...... 27 2. The Secondary Considerations Argued By Plaintiff Do Not Rebut The Strong Prima Facie Case Of Obviousness........................................ 28 a. No Unexpected Results .............................................................. 29 b. No Credible Evidence Of Skepticism Or Surprise....................... 30 c. Copying, Even If Shown, Is Irrelevant In The ANDA Context....................................................................................... 30 d. Any Commercial Success Enjoyed By Adenoscan® Does Not Rebut Obviousness Here...................................................... 31 i. The sales levels achieved by Adenoscan Are Explained By the Interplay of Economic Factors............. 31 (1) Adenoscan® Entered The Pharmacologic Stress Market at at Fortuitous Time ..................... 32 (2) Fujisawa's Extensive Marketing and Promotion Drove Adenoscan®'s Market Share Growth ...................................................... 32 (3) Adenoscan®'s Increasing Sales Were Also Due to the General Growth of the Pharmacologic Stress Market .............................. 33 ii. Dr. Hay's Analysis Is Unsound and His Testimony Unreliable ....................................................................... 34 iii. Dr. Leffler is Highly Qualified to Serve as an Expert in This Case......................................................... 34 e. The Lack Of Specific Suggestion Is Irrelevant............................ 35 f. Simultaneous Invention Suggests Obviousness........................... 36 B. CLAIMS 23(17), 23(18) AND 43 OF THE `877 PATENT ARE INVALID AS ANTICIPATED ......................................................................... 36 1. The `296 Patent Is Prior Art ................................................................... 36 2. Claim 23(18) Is Anticipated By The `296 Patent .................................... 38 CONCLUSION............................................................................................................. 38

III.

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TABLE OF AUTHORITIES CASES Page

Alpex Computer Corp. v. Nintendo Co., No. 86-1749, 1994 WL 681752 (S.D.N.Y. Dec. 5, 1994) .................................................... 30 Aventis Pharma Deutschland GmbH v. Lupin Ltd., 2006 WL 1008962 (E.D. Va. July 17, 2006) ....................................................................... 30 Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001) ........................................................................................... 38 Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223 (Fed. Cir. 1994)............................................................................................. 36 Cable Elec. Prods. v. Genmark, Inc., 770 F.2d 1015 (Fed. Cir. 1985) ........................................................................................... 30 In re Fla. Microsoft Antitrust Litig., 2002 WL 31423620 (Fla. Cir. Ct. 2002).........................................................................23, 35 Friction Div. Prods., Inc. v. E. I. Du Pont de Nemours & Co., Inc., 693 F. Supp. 114 (D. Del. 1988) ......................................................................................... 33 In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004) ........................................................................................... 28 In re GPAC Inc., 57 F.3d 1573 (Fed. Cir. 1995)............................................................................................. 30 Invitrogen Corp. v. Clontech Labs., Inc., 429 F.3d 1052 (Fed. Cir. 2005) ........................................................................................... 36 ISCO Int'l, Inc. v. Conductus, Inc., 279 F. Supp. 2d 489 (D.Del. 2003) ..................................................................................... 37 J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563 (Fed. Cir. 1997) ........................................................................................... 31 In re Kahn, 441 F.3d 977 (Fed. Cir. 2006)............................................................................................. 27 In re Koller, 613 F.2d 819 (C.C.P.A. 1980)............................................................................................. 28 Kridl v. McCormick, 105 F.3d 1446 (Fed. Cir. 1997) ........................................................................................... 36 - iii DB01:1797288.2 058956.1016

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KSR Int'l Co. v. Teleflex, Inc., 127 S.Ct. 1727 (2007)......................................................................................................... 35 Lindemann Maschinenfabrik GmbH v. American Hoist & Derrick Co., 730 F.2d 1452 (Fed. Cir. 1984) ........................................................................................... 36 Mahurkar v. C.R. Bard Inc., 79 F.3d 1572 (Fed. Cir. 1996)............................................................................................. 36 McNeil-PPC, Inc. v. L. Perrigo Co., 337 F.3d 1362 (Fed Cir. 2003) ............................................................................................ 32 Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) ........................................................................................... 28 Merck & Co., Inc. v. Teva Pharms USA, Inc., 405 F.3d 1338 (Fed Cir. 2005) ........................................................................................... 34 Optivus Tech., Inc. v. Ion Beam Apps. S.A., 469 F.3d 978 (Fed. Cir. 2006)............................................................................................. 27 Pacifica Technica Corp. v. U.S., 2 Cl.Ct. 170 (1983) ............................................................................................................. 31 In re Petering, 301 F.2d 676 (C.C.P.A. 1962)............................................................................................. 38 Pfizer, Inc. v. Apotex, Inc. 480 F.3d 1348 (Fed. Cir. 2007) ......................................................................................27, 29 Pfizer Inc. v. Teva Pharms. USA, Inc., 461 F. Supp. 2d 271 (D.N.J. 2006)...........................................................................23, 31, 35 Revlon, Inc. v. Carson Prods. Co., 602 F. Supp. 1071 (S.D.N.Y. 1985) .................................................................................... 33 In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ........................................................................................... 29 In re Soni, 54 F.3d 746 (Fed. Cir. 1995)............................................................................................... 29 Speller v. U.S., 14 Cl. Ct. 170 (1988) .......................................................................................................... 31 In re Stempel, 241 F.2d 755 (C.C.P.A. 1957)............................................................................................. 37

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Syntex LLC v. Apotex, Inc., 407 F.3d 1371 (Fed. Cir. 2005) ......................................................................................28, 35 In re Tanczyn, 347 F.2d 830 (C.C.P.A. 1965)............................................................................................. 37 Tec Air, Inc. v. Denso Manuf. Mich., Inc., 192 F.3d 1353 (Fed. Cir. 1999) ........................................................................................... 27 U.S. v. Adams, 383 U.S. 39 (1966) ............................................................................................................. 30 Vandenberg v. Dairy Equip. Co., 740 F.2d 1560 (Fed. Cir. 1984) ........................................................................................... 34 Wash. Legal Found. v. Legal Found. of Wash., 271 F.3d 835 (9th Cir. 2001).................................................................................... 23, 34-35 STATUTES 35 U.S.C. § 103 ........................................................................................................................ 37

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Defendants Sicor Inc. and Sicor Pharmaceuticals, Inc. (collectively "Sicor") submit the following additional Proposed Findings of Fact and Conclusions Of Law in response to the Plaintiffs' Post-Trial Proposed Findings of Fact And Conclusions of Law Concerning U.S. Patent No. 5,070,877 ("Plaintiffs' Proposed Findings"). These Additional Proposed Findings of Fact and Conclusions of Law supplement Sicor's Proposed Findings of Fact and Conclusions of Law ("Sicor's Proposed Findings") dated May 9, 2007. To the extent that any of the findings of fact set forth below or in Sicor's Proposed Findings is a conclusion of law, Sicor requests that it be adopted as such. To the extent that any of the proposed conclusions of law set forth below or in Sicor's Proposed Findings is a finding of fact, Sicor requests that it be adopted as such. I. PROPOSED ADDITIONAL FINDINGS OF FACT A. 1. ADDITIONAL FACTUAL BACKGROUND The field of MPI was still new in the late 1970s. As Dr. Wackers testified, "the

whole field was so new that you were still exploring." (Wackers, Tr: 997:15-998:5.) 2. Gould 1978 described the first use of pharmacologic stress MPI in humans. (TX

38.) At that time, there was no particular need for a pharmacologic stress agent for MPI. (Wackers, Tr. 997:15-5; 1002:7-9.). There was no widespread interest in pharmacologic stress testing for MPI until at least seven years later, after publication of an article by Dr. Boucher in 1985. (Wackers, Tr. 997:10-14.) 3. There is no evidence that adenosine was "passed over" as an alternative or that the

prevailing view was "anything but adenosine" at the relevant time in late 1987 and/or early 1988. Plaintiffs do not cite any failed attempts to use adenosine for MPI in humans. Nor do Plaintiffs cite any specific statements in the prior art instructing against the use of adenosine for

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MPI in humans. The mere lack of mention of adenosine as an alternative in various texts is entirely consistent with the lack of particular interest pharmacologic stress MPI that Dr. Wackers acknowledged and is not an indicia of the non-obviousness of the asserted claim. 4. The testimony of Gail Salzberg, a former Medco project manager, about her

discussions with other investigators using adenosine for PSVT is not probative of nonobviousness. Ms. Salzberg testified that she began working for Medco in February of 1987, and that she first discussed the use of adenosine for MPI sometime during the summer of 1987. (Salzberg, Tr. 1836:14-16; Tr. 1840:23-1841:2.) Ms. Salzberg also testified that she neither asked nor discussed other possible uses for adenosine with any other cardiology groups she visited during the months between February of 1987 and the summer of 1987. (Salzberg, Tr. 1854:3-10.) 5. The limited availability of adenosine in pharmaceutical grade is a factor that

limited its widespread use before 1987. Pharmaceutical grade adenosine for intravenous administration to humans had only recently become available in 1987. (TX 52 at AST009465;Tr. 1023:22-1024:6.) 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. 2119:7-2120:10.) 6. One of the two named inventors on the `877 patent, Dr. Hilleman, told Medco in

September 1987 that his group "would obviously like to ask for intravenous adenosine supplies to meet our needs to complete these studies." (TX 1194.) Both Dr. Hilleman and Medco project manager Gail Salzberg testified that this request was obvious because Medco was the only source of pharmaceutical grade adenosine at the time (Salzberg, Tr. 1854:22-1855:16; Hilleman, Tr. 2119:13-2120:10.)

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7.

Obtaining 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. (Mohiuddin, Tr. 1896:9-18; 1897:9-14; Hilleman, 2148:523.) 8. The importance of having a source of pharmaceutical grade drug product for use

in humans was confirmed by Sicor's expert, Dr. Strauss. Dr. Strauss testified that he used ethyl adenosine in the 1970s because it was made available to him by Abbott, and he expected to test the drug in animals then move to human use. (Strauss, Tr. 654:3-10.) Dr. Strauss stopped working with ethyl-adenosine when Abbott withdrew supplies such that he no longer had a source of sterile pyrogen-free pharmaceutical grade product (Strauss, Tr:654:11-16.) B. 9. THE ASSERTED CLAIMS OF THE `877 PATENT At trial, Plaintiffs asserted only three claims of the `877 patent: 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.) 10. Claim 23(17) requires an amount of adenosine "sufficient to provide coronary

artery dilation." (TX 320 at claim 23(17). 11. Claim 23(18) requires an adenosine infusion dose "of about 140 mcg/kg/minute."

(Id. at claim 23(18).) 12. Claim 43 requires a dose of "adenosine in order to provide coronary artery

dilation." (Id. at claim 43.) 13. id.) 14. An optimal level of vasodilation is not a claim element of any of the asserted Maximal vasodilation is not a claim element of any of the asserted claims. (See

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15.

A balance or optimization of side effects and efficacy is not a claim element of

any of the asserted claims. (See id.) 16. The `877 patent does not disclose any recognition that some amount of discomfort

was necessary for adequate vasodilation. (See id.) 17. The asserted claims are directed to a method of detecting and assessing coronary

artery disease in a human. (See id. at col. 8, ll. 63-65; col. 10, ll. 8-9.) 18. (See id.) 19. 20. The asserted claims do not specify an age range. (See id.) The asserted claims do not specify that the humans must be patients or members The asserted claims do not limit the human population to whom the claims apply.

of any particular patient population. (See id.) C. THE PRIOR ART DID NOT TEACH AWAY FROM THE USE OF ADENOSINE FOR MPI 1. 21. Adenosine Was Known In The Art As A Potent Coronary Vasodilator

A person of ordinary skill in the art would have known adenosine was a potent

coronary vasodilator. (Strauss, Tr. 705:19-706:4; see also Mohiuddin, Tr. 1858:5-12; Hilleman, Tr. 2131:4-8.) 22. The 1985 edition of the textbook of pharmacology commonly used by students

and physicians in 1985, Goodman and Gilman, states that "[a]denosine, 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.) 2. 23. The Prior Art Taught Doses Of Adenosine That Were Likely To Work For MPI

The prior art included use of dipyridamole for MPI. Dipyridamole was known to

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endogenous adenosine was known to cause the vasodilation needed to perform MPI. (See, e.g., Strauss, Tr. 679:16-680:7; Wackers, Tr. 908:19-24; TX 93, TX 39, TX 220, TX 275; D.I. 146 at ¶46.) 24. In light of the knowledge in the art concerning dipyridamole, a person of ordinary

skill in the art would have known that there was necessarily an effective dose of adenosine that could cause vasodilation sufficient to perform MPI, because that person of skill in the art would have know that "if dipyridamole is selected as the vasodilator, that the effector drug, if you will, is adenosine . . . ." (Strauss, Tr. 670:12-23.) 25. The prior art disclosed the safe intravenous infusion of adenosine to humans at

various doses. (See D.I. 147 at ¶¶ 68-110.) Based on the prior art, a person of ordinary skill in the art would have reasonably expected adenosine in the range of doses between 20 and 200 mcg/kg/min to work for MPI. (See id.) 26. Based on the prior art, including but not limited to Biaggioni 1986, Conradson,

Fuller and Biaggioni 1987, a person of ordinary skill in the art would have reasonably expected that the majority of conscious humans can tolerate an intravenous infusion of adenosine at doses ranging from 100 to 140 mcg/kg/min. (See D.I. 147 at ¶¶ 86-106; see also TX 48, TX 220, TX 226; TX 1208.) 3. In Arguing That The Prior Art Taught Away Or Was Inconsistent, Plaintiffs Ignore The Significance Of Differences In Doses And Methods of Administration

27.

A person of ordinary skill in the art in 1987 would have understood the difference

between bolus injection and continuous intravenous infusion. (Strauss, Tr. 677:9-678:2.) 28. A person of ordinary skill in the art in 1987 would have understood that

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29.

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

a short half-life. (Strauss, Tr. 675:13-21.) 30. A person of ordinary skill in the art in 1987 would have understood that the short

half-life of adenosine provided a safety benefit. (See, e.g., TX 1171 at 335, 345; Strauss, Tr. 672:17-673:2, 673:17-674:11, 675:13-21.) The person of ordinary skill in the art in 1987 would have understood that the short half-life would enable any negative side effects to be terminated almost immediately upon termination of the infusion. (Strauss, Tr. 742:2-18; see also Hilleman, Tr. 2137:22-2139:7.) The person or ordinary skill in the art would have perceived this as a benefit over dipyridamole infusion in which the effects endured past the time necessary to complete the test. (Strauss, Tr. 676:9-678:2, 742:2-18; see also Hilleman, Tr. 2137:22-2139:7.) 31. By 1987, the art taught doses of adenosine that were likely to cause controlled

hypotension in anesthetized humans undergoing cerebral aneurysm surgery. (TX 112; TX 1169; TX 1171; D.I. 147 at ¶¶ 68-85.) A person of ordinary skill in the art would have understood that doses of adenosine likely to be successful for MPI would be less than the doses needed to induce controlled hypotension for surgery. (Strauss, Tr. 708:10-709:12, 705:19-707:2, 747:10748:13, 748:22-749:20.) 4. 32. Plaintiffs Ignore The Knowledge Of Ischemia In The Prior Art

The prior art, including Gould 1978 and Albro, taught use of dipyridamole

infusion as a pharmacologic stress agent for MPI. (TX 38; TX 93.) Gould 1978 teaches that dipyridamole infusion can cause ischemia in a patient undergoing MPI. (TX 38 at 286.) Albro also teaches that dipyridamole infusion for MPI can cause myocardial ischemia. (TX 93 at 756; Strauss, Tr. 672:17-674:11.)

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33.

At trial Dr. Strauss placed the risk of ischemia in proper perspective: Now to put this in perspective, it's important to recognize that when patients are studied with exercise, that the patients always become ischemic, because it is the intent of stressing the person in that fashion.

(Strauss, Tr. 689:10-14.) Although exercise stress necessarily causes ischemia in the heart patients undergoing MPI, exercise stress remains the preferred method of stress testing, even today. (Wackers, Tr. 996:25-997:3.) 34. The prior art taught that ischemia was less likely with pharmacologic stress MPI

using dipyridamole (which was known to be acting through adenosine) than with exercise. (TX 38 at 285.) 35. The known characteristics of adenosine, in particular its short half-life which

enabled negative side effects to cease almost immediately upon termination of administration, would have encouraged a person of skill in the art to use adenosine instead of dipyridamole for MPI because ischemia, if it occurred, could be reversed more rapidly after adenosine infusion. (Strauss, Tr. 673:17-674:11; 688:22-690:9.) 5. 36. 1987. 37. Statements in a 1970 article (TX 214) would not have discouraged a person of None Of The References On Which Plaintiffs Rely Taught Away ­ Either Alone or In Combination With Other Teachings In the Art

The prior art as a whole did not teach away from the use of adenosine for MPI in

ordinary skill in the art from using adenosine for MPI in 1987. Plaintiffs cite to a 1970 article that stated that use of adenosine in cardiovascular therapy had been precluded. (D.I. 146 at ¶ 38, citing TX 214 at 415.) TX 214, a 1970 article, does not reflect the state of the art in 1987. TX 214 is not medical literature of any relevant time. (Compare D.I. 146 at ¶ 38 with TX 214.) By 1983, the prior art reflected therapeutic use of adenosine for terminating tachycardia.

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(TX 36.) In addition, the 1970 statement in TX 214 concerned therapeutic, not diagnostic, use. (TX 214.) 38. To the extent the prior art taught that adenosine could have systemic effects, such

effects were at high doses and by bolus administration. (Strauss, Tr. 790:18-23.) 39. The 1983 publication The Coronary Circulation in Health and Disease, by Dr.

Melvin Marcus ("Marcus 1983", TX 217) did not teach away from use of adenosine for MPI in 1987. Marcus 1983 states that, "[b]ecause of the hypotensive effects of adenosine, it is not utilized clinically to produce maximal coronary dilation." (Id. at 430.) But Marcus 1983 described the use of adenosine in animals at very high doses. (TX 217 at 430-31; Tr. 800:18801:9.) By the middle of 1987, several references in the art including Sollevi 1984, Sollevi 1986 and Owall had disclosed that lower doses of adenosine would achieve controlled hypotension in anesthetized humans than Marcus 1983 used in dogs. (See TX 112; TX 1171; TX 1169.) These references after Marcus 1983 described doses of 200 mcg/kg/min of adenosine, or more, to induce controlled hypotension in humans. (See id.) Thus, in 1987 a person of skill in the art would not have been discouraged from using adenosine for MPI in humans at doses that were less than those that were known to produce hypotension in humans, which had been shown to be far below those described in the 1983 Marcus reference. (See Strauss, Tr. 759:14-22.) 40. A 1983 article entitled Adenosine: electrophysiologic effects and therapeutic use

for terminating paroxysmal supraventricular tachycardia, (TX 36, "DiMarco 1983") did not teach away from the use of adenosine for MPI in 1987. DiMarco 1983 describes the use of adenosine to treat heart arrhythmias by inducing AV block. (TX 36.) The adenosine administration described in DiMarco 1983 is rapid bolus injection, not continuous intravenous

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infusion. (Strauss, Tr. 760:13-20; TX 36.) DiMarco 1983 also described the advantages associated with adenosine's rapid clearance from the system, including the lack of persistent drug effect and rapid clearance that would allow a physician to titrate the adenosine dose individually, "gradually increasing the dose until the arrhythmia is stopped." (TX 36 at 1261.) A person of skill in the art in 1987 would have understood the distinction between rapid bolus injection, which is an all-at-once method of application appropriate for rapidly halting an inprocess cardiac arrhythmia, and continuous IV infusion used to create a stable effect for the duration of the infusion. (Strauss, Tr. 677:9-678:2.) DiMarco 1983 would not have discouraged that person of ordinary skill in the art from using adenosine for MPI in 1987. (Strauss, Tr. 760:13-20.) 41. A 1985 article entitled, Diagnostic and Therapeutic Use of Adenosine in Patients

With Supraventricular Tachyarrhythmias ("DiMarco 1985", TX 45) did not teach away from the use of adenosine for MPI in 1987. Like DiMarco 1983, DiMarco 1985 describes intravenous bolus doses of adenosine. (TX 45 at 418.) A person of ordinary skill in the art would understand the difference between bolus injections and continuous infusions. (Strauss, Tr. 677:9-678:2.) In addition, DiMarco 1985 states that "overdosage" of adenosine leads to hypotension. (TX 45 at 423.) (emphasis added). By 1987, the prior art taught what doses of adenosine were necessary to induce hypotension in anesthetized patients. (See TX 112; 1169; 1171.) A person of ordinary skill in the art would have reasonably expected that doses below the range of doses that cause hypotension would work for MPI. (See Strauss, Tr. 708:10709:12.) 42. Biaggioni 1986 taught toward, not away from, the use of adenosine for MPI.

(TX 48). Biaggioni 1986 cites art from 1930 and 1933 concerning the effect of "large boluses

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of the drug." (TX 48 at 2229.) Although this early work may have "discouraged further research" for some period of time in the past, by the publication of Biaggioni 1986 that era had ended. Biaggioni 1986 describes two areas in which adenosine was already being used clinically in 1986 ­ the treatment of PSVT and for controlled hypotension during anesthesia. (TX 48 at 2229.) Biaggioni 1986 itself describes the results of research concerning the cardiovascular effects of adenosine in conscious subjects. (See TX 48.) The disclosures of the Biaggioni 1986 reference would have taught a person of ordinary skill in the art that continuous intravenous infusion of adenosine at a dose of 140 mcg/kg/min would likely be tolerated by a majority of subjects (5 of the 7 subjects in the study), would result in vasodilation, but would not cause hypotension. (Strauss, Tr. 717:22-719:18; TX 48.) 43. Biaggioni 1986 also notes that intravenous infusion of adenosine had already been

shown to be useful in inducing a "sustained" hypotensive effect. (Id.) A person of ordinary skill in the art in 1987 would have known that continuous infusion, as opposed to rapid bolus injection, of adenosine would result in a sustained effect. (Strauss, Tr. 677:9-678:2.) This reference and other teachings in the art such as Sollevi 1984 demonstrate that it was known in the art before 1987 that continuous infusion of adenosine would result in a stable effect during the infusion. (Strauss, Tr. 692:12-694:7; TX 112.) 44. When the entire article is considered in context, Biaggioni 1986 teaches directly

toward using adenosine infusion at a dose up to about 140 mcg/kg/min for MPI. 45. Example XIII of the `296 patent expressly teaches an adenosine dose range of 10

to 150 mcg/kg/min for MPI. (TX 275 at col.21, ll.59-61; see also Strauss, Tr. 750:2-22.) The `296 patent does not teach away from any dose within this disclosed range of doses.

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46.

The prior art, taken as a whole, demonstrates a surge of interest in adenosine use

in humans during the early and mid 1980s. Sicor refers to Sicor's Proposed Findings for a discussion of the Sollevi 1984, Sollevi 1986, Owall, Biaggioni 1986, Conradson, Fuller and Biaggioni 1987 articles as well as the `296 patent. (See D.I. 147 at ¶¶ 68-119.) These references demonstrate that persons of skill in the art were not dissuaded from using adenosine in humans, even in human patients undergoing surgery. 47. Publications after 1988 are not prior art and should not be considered as to

whether they teach away from the use of adenosine for MPI. Even if the later publications are considered, they did not teach away from the use of adenosine for MPI in 1987. 48. In a 1995 chapter entitled "Myocardial Imaging During Adenosine Infusion,

authors Dr. Mario Verani and John J. Mahmarian stated "it is interesting to speculate" as to why adenosine usage for MPI evolved as it did. (TX 240, Wackers, Tr. 953:17-24; 954:13-17.) Dr. Verani's passing speculation in 1995 is not a relevant or probative assessment of the state of the art in 1987. The evidence also establishes that in 1987 Dr. Verani was not skeptical that adenosine should be used for MPI. Dr. Verani stated in a research protocol in 1987 that given "present knowledge" of adenosine, the benefits from investigating adenosine for MPI "clearly outweigh the unlikely possibilities of side effects or complications." (TX 52 at AST0009468; Wackers, Tr. 1023:6-7; 1024:24-1025:11.) The 1995 statements neither suggest nor establish teaching away in 1987. 49. The 1990 articled entitled "Effects of Adenosine on Human Coronary Arterial

Circulation" by Robert F. Wilson and others ("Wilson," TX 46) also did not teach away as of 1987 and does not reflect that the state of the art in 1987 "taught away" from use of adenosine. Wilson refers to concerns that he states "hampered" use of adenosine in humans, but he does not

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state when use of adenosine had been "hampered" or when that ended. This comment in the 1990 Wilson publication does not establish that a person of skill in the art would have been discouraged from using adenosine in 1987. 50. The 1990 Editorial Comment entitled "Adenosine, Renewed Interest in an Old

Drug" (the "Editorial," TX 47) did not teach away from adenosine use in 1987. Plaintiffs have cited to the portion of the Editorial that states that adenosine "never achieved clinical usefulness . . ." (See D.I. 145 at 7.) From context, "never" in the Editorial can only mean the time from 1929 until sometime unspecified time before the date of the Editorial in 1990. The Editorial also states "[h]owever, adenosine is now becoming a clinically relevant compound. There is increasing interest in 1) its application in the diagnosis and treatment of supraventricular arrhythmias, 2) its potential importance in the evolution and treatment of myocardial ischemia, and 3) its use as an ultrashort-acting coronary vasodilator." (TX 47 at 1854.) At a minimum, "never" as used in the Editorial must have ended by 1983 when DiMarco 1983 was published, and the statements in the Editorial are not credible evidence that in 1987 the state of the art taught away from using adenosine in humans. 51. The teachings in the prior art at the relevant time suggested the use of adenosine

for MPI. The prior art did not teach away from this use. D. PLAINTIFFS PRESENT NO SECONDARY CONSIDERATIONS THAT REBUT THE STRONG CASE OF OBVIOUSNESS 1. 52. No Unexpected Results

The result of adenosine infusion within the claimed dosages ranges was expected

based on the teachings in the prior art. The evidence does not show any unexpected results for an adenosine infusion dose at any rate, including a rate of 140 mcg/kg/min.

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53.

There is no evidence that a dose of about 140 mcg/kg/min provides any

unexpected or unpredictable benefits. 54. The named inventors of the `877 patent did not identify any unexpected or

unpredictable results from the use of a dose of about 140 mcg/kg/min of adenosine for MPI. 55. Nothing in the `877 patent supports the proposition that the invention included the

recognition that some discomfort may accompany the use of adenosine as a pharmacologic stress agent. (See TX 320.) Tolerable side effects of adenosine at an infusion dose of 140 mcg/kg/min were known in the art in 1987. (See, e.g., TX 48 at 2233; TX 1208 at 311.) The side effects of dipyridamole were known by those of ordinary skill in the art to be similar to those reported in art for adenosine, and a person of ordinary skill in the art would have expected these types of effects from adenosine infusion. (Strauss, Tr. 720:11-14.) 56. There is also no evidence in the record that "about 140" mcg/kg/min results in any

better images or any greater accuracy than any other dose between 60 and 120 mcg/kg/min. 57. There is no evidence that the named inventors of the `877 patent made any

determination that a dose of about 140 mcg/kg/min provided any better image quality than any other dose. The named inventor's first set of infusions of adenosine to humans was to normal volunteers. (See TX 295.) Dr. Mohiuddin did not remember why a dose of 140 mcg/kg/min was chosen, but he thought it was based on experience with side effects of adenosine. (Mohiuddin, Tr. 1878:2-18.) The written record of the infusion to healthy volunteers shows that the dose of 140 mcg/kg/min was infused to each of the volunteers. (TX 295 at AST0004333.) There is no evidence that the inventors compared the image quality at 140 mcg/kg/min in these healthy volunteers with the image quality at any other dose prior to their use of adenosine for MPI in heart patients.

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58.

The named inventors later infused adenosine to 15 different patients at doses from

60 to 140 mcg/kg/min. (Wackers, Tr. 1018:2-17; TX 296 at 4357.) The dose of 140 mcg/kg/min was used in only two of the 15 patients described in the study. (Wackers, Tr: 1018:13-17; TX 296 at 4357.) The study results show that doses of 60, 100 and 120 mcg/kg/min also resulted in successful identification of myocardial dysfunction in those patients, as occurred in the case of the 140 dose (Wackers, Tr: 1017:14-1018:12; TX 296 at 4357, 4364.) The evidence of record concerning what doses of adenosine will work for MPI demonstrates that doses of 60, 100 or 120 mcg/kg/min will work. (See id.) 59. The Wilson study on which Plaintiffs rely shows only a minor difference in

coronary blood flow reserve between the dose of 100 mcg/kg/min and 140 mcg/kg/min. (TX 46 at 1601, Table 4 and Figure 4.) The insignificance of the difference is also shown in the later published textbook Clinical Nuclear Cardiology, a text that cites to Wilson in support of a graph showing the coronary flow reserve at 100 and 140 mcg/kg/min of adenosine as equal. (TX 5011 at 235, figure 14.1; Tr. 1030:4-12.) 60. The data in Wilson does not include results for intravenous doses of either 120 or

160 mcg/kg/min of adenosine. (See generally TX 46.) Wilson does not compare, describe or discuss the quality of myocardial perfusion images at any dose. Id.) The data show no significant difference between doses of 100 and 140. (Id.) Neither Wilson nor anything else in the record suggests that a dose of "about 140" mcg/kg/min of adenosine had unexpected or unpredictable results when used for MPI.

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2. 61.

No Skepticism or Teaching Away

Plaintiffs have not demonstrated any skepticism by persons skilled in the art

during the relevant time. 62. Nothing in the December 31, 1987 letter from Dr. Carl W. White to Gail R.

Salzberg of Medco shows skepticism in the art. (TX 53.) Dr. White states, "I am not certain how effective and safe adenosine would be as a coronary vasodilator for this purpose but would be interested in discussing this further." (TX 53.) Dr. White was sufficiently interested in using adenosine and sufficiently convinced that adenosine was likely to work that he went on to state in the same letter: We would definitely be interested in studying adenosine with our Doppler catheter to measure coronary flow reserves. I am certain that a protocol could be easily worked out comparing papaverine and adenosine. There are also other uses of intracoronary adenosine which we can envision that might also be of considerable interest to you. (TX 53.) This offer to work out a protocol and devote research time as of December 1987 does not suggest that the author was skeptical about whether adenosine would work. 63. The letter to the editor published in a June 1990 journal does not suggest

skepticism. (TX 169.) The letter notes the report of two instances of heart block in connection with a study concerning the use of adenosine for MPI that was published in December of 1989. (See id.) The letter asks for more detail about the two instances and expresses the need for more study and for caution during that study. (See id.) At most, this letter raises questions. It does not express disbelief that adenosine worked as described. 64. For many of the same reasons that they did not "teach away", none of the Wilson

article, the Editorial, or the 1995 Verani chapter support a finding of about the use of adenosine for MPI, either in 1990 or before. In fact, the Editorial concludes that "adenosine holds promise

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as a safe and effective coronary vasodilator that could be useful in studying the normal and abnormal coronary circulation in humans." (TX 47 at 1856.) 65. The hearsay testimony from one sales representative that some customers were

concerned about the use of Adenoscan® even as of its launch in 1995 also does not support skepticism. (See D.I. 145 at 17-18.) None of these customers appeared as witnesses. The only testimony presented was from one sales representative with a limited sales area. (See D.I. 145 at 17-18; Tr. 1535:11-1537:1.) That same sales representative testified that she was still trying to convince doctors within her sales area to switch from dipyridamole to adenosine as late as 2003. (See Tr. 1542:10-21.) Plaintiffs have not contended that the purported skepticism endured until 2003 ­ to do so would contradict their argument as to the commercial success of Adenoscan®. Ms. Klose's testimony is insufficient to demonstrate skepticism at any time. 66. The hearsay statement, which is based on Dr. Wackers' testimony as to what he

believes Dr. Marcus said at a conference almost twenty years ago, is not evidence of skepticism. Even assuming Dr. Marcus made the statement, it was in the context of a meeting where the general response was "great interest" in and "general excitement" about using adenosine for MPI. (Tr. 946:24-947:11; 1027:21-25.) Dr. Wackers did not recall Dr. Marcus's exact words. (Tr. 1026:23-1027:12.) Whatever Dr. Marcus may have said was, at most, a caution, not a statement that Dr. Marcus did not think the drug would work. (Id.; see also Tr. 1027:13-20.) 67. The fact that the audience attending the cardiology meeting in 1989 responded to

a presentation concerning the use of adenosine for MPI with "great interest" and that "[p]eople were very interested in this alternative way of doing stress testing" is strong evidence that there was no skepticism in the art. (Wackers, Tr. 946:16-947:3.) Instead, there was there was "a

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general excitement and interest" in the adenosine protocol at that 1989 meeting, which is far from skepticism. (Wackers, Tr. 1027:21-1028:3.) 68. Finally, Dr. Strauss' testimony that he titrated up to a dose of 140 mcg/kg/min

when he began using adenosine for MPI in 1991 does not show skepticism. (See Strauss, Tr. 779:23-780:14.) The salient fact is that Dr. Strauss was actually infusing adenosine into humans for purposes of MPI. (See TX 314.) This is not evidence of skepticism. 3. Sicor Has Shown That Any Alleged Commercial Success Is Due To Economic Factors, Not To The Claimed Invention a. There Is No Nexus Between Any Alleged Commercial Success of Adenoscan® And Any Alleged Superiority Of The Subject Matter Of The Asserted Claim

69.

The sales levels achieved by Adenoscan® are explained by the interplay of four

economic factors and do not demonstrate any particular value of the claimed invention that would suggest that the `877 patent was not obvious at the relevant time: (1) There was only one other FDA-approved competitor in the pharmacological stress-testing market at the time of Adenoscan® entry; Adenoscan® became the only promoted product in the pharmacological stress testing market shortly after its entry; Extensive marketing and promotion of Adenoscan® by Fujisawa; and Growth in demand for pharmacological stress testing unrelated to the asserted inventions

(2)

(3)

(4)

(Leffler, Tr. 1579:3-1582:13; DTX 3133; see also D.I. 143 at 32-34 and D.I. 147 at ¶¶ 168-225.) 70. The sales levels achieved by Adenoscan® are explained by these factors,

not any particular value of the claimed invention. (See D.I. 147 at ¶¶ 168-225.)

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i. 71.

Adenoscan® Entered the Pharmaceutical Stress Market at a Fortuitous Time

Fujisawa had been working for years to secure FDA approval for and

launch Adenoscan. (See, e.g., TX 1226 at AST0065726-727.) In that time, the company developed countless strategic relationships with physician advocates and sponsored the activities of the American Society of Nuclear Cardiology ("ASNC"). (Leffler, Tr. 1611:10-15, 1612:9-1613:4; White, Tr. 1252:17-25, 1339:4-15; TX 1078 at AST006674.) Fujisawa was hardly the "new kid on the block." (See generally, D.I. 147 at ¶¶ 181-208.) 72. Fujisawa launched Adenoscan® in the pharmacological stressor market at

a propitious time. (D.I. 147 at ¶¶ 169-180.) Because the manufacturer of Persantine®, the only other directly-competing product, ceased promotion spending after Persantine® went generic in late 1996, Adenoscan® had the good fortune, not long after its launch, to become the only product being advertised to the prescribers of pharmacological stress tests. (See id.) 73. The audience for the Adenoscan® marketing message was relatively price

insensitive. The prescribing physicians do not themselves pay for the product and expect that their patients will be covered by federal or private health insurance. (Leffler, Tr. 1691:11-1692:4.) ii. 74. Fujisawa's Extensive Marketing and Promotion Drove Adenoscan®'s Market Share Growth

The evidence shows that Fujisawa's promotion of Adenoscan was not

"typical" in the industry. (D.I. 147 at ¶¶ 181-208.) Fujisawa's spending was devoted to extensive traditional and non-traditional marketing activities, including substantial detailing efforts; support of the American Society of Nuclear Cardiology ("ASNC"); - 18 DB01:1797288.2 058956.1016

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support of physician advocates; provision of financial incentives such as trial product and pumps to prospective customers; sole sponsorship of industry "educational initiatives"; and promotion of Adenoscan® for new uses and user populations. (See id.) 75. On cross-examination, Dr. Hay admitted that the 6% industry-standard

average promotion-to-sales ratio that he relied on for his testimony that Fujisawa's spending was "typical" was essentially a concocted number and inappropriately applied to the pharmacological stress market. (Hay, Tr. 1760:19-24, 1761:3-9, 1763:15-18, 1764:1-1765:6.) 76. Dr. Hay's 6% was not based on reliable data; without any basis in fact, Dr.

Hay "calculated" this 6% ratio as the "midpoint" between two other numbers that are based on reliable data: the 12% industry average for drugs sold primarily in retail pharmacies and the 3.1% industry average for drugs sold primarily in hospitals. (Hay, Tr. 1761:12-1762:6.) 77. Dr. Hay admitted that the appropriate average promotion-to-sales ratio for

Adenoscan® is 3.1% because pharmacological stress products are sold primarily in hospitals and clinics, and not in retail pharmacies. (Hay, Tr. 1760:19-24; Tr. 1761:3-9, 1763:15-18, 1764:1-1765:6.) 78. Dr. Hay also admitted that if a line were drawn at the 3% mark on the

misleading demonstrative used to illustrate his testimony, it would be clear that Fujisawa's marketing and promotional spending would exceed the average in every single year from 1995 through 2005. (Hay, Tr. 1766:18-1777:12; DTX 2041.) 79. Fujisawa's advertising and promotional spending in at least the years

1996, 1999 and 2001 was in fact roughly twice as high as the average promotional

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spending for hospital-dominated products in those years. (Hay, Tr. 1766:18-1777:12; DTX 2041.) This is especially remarkable given that the pharmacological stress market is very concentrated, requiring fewer resources to reach the marketing audience. (D.I. 147 at ¶¶ 182-186.) It is also remarkable in a market in which, as Plaintiffs argue, the consumers are "expert," and therefore "not swayed" by product promotion. (D.I. 146 at 119.) iii. 80. Adenoscan's Increasing Sales Were Also Due to the General Growth of the Pharmacologic Stress Market

Despite Plaintiffs' representations concerning relative market shares,

Adenoscan® did not grow market share at the expense of dipyridamole, the incumbent product in the pharmacological stress market. (Leffler, Tr. 1600:6-16, 1632:4-7; DTX 3132; see also D.I. 147 at ¶ 218-220.) 81. Although the market was ripe for a new entrant when Fujisawa launched

Adenoscan®, it took over six years for the sales of Adenoscan® to overtake dipyridamole, even with the differential in the prices of the products. (D.I. 147 at ¶¶ 212-13.) 82. The higher overall level of growth achieved by Adenoscan® can be

attributed to the company's extensive marketing and promotion investment in creating and capturing additional user populations for the product. (D.I. 147 at ¶¶ 198-202.) 83. The higher overall growth level is also attributable to a general growth in

demand for pharmacological stress testing unrelated to the asserted invention, and due instead to demographic phenomena such as the increased aging of the American population and the rise in American obesity. (D.I. 147 at ¶ 215.) As Plaintiffs' witness

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Mr. White pointed out, "rising water raises all the boats"--i.e., dipyridamole as well as Adenoscan®. (White, Tr. 1257:11-12.) 84. Adenoscan®'s success is thus based on a fortuitous market occurrence and

is not probative of non-obviousness. (See also D.I. 147 at ¶¶ 168-225.) b. 85. Dr. Hay's Analysis Is Unsound and His Testimony Unreliable

As demonstrated infra, the testimony of Plaintiffs' expert, Dr. Hay, was

unreliable and his analysis of the economic issues in this case was inaccurate. 86. A discussed supra, Dr. Hay relied on a concocted industry average that is

inappropriate for the niche market of pharmacological stress agents. 87. In addition, Dr. Hay did not conduct his analysis based on the actual facts

in this case. For example, in response to questions about Fujisawa's 86-member sales force, which Dr. Hay had earlier disagreed was twice the size of the sales force of its competitor, DuPont, Dr. Hay admitted when pressed that he "[didn't] know exactly what DuPont was doing." (Hay, Tr. 1774:24-1776:19.) Despite this lack of knowledge, Dr. Hay testified on direct to an opinion on the relative detailing efforts of Fujisawa and DuPont. (Id.) 88. Dr. Hay also used dollar-based market share as a preferred measure of the

relative success of Adenoscan® and dipyridamole (Hay, Tr. 1777:11-1778:3) even though Astellas's own Senior Vice President of Marketing, Richard White, testified that the preferred measure used internally by Astellas to gauge the success of its products is market share of procedures performed. (White, Tr. 1286:23-1287:9.) 89. Market share of procedures performed is a more appropriate measure of

relative demand in a market because if one product is generic, and therefore lower-

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priced (e.g., dipyridamole) and another is branded, and therefore priced much higher than the generic (e.g., Adenoscan®), then even if both products sell just one unit, the branded product will appear to have a much higher dollar-based market share even though the products' respective market shares of procedures performed are equal. (Hay, Tr. 1779:2-7.) 90. Dr. Hay also inappropriately chose to use gross sales to calculate market

shares and promotion-to-sales ratios, even though he admitted on cross examination that gross sales is an "inflated number" and that Mr. White testified that net sales "represents the money that the company actually takes in for the sales of its product" because it factors out "certain returns and allowances." (White, Tr. 1236:21-1237:3; Hay, Tr. 1788:2-15.) 91. At several points throughout his testimony, Dr. Hay was intent on

criticizing Dr. Leffler's testimony even though he had either incorrectly heard the testimony or had failed to listen to it altogether. (Hay, Tr. 1767:13-1768:14.) In one instance, Dr. Hay was forced to admit that his criticism on direct examination of Dr. Leffler's calculation of a promotion-to-sales ratio was based on a calculation that Dr. Leffler had revised since his opening report and had been not presented to the Court at trial. (Hay, Tr. 1773:25-1774:23.) Dr. Hay's apparent personal bias against Dr. Leffler and his disregard of the facts make him an unreliable source for this Court to rely on. (See id.). c. 92. Dr. Leffler Is A Highly Qualified Expert

The trial record contradicts Plaintiffs' attempt to characterize Dr. Leffler

as anything less than a highly qualified and credible expert witness in this case.

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93.

Dr. Leffler is an Associate Professor of Economics at the University of

Washington, and he has been a practicing economist for over 32 years since receiving his Ph.D. in economics from the University of California at Los Angeles in 1977. (Leffler, Tr. 1562:2-11, 17-18.) 94. Dr. Leffler's teaching and research focus is the government regulation of

business, which includes antitrust issues, patent issues, and contract issues. (Leffler, Tr. 1562:19-24.) 95. Dr. Leffler has extensive expertise in the economics of the pharmaceutical

industry owing to work he completed in support of his doctoral thesis, a still frequentlycited article he wrote on the role of advertising and promotion in the success of pharmaceutical products, a position as a resident scholar at Pfizer Pharmaceuticals, and consulting projects he has performed over the years for various pharmaceutical companies. (Leffler, Tr. 1564:4-1566:10, 1568:7-23.) 96. In addition to serving as a consultant to the Department of Justice, Dr.

Leffler has been qualified as an expert witness in federal and state courts as well as before state agencies and federal regulatory agencies such as the Federal Trade Commission. (Tr. 1563:7-12, 1564:2-3.) 97. Dr. Leffler's qualifications have been specifically acknowledged, and his

economic analyses adopted, by several federal and state courts. See, e.g., Wash. Legal Found. v. Legal Found. of Wash., 271 F.3d 835 (9th Cir. 2001); Pfizer Inc. v. Teva Pharms. USA, Inc., 461 F. Supp. 2d 271 (D.N.J. 2006); In re Fla. Microsoft Antitrust Litig., 2002 WL 31423620 (Fla. Cir. Ct. 2002).

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98.

Plaintiffs complain about a typographical error on one of the

demonstrative exhibits that Dr. Leffler discussed during his testimony, (D.I. 146 at ¶ 126), but Dr. Leffler clearly explained to the Court that the data the exhibit (DTX 3131) was meant to display was also before the Court in DTX 3132 and DTX 3134, which did not contain the typographical error. (Leffler, Tr. 1697:13-1698: 23.) 99. Plaintiffs also complain that Dr. Leffler used IMS data to calculate a

promotion-to-sales ratio and considered IMS data in other sections of his economic analysis (D.I. 146 at ¶ 128), but Dr. Leffler openly acknowledged that because there is a certain level of underreporting in IMS sales figures, IMS data is not the most appropriate source of data for the calculation of a promotion-to-sales ratio, and he certainly did not present such a calculation to the Court. (Leffler, Tr. 1673:9-12.) 100. Dr. Leffler also educated the Court as to why IMS data is appropriate for

the purpose of comparing the relative sales performance and market shares of the pharmaceutical products of concern in this suit. (Leffler, Tr. 1586:4-23, 1587:9-1589:7.) Other data sources, such as Astellas' internal sales figures and measures of scans performed in the market, are not sufficient for this purpose. (Leffler, Tr. 1589:8-19.) 101. Plaintiffs assert that Dr. Leffler "disavowed" his conclusion that there was

a slowing of the revenue growth rate from the late 1990s through mid-2000 (D.I. 146 at ¶ 127), but this is not true. 102. First, Dr. Leffler pointed out that the gross sales figures on which

Plaintiffs rely are not real numbers, but rather "accounting numbers" that do not include price concessions, returns, and other allowances and therefore do not truly reflect the

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amount of money the company has generated from a product. (Leffler, Tr. 1700:241701:6.) 103. Second, Dr. Leffler explained that when looking at the net sales data, one

sees a so-called "second wind" in or about mid-2000, which reflects "a therapeutic category explosion," resulting in an increasing, rather than declining, growth rate from that point forward. (Leffler, Tr. 1701:7-1702:17.) 104. Dr. Leffler further pointed out that Adenoscan®'s growth following mid-

2000 was in part due to its ability to benefit from the category explosion to a greater extent than its competitor since it was the only product being promoted in the market. (Leffler, Tr. 1702:22-1703:3.) 105. Plaintiffs also attempt to discredit Dr. Leffler by asserting that "Dr. Leffler

never consulted any physicians" about what product qualities or benefits drive their purchasing decisions, (D.I. 146 at ¶ 125), but as an economist, it would have been inappropriate for Dr. Leffler to engage in research to determine whether or not Adenoscan® is or is not in fact a superior product. (Leffler, Tr. 1570:23-1571:21, 1631:5-11.) E. THE `296 PATENT AND/OR THE KAROLINSKA REQUEST DISCLOSE MORE THAN THE NAMED INVENTORS' PROTOCOL DISCLOSED AND ARE PRIOR ART In an attempt to antedate certain prior art, including Example XIII of the `296

106.

patent, Plaintiffs rely on a protocol entitled "Clinical Utility of Adenosine in Radionuclide Myocardial Imaging" in order to prove a conception date prior to Dec. 28, 1987 ("the Protocol", TX 57). 107. The protocol is a research proposal that calls for routine experimentation to

determine an adequate dose of adenosine for MPI. (See TX 57; Wackers, Tr. 1013:4-7.; see - 25 DB01:1797288.2 058956.1016

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also D.I. 145 at 37 referring to the Protocol as "a testing protocol.") Dr. Wackers testified that the Protocol did not constitute conception of any specific dose of adenosine for MPI. (Wackers, Tr. 1013:13-22; 1015:15-1016:1.) 108. None of the three endpoints proposed in the Protocol specifies an endpoint related

to whether sufficient vasodilation for effective MPI was achieved. (TX 57 at AST0001046; Wackers, Tr. 1013:1-12.) 1. 109. 110. Example XIII Of The `296 Patent

Example XIII disclosed more to a person of skill in the art than did the Protocol. Example XIII teaches that, for purposes of MPI, adenosine will work as a

vasodilator for MPI and 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; Strauss, Tr. 750:12-22.) The `296 patent discloses twelve other examples teaching adenosine at varying doses for different purposes. (See TX 275.) Example XIII therefore teaches that each dose in the range of 10 to 150 mcg/kg/min will work for MPI, depending on the patient. (See Strauss, Tr. 750:12-22.) 111. A person of ordinary skill in the art would understand from the `296 patent and

Example XIII that the endpoint of titration would be sufficient coronary vasodilation to perform MPI in that particular patient. (TX 275 at col. 21, ll. 59-61; Strauss, Tr. 839:8-17.) 112. Example XIII of the `296 patent is prior art to the `877 patent. 2. 113. The Karolinska Request

The Karolinska Request discloses that adenosine could be used to replace

dipyridamole as the pharmacologic stress agent for MPI at a dose of 60 mcg/kg/min. (TX 1193 at SIC010943-44; Strauss, Tr. 754:9-13, 755:6-14.) 114. The Karolinska Request discloses more than was disclosed in the Protocol. - 26 DB01:1797288.2 058956.1016

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115.

The Karolinska Request was publicly available and is valid prior art to the `877

patent. (See TX 1193 at SIC010937.) II. PROPOSED CONCLUSIONS OF LAW A. 1. CLAIMS 23(17), 23(18) AND 43 OF THE `877 PATENT ARE INVALID AS OBVIOUS The Court must determine whether Sicor "has met its burden by clear and

convincing evidence by considering the totality of the evidence, including any rebuttal evidence presented by the patentee." See Pfizer, Inc. v. Apotex, Inc. 480 F.3d 1348, 1360 (Fed. Cir. 2007); see also Tec Air, Inc. v. Denso Manuf. Mich., Inc., 192 F.3d 1353, 1360 (Fed. Cir. 1999) ("`Whether the evidence presented [by patentee] suffices to rebut the prima facie case is part of the ultimate conclusion of obviousness and is therefore a question of law.'" (quoting In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1998))) (emphasis in original). 2. Sicor has proved obviousness of the asserted claims by clear and convincing

evidence. Plaintiffs' evidence of certain secondary indicia of non-obviousness is insufficient to rebut Sicor's showing of obviousness. Accordingly, Claims 23(17), 23(18) and 43 of the '877 patent were obvious in light of the prior art at the time of the invention. 1. 3. Sicor Has Shown Obviousness By Clear And Convincing Evidence

Sicor has demonstrated that, when the prior art is considered as a whole, a person

of ordinary skill in the art in 1987 would have been motivated to use adenosine for MPI. 4. A reference may teach away from the claimed invention "when a person of

ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant." Optivus Tech., Inc. v. Ion Beam Apps. S.A., 469 F.3d 978, 989 (Fed. Cir. 2006) (quoting In re Kahn, 441 F.3d 977, 990 (Fed. Cir. 2006)). Whether a reference "teaches away" - 27 DB01:1797288.2 058956.1016

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should be considered based on the teachings of the prior art as a whole, and should not be based on isolated statements taken out of context. See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1166 (Fed. Cir. 2006) ("[T]he prior art must be considered as a whole for what it teaches.") (emphasis in original). 5. Whether the prior art teaches away from, or motivates toward, a combination is a

question of fact. In re Fulton, 391 F.3d 1195, 1199-1200 (Fed. Cir. 2004). 6. The Federal Circuit has provided some guidance as to the types of things that do

not "teach away." Disclosure in the prior art of variety of alternatives, without specific dissuasion from a particular choice, does not constitute teaching away from any one of the alternatives. Id. at 1201. In addition, a reference "that does not specifically refer to one element of a combination does not, per se, teach away." Syntex LLC v. Apotex, Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005). 7. 1987. 8. Reference that are not prior art may be used only in limited circumstances to show The prior art as a whole did not teach away from the use of adenosine for MPI in

the state of the art at the relevant time. See In re Koller, 613 F.2d 819, 824 (C.C.P.A. 1980). 9. The use of adenosine for MPI, at the doses identified in the asserted claims,

including within the range of 20-200 mcg/kg/min and at a dose of about 140 mcg/kg/min would have been obvious to a person of ordinary skill in the art in 1987. (See D.I. 147 at ¶¶64-119.) 2. 10. The Secondary Considerations Argued By Plaintiff Do Not Rebut The Strong Prima Facie Case Of