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

Civil Action No.: 05-0336-SLR

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

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TABLE OF CONTENTS Page I. II. INTRODUCTION ...............................................................................................................1 SICOR FAILED TO PROVE OBVIOUSNESS IN VIEW OF THE SOLLEVI PRIOR ART.........................................................................................................................2 A. "Common Sense" Informed by the Prior Art Would Have Led One of Ordinary Skill to Retain the Dipyridamole Pretreatment, Not Omit It....................4 1. Sicor Offers No Explanation of Why Dr. Sollevi and Dr. Fukunaga Used and Recommended Dipyridamole Pretreatment If Mere "Common Sense" Would Have Led One to Omit It......................................................................................................5 Sicor's Purported "Suggestions" to Omit Pretreatment with Dipyridamole Would Not Have Overcome the Clear Teaching Away In the Art ...........................................................................................8 Sicor's Assertion that One of Ordinary Skill Would Have Believed that Dipyridamole's Effect Was Waning Is Untimely and Contradicted by the Record.................................................................13

2.

3.

B.

One of Ordinary Skill in the Art Would Not Have Expected Adenosine to Be Useful For Any Application Other than Controlled Hypotension ...............16 1. 2. The Prior Art Cited by Sicor Related to Controlled Hypotension ...............................................................................................16 Dr. Binkley's Testimony Concerning Proposed Alternative Uses for Adenosine Infusion Was Not Disclosed in His Expert Report.........................................................................................................18 Sicor's Proposed Alternative Medical Uses for Adenosine Are Technically and Legally Deficient.............................................................21 a. b. c. 4. Heart Failure ..................................................................................21 Hypertension ..................................................................................22 Limb Ischemia ...............................................................................22

3.

Sicor Has Not Demonstrated Any Reasonable Expectation of Success In Using Adenosine For Other Medical Applications..................23

III.

SICOR FAILED TO PROVE OBVIOUSNESS IN VIEW OF THE FUKUNAGA PRIOR ART ...............................................................................................25

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A. B. IV.

Sicor Ignores Direct Evidence of ATP's Direct Vasodilating Activity in Human Patients in Favor of Assumptions by Dr. Binkley ................................25 Sicor's Assertion of What One of Ordinary Skill Would Have Done is Flatly Contradicted by What Dr. Fukunaga Actually Did......................................27

SICOR DISMISSES THE CONTEMPORANEOUS EVIDENCE OF NONOBVIOUSNESS .......................................................................................................28 1. Contemporaneous Writings Show Serious Concerns About the Side Effects Sicor Dismisses as Unimportant............................................28 a. Dr. Berne's Publication of the Adenosine Hypothesis Did Not Lead to Consideration of Adenosine as a Pharmaceutical Vasodilating Agent...............................................29 Dr. Sollevi's Testimony and the 1980s-Vintage Correspondence of Drs. Berne and Robicsek Is Compelling Evidence of the State of Mind of Experts in the Field and Is Not Inadmissible Hearsay ................................30

b.

2. 3. V. VI.

It Was Unexpected that Such a Low Dose of Adenosine Could Be Used In the Absence of Dipyridamole .................................................35 Sicor's Critique of the Commercial Success of Adenoscan® Rings Hollow In the Face of Its Efforts to Copy the Drug ........................36

SICOR FAILED TO PROVE ANTICIPATION IN VIEW OF FUKUNAGA.................39 CONCLUSION..................................................................................................................41

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TABLE OF AUTHORITIES FEDERAL CASES Page(s) Al-Site Corp. v. VSI Int'l, Inc., 174 F.3d 1308 (Fed. Cir. 1999)................................................................................................12 Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286 (Fed. Cir. 2006)..........................................................................................26, 27 In re Bell, 991 F.2d 781 (Fed. Cir. 1993)....................................................................................................8 In re Bowen, 492 F.2d 859 (C.C.P.A. 1974) .................................................................................................23 Burlington Indus., Inc. v. Quigg, 822 F.2d 1581 (Fed. Cir. 1987)................................................................................................30 Capon v. Eshar, 418 F.3d 1349 (Fed. Cir. 2005)................................................................................................23 Citizen's Fin. Group, Inc. v. Citizens Bank of Evans City, 383 F.3d 110 (3d Cir. 2004).....................................................................................................30 Coal. to Save Our Children v. State Bd. of Educ., 90 F.3d 752 (3d Cir. 1996).......................................................................................................19 In re Cook, 439 F.2d 730 (C.C.P.A. 1971) .................................................................................................23 Diamond Rubber Co. v. Consol. Rubber Tire Co., 220 U.S. 428 (1911).............................................................................................................5, 36 In re Doumani, 281 F.2d 215 (C.C.P.A. 1960) ...........................................................................................17, 18 In re Dow Chem. Co., 837 F.2d 469 (Fed. Cir. 1988)..................................................................................................30 Dystar Textilfarben GMBH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006)............................................................................................8, 28 F.T.C. v. Freeman Hospital, 911 F. Supp. 1213 (W.D. Mo. 1995) .......................................................................................36 iii

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George v. Celotex Corp., 914 F.2d 26 (2d Cir. 1990).......................................................................................................32 Graham v. John Deere Co., 383 U.S. 1 (1966).....................................................................................................................28 Hobbs v. Beach, 180 U.S. 383 (1901).................................................................................................................29 Howerton v. Grace Hospital, No. 4:90CV187, 1995 WL 787529 (W.D.N.C. July 5, 1995) .................................................36 Interconnect Planning Corp. v. Feil, 774 F.2d 1132 (Fed. Cir. 1985)..................................................................................................7 KSR Int'l. Co. v. Teleflex, Inc., 127 S.Ct. 1727 (2007)........................................................................................8, 23, 24, 25, 34 Kraft Gen. Foods, Inc. v. BC-USA, Inc., 840 F.Supp. 344 (E.D. Pa. 1993) .............................................................................................30 In re Kratz, 592 F.2d 1169 (C.C.P.A. 1979) ...............................................................................................23 In re Lemin, 364 F.2d 864 (C.C.P.A. 1966) .................................................................................................34 Loom Co. v. Higgins, 105 U.S. 580 (1881)...................................................................................................................5 In re Methionine Antitrust Litig., No. 00-1311, 2003 WL 22048232 (N.D. Cal. Aug. 26, 2003) ................................................36 In re Oelrich, 579 F.2d 86 (C.C.P.A. 1978) .............................................................................................12, 34 Ormco Corp. v. Align Tech, Inc., 463 F.3d 1299 (Fed. Cir. 2006)..........................................................................................38, 39 Potts v. Creager, 155 US 597 (1895).....................................................................................................................5 In re Rinehart, 531 F.2d 1048 (C.C.P.A. 1976) ...............................................................................................23

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Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373 (Fed. Cir. 2003)................................................................................................40 In re Shetty, 556 F.2d 81 (C.C.P.A. 1977) ...................................................................................................23 Threadgill v. Armstrong World Indus., Inc., 928 F.2d 1366 (3d Cir. 1991)...................................................................................................32 United States v. Adams, 383 U.S. 39 (1966).............................................................................................................30, 34 United States v. Kairys, 782 F.2d 1374 (7th Cir. 1986) .................................................................................................32 United States v. Stelmokas, 100 F.3d 302 (3d Cir. 1996)...............................................................................................31, 32 Verdegaal Bros., Inc. v. Union Oil Co. of Cal., 814 F.2d 628 (Fed. Cir. 1987)..................................................................................................39 In re Wesslau, 353 F.2d 238 (C.C.P.A. 1965) ...........................................................................................10, 28 Zenith Labs. Inc. v. Bristol-Myers Squibb Co., 19 F.3d 1418 (Fed. Cir. 1994)..................................................................................................27 FEDERAL STATUTES 35 U.S.C. § 282..............................................................................................................................17 Fed. R. Civ. P. 26(a)(2)(B) ......................................................................................................18, 20 Fed. R. Civ. P. 37(c)(1)............................................................................................................18, 20 Fed. R. Evid. 803(3).......................................................................................................................30 Fed. R. Evid. 803(16)...............................................................................................................31, 32 Fed. R. Evid. 901(b)(4) .................................................................................................................32 Fed. R. Evid. 901(b)(8) ............................................................................................................31, 32

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I.

INTRODUCTION Sicor's current theory of the case utterly contradicts the actual contemporaneous evidence

in the prior art. Sicor suggests that one of ordinary skill would have believed it to be safer to administer an adenosine infusion to patients without dipyridamole pretreatment even though Dr. Sollevi had specifically included dipyridamole to reduce the chance of side effects with adenosine infusion and Dr. Fukunaga, another leader in the field, had recommended using dipyridamole for safety reasons in patients administered an infusion of ATP. Data in the scientific literature suggested that dangerously high doses of adenosine would be required in the absence of dipyridamole. Thus, Dr. Sollevi's ultimate success in performing controlled hypotension with an adenosine infusion at low doses without dipyridamole pretreatment was completely unexpected. Dr. Sollevi's fundamental method lies at the heart of the commercial use of adenosine today, a use that Sicor seeks to copy and that it admitted just before trial infringed U.S. Patent No. 5,731,296 (the `296 patent). Facing these difficult facts and an uphill battle at trial, Sicor repeatedly sought to change its theory of the case by relying on new information that was beyond the scope of its expert reports. It offered a wholly new theory that the dipyridamole pretreatment would have "worn off" by the end of the period of hypotension in Dr. Sollevi's studies so that one of ordinary skill would conclude that the pretreatment was not important. Besides never having been disclosed in Sicor's expert reports, this theory was factually flawed, as the prior art itself showed a continued strong effect of dipyridamole even after the hypotension period. Sensing the difficulty in showing that one of ordinary skill would have believed it safe to administer an adenosine infusion without dipyridamole pretreatment for the purposes described in the prior art, Sicor offered another wholly new theory that an ordinary cardiologist would have viewed a lower dose adenosine infusion as a suitable substitute for standard vasodilators in

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treatment of maladies such as congestive heart failure, limb ischemia, or hypertension. This attempt to change horses in midstream forced Sicor to elicit further expert testimony that was nowhere in its expert reports. Predictably, that testimony was, at best, simplistic and failed to account for the very properties of adenosine that had long prevented its use in the art. Even Sicor's expert, Dr. Binkley, whose primary field is heart failure, admitted that he has never used adenosine to treat patients with heart failure, despite opining that such treatment would have been an obvious choice in 1985. Fundamentally, Sicor's case is grounded on ex post reasoning supported almost entirely by the naked opinion of its expert, Dr. Binkley, who was not working in the field at the relevant time and whose testimony conflicts with what the evidence shows about those who were. Such shaky underpinnings hardly constitute clear and convincing evidence of obviousness and cannot support Sicor's conclusion of invalidity. II. SICOR FAILED TO PROVE OBVIOUSNESS IN VIEW OF THE SOLLEVI PRIOR ART In its expert reports and at trial, Sicor asserted that two prior art abstracts published by Dr. Sollevi more than one year before the effective filing date of the `296 patent (TX-1170 and TX-37, Sollevi I and Sollevi II, respectively) would have rendered his claimed invention obvious to one of ordinary skill in the art. (DB1 2). Both abstracts described the use of adenosine together with a dipyridamole pretreatment to induce controlled hypotension (reduction of blood pressure by about 40%) in a small group of patients during surgery. Sicor has alleged that it would have been obvious to eliminate the dipyridamole pretreatment and simply increase the

As used herein, "DB" refers to Defendants' Post Trial Brief (D.I. 150) and "PB" refers to Plaintiffs' Post Trial Brief (D.I. 151), both filed on May 9, 2007.

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adenosine dose to achieve the same physiological effect. This obviousness allegation was resoundingly refuted by the trial evidence. The stated purpose of the dipyridamole pretreatment in Sollevi I and II was to reduce the necessary dose of adenosine administered to the patients. (TX-1170; Sollevi 438:17-439:8.) Dr. Sollevi further explained that dipyridamole pretreatment would allow a more stable concentration of adenosine and "stabilize" or reduce the concentration gradient between the heart (where adenosine could cause heart block) and the peripheral circulation (where it lowered blood pressure). (Sollevi 438:17-439:8.) Dr. Sollevi had to administer an average dose of 140 mcg/kg/min of adenosine in patients treated with dipyridamole. (TX-1170; Sollevi 442:19-23.) Neither Dr. Sollevi nor anyone else knew how much adenosine would have to be administered in the absence of dipyridamole to obtain a similar reduction in blood pressure, but the expectation was that much more would have been required. (See Klabunde 1050:11-1051:8; Sollevi 439:24-440:17, 448:19-449:8.) Prior art studies involving induction of hypotension with ATP rather than adenosine had shown that approximately 12 times more ATP was required in the absence of dipyridamole (Klabunde 1050:24-1051:8), but studies of adenosine-induced hypotension in dogs suggested that an even larger dose could be necessary--on the order of 100 to 200 times more in the absence of dipyridamole (compare TX-40 at 70-71 with id. at 73 (reporting mean dose of 3 mg/kg/hr with dipyridamole compared to 600 mg/kg/hr without); Klabunde 533:24-536:1, 1050:15-23). Even if the necessary increase had only been 10-fold (i.e., 1,400 mcg/kg/min rather than 140 mcg/kg/min), administering such a high dose of adenosine by continuous infusion would not have been obvious, it would have been unthinkable. (Klabunde 537:18-538:6.)

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A.

"Common Sense" Informed by the Prior Art Would Have Led One of Ordinary Skill to Retain the Dipyridamole Pretreatment, Not Omit It

Sicor contends that "ordinary creative insights" and "common sense" would have led one of ordinary skill in the art to administer adenosine without a dipyridamole pretreatment. (DB 3, 22.) Yet, safety concerns caused more than 50 years to elapse between the first test of adenosine administration to humans and the first test of continuous adenosine infusion in conjunction with dipyridamole pretreatment by Dr. Sollevi. (See Klabunde 516:4-517:17, 520:24-522:2; Strauss 766:7-767:18.) Dr. Sollevi had specifically used dipyridamole pretreatment to reduce the dose of adenosine and prevent side effects (TX-1170; Sollevi 438:17-439:8), and an article by Dr. Fukunaga also recommended using dipyridamole as a way to reduce side effects in connection with ATP administration (TX-51; Klabunde 540:15-541:8). To suggest that both researchers were not just wrong but dangerously stupid, and that one of ordinary skill would have believed administration of adenosine without dipyridamole to be safer, strains credulity and is the purest form of hindsight. The Supreme Court has recognized for decades that after-the-fact assertions that a patented invention was the result of mere common sense should be viewed skeptically, particularly where those assertions are supported by little more than bare expert opinion: Many things, and the patent law abounds in illustrations, seem obvious after they have been done, and, `in the light of the accomplished result,' it is often a matter of wonder how they so long `eluded the search of the discoverer . . . .' Knowledge after the event is always easy, and problems once solved present no difficulties, indeed, may be represented as never having had any, and expert witnesses may be brought forward to show that the new thing which seemed to have eluded the search of the world was always ready at hand and easy to be seen by a merely skillful attention. But the law has other tests of the invention than subtle conjectures of what might have been seen and yet was not.

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Diamond Rubber Co. v. Consol. Rubber Tire Co., 220 U.S. 428, 434-35 (1911) (citation omitted). See also Potts v. Creager, 155 US 597, 608 (1895) ("The apparent simplicity of a new device often leads an inexperienced person to think that it would have occurred to any one familiar with the subject; but the decisive answer is that with dozens and perhaps hundreds of others laboring in the same field, it had never occurred to any one before."); Loom Co. v. Higgins, 105 U.S. 580, 591 (1881) ("Now that it has succeeded, it may seem very plain to any one that he could have done it as well. This is often the case with inventions of the greatest merit."). Sicor's unlikely conjecture, based on unsupported ex post expert opinions, cannot satisfy its burden of proving invalidity by clear and convincing evidence. This is particularly so where, as here, most of those opinions were not properly disclosed during expert discovery and were contradicted by direct contemporaneous evidence presented at trial. 1. Sicor Offers No Explanation of Why Dr. Sollevi and Dr. Fukunaga Used and Recommended Dipyridamole Pretreatment If Mere "Common Sense" Would Have Led One to Omit It

Acceptance of Sicor's assertion that "common sense" would lead to recognition that adenosine infusion would be safer without dipyridamole (DB 22, 31) would require the Court to conclude that Dr. Sollevi, one of the world's leading experts on adenosine and dipyridamole, knew less than one of ordinary skill and was foolish to include dipyridamole in the first place. Dr. Sollevi had, however, spent five to six years studying the pharmacology and physiology of adenosine and adenosine analogs in various species prior to embarking on his human studies. (Sollevi 434:12-17.) He had studied and was fully aware of the effects of dipyridamole. (Sollevi 477:15-478:1.) But he concluded that it would be safer to administer adenosine infusions to his surgical patients after dipyridamole pretreatment, particularly as a way of reducing the likelihood

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of AV block. (Sollevi 438:17-439:6.) Indeed, Dr. Sollevi noted that in the prior human studies in which larger doses of adenosine were administered as a bolus, only AV block was observed, not a hypotensive vasodilator effect. (TX-36 at 1259; see Sollevi 460:3-20, 487:6-14.) Reducing the dose of adenosine through dipyridamole pretreatment also reduced the potential for kidney toxicity due to uric acid accumulation. (See Sollevi 440:18-441:5.) Dr. Sollevi further explained that dipyridamole stabilized the concentration gradient between the heart and the peripheral circulation. (Sollevi 438:17-439:6.) This is important because intravenously administered adenosine will reach the heart before it is transported to the more distant portions of the circulatory system. (See Binkley 250:5-251:19.) Thus, there is a steep "gradient" in adenosine concentration with the highest concentrations near the heart and lower concentrations in the more peripheral parts of the arterial circulation. See id. However, it is these more distant sites in the circulation that regulate blood pressure through selective arterial vasodilation. (Binkley 248:4-249:3.) Thus, whatever the necessary concentration of adenosine is to cause selective vasodilation in the periphery, a higher amount will be experienced by the heart before the drug passes along to the periphery.2 Dr. Sollevi used dipyridamole to flatten the adenosine concentration gradient between the heart and the periphery by slowing down the metabolic breakdown of adenosine. (Sollevi 438:17-439:6.) As a practical consequence, less adenosine would need to be present at the heart to get the same amount to the periphery. Thus, Dr. Sollevi had good reason to administer dipyridamole as a way of improving patient safety, and there is no evidence that one of ordinary skill in the art would have reached the opposite conclusion.
2

Dr. Biaggioni commented on this phenomenon, which results from the short half-life of adenosine, in a 1986 article that is not prior art to the `296 patent but was acknowledged as authoritative by Dr. Klabunde. (TX-48 at 2235; Klabunde 520:24-521:4.)

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Indeed, Sicor's "common sense" argument also requires the Court to conclude that Dr. Fukunaga was foolish to recommend using dipyridamole pretreatment in connection with infusion of ATP. After publishing his initial study on the administration of a continuous infusion of ATP to patients to induce controlled hypotension in the Fukunaga 1982 abstract (TX-42), Dr. Fukunaga published a second study two years later in which his patients were pretreated with dipyridamole before infusion of the ATP. (TX-51; Fukunaga 1984.) Dr. Fukunaga explicitly suggested that dipyridamole be administered as a way of avoiding the problem of buildup of metabolites like uric acid. (Id.; Klabunde 540:15-541:8.) Thus, Dr. Fukunaga recognized the value of dipyridamole in reducing the chances of side effects in connection with ATP administration. While Sicor contends that "common sense" would have led one of ordinary skill to eliminate the dipyridamole pretreatment described in the Sollevi I and Sollevi II abstracts and to conclude that administration of adenosine would be safer without it, Sicor offers no explanation of why Dr. Fukunaga reached a directly contrary conclusion with respect to administration of ATP. To support its common-sense argument, Sicor notes that it is always preferable to administer one drug rather than two. (DB 22.) Both Dr. Sollevi and Dr. Fukunaga plainly would have had the same preference. Yet, each of them co-administered dipyridamole because they felt it had important safety benefits. There is, therefore, a logical disconnect between the ex post opinions of Sicor's expert and the testimony and writings of those who were actually present at the relevant time. Of the two, the Federal Circuit has held the latter to be more reliable. Interconnect Planning Corp. v. Feil, 774 F.2d 1132, 1143 (Fed. Cir. 1985) ("A retrospective view of the invention is best gleaned from those who were there at the time.").

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While the Supreme Court in KSR instructed courts not to overlook common sense in analyzing obviousness, this Court should be highly skeptical when a defendant resorts to purported "common sense" that contradicts the clear teaching of the prior art. See KSR Int'l. Co. v. Teleflex, Inc., 127 S.Ct. 1727, 1742 (2007). The "common sense" suggested by Sicor is nothing more than the same thinly disguised hindsight accused infringers have relied on since the 1800s to minimize the perceived importance of a patented invention. 2. Sicor's Purported "Suggestions" to Omit Pretreatment with Dipyridamole Would Not Have Overcome the Clear Teaching Away In the Art

Sicor argues that dipyridamole would prolong any side effects that would occur because dipyridamole has a longer half-life than adenosine. (DB 31.) But as discussed above, Dr. Sollevi believed such side effects would be less likely to occur due to the lower dose and smoother adenosine concentration gradient attained with dipyridamole pretreatment. (Sollevi 438:17-439:6, 440:18-441:5.) Moreover, the use of dipyridamole by both Dr. Sollevi and Dr. Fukunaga to reduce the dose of adenosine (or ATP) administered, thereby reducing the chance of side effects, clearly would have taught away from administering adenosine by infusion without dipyridamole pretreatment. Although Sicor discusses concerns about side effects primarily in its consideration of objective or "secondary" indicia of nonobviousness, the question of whether a reference teaches away rather than toward a claimed invention is part of the factual inquiry required to determine the scope and content of the prior art on which Sicor bears the burden of proof by clear and convincing evidence. Dystar Textilfarben GMBH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360 (Fed. Cir. 2006); see also In re Bell, 991 F.2d 781, 784 (Fed. Cir. 1993) ("What a reference teaches and whether it teaches toward or away from the claimed invention are questions of fact."). Here, Sicor's conjecture that one of ordinary skill would have believed 8

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administration of adenosine infusion would be safer in the absence of dipyridamole pretreatment must be weighed against the clear fact that (1) the art had refused for safety reasons to use adenosine in humans for 50 years after discovery of its vasodilating properties (see, e.g., Klabunde 521:5-23; Strauss 766:7-767:18), (2) the only known human medical use of adenosine alone was to interfere intentionally with electrical conduction in the heart (to treat PSVT) (see, e.g., TX-36; TX-45; Klabunde 523:18-524:10), (3) both the Sollevi I and II abstracts and the Fukunaga 1984 abstract taught that dipyridamole pretreatment should be used to minimize the dose of adenosine or ATP, and (4) Fukunaga 1984 explicitly made the point that use of dipyridamole would have "greatly avoided" the problem of accumulation of toxic metabolites (TX-51). In an effort to respond to these clear teachings, Sicor relied on a previously undisclosed 1984 article by Berne (TX-5000, Berne 1984), noting that dipyridamole potentiated AV block induced by hypoxia or ischemia. (See DB 11.)3 Sicor's reliance on Berne 1984 is both untimely and misplaced. While Sicor asserts that one of ordinary skill would have learned from Berne 1984 that dipyridamole pretreatment should be omitted, that assertion conveniently ignores the fact that the article is entirely about adenosine's potent ability to interrupt the electrical conduction in the heart and that the only clinical use for adenosine discussed in the article is in the treatment of PSVT. (TX-5000 at 1196.) While the Berne 1984 article noted that dipyridamole potentiated the natural physiological effect of AV block, which occurred after induction of hypoxia or ischemia in laboratory animals, it concluded that such potentiation occurred because endogenous Despite admitting at trial that TX-5000 had not been previously disclosed and representing to the Court that it was not being offered into evidence, Sicor repeatedly relies on that very exhibit, citing it no less than five times in its brief. (Compare Binkley 1505:6-20 with DB 10, 11, 12, 30.)
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adenosine was causing the AV block. (Id. at 1195-96.) This can hardly be read as supporting the use of exogenous adenosine as a clinical vasodilator. Even if the article had shown that dipyridamole potentiated AV block caused by high doses of exogenous adenosine, such a teaching would not be inconsistent with the clear benefit of using dipyridamole to reduce the necessary dose of adenosine and avoid the need for administering AV block-inducing doses in the first place. Far from teaching the clinical benefits of administering adenosine infusions without dipyridamole pretreatment, the Berne 1984 article merely reinforced the teaching that adenosine causes AV block even when the dose was "small and did not reduce systemic blood pressure." (TX-5000 at 1196.) It is elementary patent law that a defendant may not "pick and choose from any one reference only so much of it as will support a given position, to the exclusion of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art." In re Wesslau, 353 F.2d 238, 241 (C.C.P.A. 1965). Accordingly, Sicor's reliance on a single out-of-context idea in the Berne 1984 article is misplaced and ineffective in countering the teaching away in the art. Moreover, Berne 1984 (TX-5000) and witness testimony about it should be excluded because Sicor never disclosed the document during discovery and it was never commented on by any expert prior to trial. See Plaintiffs' Opening Brief (PB) § VIII.A. Sicor does not even argue that the document was disclosed, but instead makes the completely baseless assertion that the article was referred to in correspondence between Dr. Berne and Dr. Sollevi. (See DB 12; see also fn. 2, supra.) This assertion tests the boundaries of good faith, as it is not supported by any witness or other evidence and is flatly contradicted by the testimony of Dr. Sollevi, who identified DiMarco 1983 (TX-36) as the publication referred to in the correspondence. (Sollevi

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460:18-20.) Indeed, Sicor plainly chose not to ask Dr. Sollevi about the article when it had the opportunity to do so at trial. Sicor further relies on a speculative statement in an article by Kassell (TX-40) that dipyridamole pretreatment might not be necessary in humans to avoid excessive fluid administration. (DB 22.) The problem of adenosine infusion in human patients was not simply the volume of fluid carrier needed to contain the adenosine, which was the problem addressed in the portion of Kassell cited by Sicor. The problem was concern that the amount of the adenosine active ingredient could cause heart block or build up of undesirable metabolites in human patients. The Kassell statement is, therefore, utterly irrelevant to the question of whether a person of ordinary skill would have perceived the dipyridamole pretreatment in Sollevi I and Sollevi II to be an unnecessary human safety precaution. More significantly, the experiments reported by Kassell were in dogs, not humans. By the time of the invention of the `296 patent, there was no need to speculate about the relationship between the amount of adenosine with dipyridamole pretreatment needed to achieve a 40% reduction in blood pressure in dogs (Kassell) versus humans. The Sollevi I and Sollevi II abstracts provided a basis for such comparison. The issue was whether elimination of the dipyridamole in Sollevi I and Sollevi II would require infusion of a dangerously high level of adenosine. The portion of Kassell relevant to this issue was his report of a dramatic increase in the amount of adenosine required in the absence of dipyridamole--two orders of magnitude more. (TX-40 at 73; Klabunde 533:15-536:1.) The possibility of needing up to 200 times more adenosine than was used in Sollevi I and Sollevi II with dipyridamole pretreatment would have made elimination of that pretreatment in humans unthinkable. (Klabunde 535:13-536:8.)

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Moreover, the subsequent actions of Dr. Sollevi and Dr. Fukunaga in treating actual human patients, where both recommended dipyridamole pretreatment, are more compelling than the speculative statements of Kassell based on his dog work. As the Federal Circuit has stated: In determining how the Oelrich disclosure was interpreted by those skilled in the art, we are more impressed by what those so skilled Did than by what they Said. Even though the words of the Oelrich patent implied that sub-critical operation was feasible, it was never, in fact, considered when a concrete problem requiring such operation was actually presented to two persons of ordinary skill in the art, both intimately familiar with the Oelrich patent. In re Oelrich, 579 F.2d 86, 91 (C.C.P.A. 1978). Even the patent examiner agreed that Kassell was no impediment to the patentability of the claims issued in the `296 patent. The article and the statement relied on by Sicor was explicitly discussed in the patent specification itself (see TX-275 at col. 5, ll. 18-44), yet the examiner allowed the claims over it. Indeed, in addition to Kassell the patent examiner had before him all three of the primary references relied on by Sicor (all three are listed on the face of the patent). (See TX-275.) Such circumstances, in which a challenger offers little more than a "do over" of the patent examination process, result in an "especially difficult" burden for the party asserting invalidity. Al-Site Corp. v. VSI Int'l, Inc., 174 F.3d 1308, 1323 (Fed. Cir. 1999). Sicor's additional alleged "suggestions" in the prior art to remove the dipyridamole pretreatment suffer from similar weaknesses. For example, Sicor asserts that the Sollevi I and II abstracts "conclude[] by referring to the intravenous administration of adenosine without any reference to a dipyridamole pretreatment." (DB 27.) In reality, neither abstract "refers" to or suggests administering adenosine without dipyridamole pretreatment. To the contrary, both merely refer to the properties of adenosine that had been demonstrated in the clinical tests on patients who were pretreated with dipyridamole. (See TX-37; TX-1170.) For the reasons

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discussed above, one of ordinary skill in the art would have had good reason to believe that such pretreatment was an important part of the overall protocol. Likewise, Sicor mischaracterizes in its brief the dose of adenosine disclosed in the Sollevi I and II abstracts, suggesting that both disclosed "administration of adenosine at a rate of 140 µg/kg/min, which falls within each of the claimed rates of administration." (DB 27.) Of course, the "claimed rates of administration" are rates of administration without dipyridamole pretreatment, whereas the only doses disclosed in the abstracts were with dipyridamole pretreatment. Sicor's citation to case law about "dose optimization" is thus irrelevant in view of the fact that the prior art dose information was not even in the context of the claimed method. Indeed, as discussed above, one of ordinary skill in the art would have expected that much higher doses of adenosine would be required if the dipyridamole pretreatment were to be eliminated. See Section II., supra, third paragraph. 3. Sicor's Assertion that One of Ordinary Skill Would Have Believed that Dipyridamole's Effect Was Waning Is Untimely and Contradicted by the Record

Based on the work of Dr. Klabunde and Dr. Sollevi's own abstracts and publications, one of ordinary skill in the art would have expected that dipyridamole would have a large inhibitory effect on adenosine metabolism even at the end of the surgical hypotension period described by Dr. Sollevi. (Klabunde 530:18-532:3.) Sicor contends in its brief (DB 26), however, and Dr. Binkley asserted for the first time at trial, that one of ordinary skill would have concluded there was "very little, if any, dipyridamole effect" remaining at the end of the surgical hypotensive period because of the rate of return of adenosine levels to baseline and the rate of reversal of the blood pressure effect when the infusion was stopped (Binkley 154:1-17, 147:1221). This theory, like many others offered by Dr. Binkley at trial, was not disclosed in his expert

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reports. (Objection at 155:15-19, 261:12-262:14; TX-26; TX-43.) Moreover, it is completely unsupported by the record. To the contrary, according to the Sollevi II abstract (TX-37), in the presence of dipyridamole, adenosine levels did not return to control levels until 3 to 9 minutes after the adenosine infusion was discontinued at the end of the surgical hypotensive period. (TX-37; Klabunde 530:9-532:3.) This is a clear indication of the continuing effects of dipyridamole. Based on adenosine's known short half-life (<10 seconds), one of ordinary skill would have expected adenosine blood levels to return to normal in only 30 to 40 seconds in the absence of dipyridamole. (Klabunde 531:1-532:3.) Dr. Binkley admitted as much on cross-examination, contradicting his earlier testimony. (Binkley 265:13-23.) The slow return to normal of the adenosine levels (3 to 9 minutes versus 30 to 40 seconds) thus demonstrated that dipyridamole had a strong and continuing effect on adenosine metabolism throughout the period of hypotension. (Klabunde 531:11-532:3.) The facts on cross-examination having undermined his initial opinion that the effects of dipyridamole had worn off, Dr. Binkley offered rebuttal testimony on yet another new theory. This theory had also not been previously disclosed in Dr. Binkley's expert reports. (See Binkley 1385:10-1386:6, 1392:17-23, 1397:13-14.) Most of this second theory concerned the so-called "functional half-life" of dipyridamole, which Dr. Binkley testified was between 30 and 40 minutes and corresponded to the half-life of the "physiological effect of the drug." (Binkley 1380:20-1381:22.) This new theory was contradicted, however, by Dr. Binkley's deposition

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testimony that "[t]he half-life of dipyridamole is 40 to 80 minutes and, therefore, you could have greatly prolonged effects of both the dipyridamole and the adenosine."4 (Binkley 1474:8-23.) Furthermore, regardless of Dr. Binkley's view on the half-life of dipyridamole, the literature available prior to the filing date of the `296 patent would still have led one of ordinary skill in the art to conclude that dipyridamole was having a powerful inhibiting effect on adenosine metabolism, even at the end of the hypotensive period. (Klabunde 531:1-532:3.) For example, Dr. Sollevi published an article in 1984 concerning the effect of dipyridamole treatment in humans showing that even 75 minutes after administration of dipyridamole, the blood levels of adenosine were elevated and the amount of dipyridamole in the blood was 0.8 micromolar. (TX-1173 at 167; Binkley 1480:4-22.) At that concentration, the level of inhibition of adenosine breakdown would have been slightly less than 90 percent. (Klabunde 1039:15-1040:14.) Consequently, persons of ordinary skill would have expected that dipyridamole was continuing to greatly reduce the necessary dose of adenosine throughout even the longest hypotensive period of adenosine treatment in Dr. Sollevi's studies. (See TX-1170 (reporting mean adenosine infusion time of 33 minutes, range 12 to 71 minutes); Klabunde 1042:15-22.) There is certainly no clear and convincing evidence that such persons would have recognized that dipyridamole was having no effect at the end of the adenosine infusion.

On redirect, Dr. Binkley asserted that his deposition testimony was not referring to the "functional" half-life of dipyridamole, but that assertion is itself inconsistent with the entire thrust of his deposition testimony, which was that the 40 to 80 minute half-life of dipyridamole could lead to "greatly prolonged effects of both the dipyridamole and the adenosine." (Binkley 1507:8-12, 1474:8-23.)

4

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B.

One of Ordinary Skill in the Art Would Not Have Expected Adenosine to Be Useful For Any Application Other than Controlled Hypotension

Sicor's other assertions of obviousness in view of the Sollevi I and II abstracts are also both untimely and unmeritorious. Sensing the frailty of its argument for removal of dipyridamole from the processes of Sollevi I and Sollevi II, Sicor contends that one of ordinary skill in the art would have expected adenosine to be useful at lower doses for medical purposes other than inducing controlled hypotension. (DB 3.) But the only prior art it identified and relied upon at trial concerned surgical hypotension, not other medical uses. (Binkley 285:11-20; Klabunde 528:12-529:1; DTX-2002). These new contentions were not disclosed in Sicor's expert reports, are devoid of the evidentiary support needed to prove them had they been properly disclosed, and are simply scientifically and legally wrong. 1. The Prior Art Cited by Sicor Related to Controlled Hypotension

As detailed in Plaintiffs' Opening Brief, for 50 years prior to the early 1980s, adenosine had been known as a compound that was too toxic and too short acting to have any useful human medical purpose. (Plaintiffs' Opening Brief (PB) at §§ III.A-B.) Early studies had revealed that adenosine exerted powerful inhibitory effects on the electrical signals that cause the heart to beat (AV block). (TX-48 at 2229; Klabunde 520:23-522:2; see also TX-36 at 1254; Klabunde 517:2-17.) Patients administered a bolus dose of adenosine experienced periods of slow heartbeat or temporary cardiac arrest, neither of which would be acceptable in a general-use vasodilator. (TX-48 at 2229; TX-36 at 1254; Klabunde 520:23-522:2.) In addition, rather than recognizing potential benefits of the short half-life of adenosine, prior art researchers saw it as a liability, believing adenosine's vasodilatory effects would be too transitory to be useful. (TX-214 at 415; Binkley 326:23-328:1; Strauss 769:23-770:20.)

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Not surprisingly in view of the state of the scientific literature, the only medical use of adenosine infusion in the prior art relied upon in Dr. Binkley's expert reports concerned selective vasodilation for inducing controlled hypotension during surgery. (Binkley 285:11-20, 1484:7-1485:7; DTX-2002.) Sicor's invalidity theory was that it would have been obvious to use adenosine for controlled hypotension without the dipyridamole pretreatment. As the trial evidence unfolded, it became clear that Sicor could not effectively rebut the evidence discussed above that one of ordinary skill in the art would have predicted that a dangerously high dose of adenosine would have been needed to induce surgical hypotension without dipyridamole pretreatment. So Sicor instead resorted on rebuttal to a wholly new theory that one of ordinary skill might use lesser amounts of adenosine to achieve lesser degrees of selective arterial vasodilation for other medical uses. Specifically, it was alleged that it would have been obvious to use adenosine without dipyridamole pretreatment in humans for myocardial imaging and to treat heart failure, hypertension, and limb ischemia. (See DB 20-21.)5 Sicor, however, did not offer into evidence any statutory prior art describing these other medical uses. Nor could it have, because no such prior art or invalidity theory had been disclosed in its expert reports or notice under 35 U.S.C. § 282. Nor did Sicor offer any substantive comparison between the pharmacologic profiles of adenosine and vasodilators previously used for these other purposes of the sort needed to prove its new obviousness allegation. In re Doumani, 281 F.2d 215, 217 (C.C.P.A. 1960) ("The
5

Sicor cites to testimony by Dr. Klabunde (1079:21-1080:2) for the proposition that lesser degrees of arterial vasodilation "would be important for other medical uses," but the cited testimony is completely inapposite (DB 20). In the testimony relied on by Sicor, Dr. Klabunde merely agreed, in response to a question about one of his own publications concerning the halflife of adenosine in dogs (TX-1036), that a general goal in understanding physiologic mechanisms might be to "stimulate other people to use what you found by using practical medical applications." (See Klabunde 1079:3-1080:2.)

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question whether such a substitution is obvious must be determined on the basis of the circumstances of each case, especially the extent to which similarity and equivalence between the substances involved are recognized in the prior art.") For example, Sicor did not offer testimony comparing the expected patient profile, mode of administration, side effect profile, potency, half-life, or other clinical characteristics of the known vasodilators to adenosine to show how "common sense" would have led to substitution of adenosine in these other medical applications and an expectation that such substitution would be safe and effective. 2. Dr. Binkley's Testimony Concerning Proposed Alternative Uses for Adenosine Infusion Was Not Disclosed in His Expert Report

While technologically and legally unmeritorious for reasons discussed in §§ II.B.3. and 4., infra, Dr. Binkley's opinions on purported alternative medical uses for adenosine should be excluded because they were not included in either of his expert reports. See Fed. R. Civ. P. 26(a)(2)(B), 37(c)(1). Dr. Binkley's opening expert report included a detailed discussion of the Sollevi I and II references and his opinion that the references would have rendered the claimed invention obvious, but the report was utterly silent as to alternative medical needs that one of ordinary skill would have reasonably expected adenosine to fill. Sicor points to paragraphs 6466 of the report as supporting Dr. Binkley's opinions (DB 20, fn.10), but these paragraphs are clearly written only in the context of adenosine's use for controlled hypotension in the Sollevi I and II abstracts and do not mention uses like treatment of "congestive heart failure," "hypertension," or "limb ischemia." Indeed, far from suggesting these other uses of adenosine, the report contends that one of ordinary skill would test various doses in an effort to find one that would result in the same physiological effects reported in the Sollevi I and II abstracts, i.e., controlled hypotension,

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without dipyridamole pretreatment and without serious side effects. As stated in paragraph 67 of Dr. Binkley's expert report, not cited by Sicor: Therefore, in my opinion, a person of ordinary skill in the art who wished to use adenosine to achieve the same physiological effects reported in Sollevi I and Sollevi II would first administer a dose of 140 µg/kg/min of adenosine as a matter of routine experimentation. If this dose was not sufficient to produce the desired effects, the person of ordinary skill would increase the dose until the desired effects were achieved. (TX-26 at 22, ¶ 67, emphasis added.) In this regard, Dr. Binkley did not even offer testimony about treatment of hypertension, heart failure, or limb ischemia with adenosine in his testimony in Sicor's case-in-chief, but only on rebuttal during the last week of trial. While Sicor apparently contends that such rebuttal testimony need not comply with the expert disclosure rules (see Tr. 1369:12-17), that contention is contrary to Third Circuit law. See Coal. to Save Our Children v. State Bd. of Educ., 90 F.3d 752, 775-76 (3d Cir. 1996) (upholding district court's exclusion of expert testimony where party failed to supplement expert reports and instead offered surprise rebuttal testimony at trial). Dr. Binkley also changed his testimony concerning the Biaggioni 1985 abstract during rebuttal. Having agreed on cross-examination during the first week of trial that the Biaggioni 1985 abstract did not show any medical use of adenosine he offered contrary testimony during rebuttal. During the first week of trial Dr. Binkley testified as follows: Q. [Mr. Lipsey] Okay. And have I correctly identified the medical uses described in those five publications in DTX-2002. Namely, controlled hypotension for the first four and no medical use in Biaggioni? A. Yes. (Binkley 256:13-17.) Yet two weeks later, on leading questioning from his own counsel, Dr. Binkley stated:

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Q. [Ms. Hassett] And do you agree with the view that the Biaggioni abstract is unrelated to any medical use that would be of significance to a person of ordinary skill in September 1985? A. Well, no, I don't really agree with that. (Binkley 1375:14-18; but see 1484:17-1485:7.) Dr. Binkley went on to expand further on his view of how the Biaggioni 1985 abstract would relate to the use of adenosine in the treatment of heart failure, a view that was not mentioned in his expert report. (See TX-26 at 26-27.) Dr. Binkley also repeatedly asserted at trial that the Biaggioni 1985 abstract demonstrated selective arterial vasodilation (see Binkley 174:5-13, 1375:20-1377:4), despite having failed to include such an opinion in his expert reports. Indeed, Dr. Binkley even admitted that he had "not stated explicitly" in his report that Biaggioni 1985 showed selective arterial vasodilation. (See Binkley 307:2-14, 1444:5-25.) Dr. Binkley's discussion of Biaggioni 1985 in his expert report was limited to what it would teach in combination with the Fukunaga 1982 abstract (TX-42). (See TX-26 at 26-27). Allowing Dr. Binkley to offer these new and undisclosed theories for the first time during the last week of trial would be unfair and highly prejudicial to the Plaintiffs. The Federal Rules require disclosure of expert opinions and provide that the consequence for failing to disclose such opinions is that they will be excluded at trial. Fed. R. Civ. P. 26(a)(2)(B), 37(c)(1). By failing to disclose Dr. Binkley's opinions, Sicor avoided the scrutiny and deposition crossexamination contemplated by the Federal Rules. Given adequate disclosure of the opinions, Plaintiffs could have asked their own experts to search the literature and respond to Dr. Binkley's bare assertion that such alternative uses for adenosine would have been obvious to an ordinary physician in September 1985. By eliciting the undisclosed opinions for the first time at trial, and after Plaintiffs' expert had testified, Sicor enjoyed the benefit of surprise without the potential for rebuttal. 20

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3.

Sicor's Proposed Alternative Medical Uses for Adenosine Are Technically and Legally Deficient

Sicor's apparent premise that all selective arterial vasodilators would be interchangeable for all medical purposes is clearly not true. Simply by way of one example apparent from the trial record, dipyridamole did not produce profound hypotension in Dr. Sollevi's studies, whereas adenosine did. (Klabunde 1166:4-9.) Without a detailed comparison between the properties of adenosine and the properties of other known vasodilators used in these other medical uses, Dr. Binkley's opinions that adenosine infusion could be used in lieu of those other vasodilators to treat heart disease, hypertension, or limb ischemia (see Binkley 1367:20-1368:2) are simply not credible and should be accorded no weight. (See Binkley 1489:24-1490:22.) a. Heart Failure

Dr. Binkley blithely opined that adenosine infusion would have been administered as a treatment for patients suffering from heart failure because other vasodilators had been so used (Binkley 1371:22-24), but he did not address concerns that would have existed about administering to patients with heart disease a compound like adenosine known to be capable of inducing slowing of the heartbeat (bradycardia), temporary cardiac arrest, and extreme hypotension. The field was so concerned about these effects that nobody used adenosine to treat heart disease for decades after its vasodilating properties were discovered. (See, e.g., TX-214 at 415.) Even in the 1990s, physicians were reluctant to administer adenosine infusions to patients with coronary artery disease because of concern over AV block. (Klose 1516:3-1517:1.) Indeed, Dr. Sollevi was sufficiently concerned about the effects of adenosine in heart patients that he excluded such patients from his studies. (TX-1170 ("Nine patients (35-58 years) without cardiopulmonary disease . . . ."); Sollevi 441:16-442:2.)

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Tellingly, despite identifying himself as a heart failure specialist who performs research on vasodilators (Binkley 74:1-4, 12-22), Dr. Binkley admitted that, even today, he has never used adenosine to treat heart failure as he proposed would have been obvious to one of ordinary skill in the art in 1985. (See Binkley 1490:5-11.) Such a disconnect between what an expert says would have been obvious and what he and everyone else actually did in the field is a strong indicator that the recently-formulated expert opinions are impermissibly based on hindsight. b. Hypertension

Dr. Binkely's vague reference to using adenosine in patients with hypertension is equally flawed. As shown in the Biaggioni 1985 abstract, administration of adenosine did not reduce mean arterial blood pressure in normal volunteers at a doses of 140 mcg/kg/min, and higher doses were not tolerable. (TX-1187; Klabunde 554:14-555:17.) Dr. Binkley did not address how one of ordinary skill in the art would have expected to find a tolerable and efficacious dose for reducing blood pressure based on the information in Biaggioni 1985. (See Klabunde 555:18-556:14.) c. Limb Ischemia

Similarly, with respect to treatment of limb ischemia, Dr. Binkley stated only that "[t]here were some efforts to do that at times with ischemic limbs with other vasodilators." (Binkley 1372:11-24, emphasis added.) This testimony does not indicate whether the "efforts" to use traditional vasodilators to treat limb ischemia actually worked and does not even establish a reasonable expectation of success with existing vasodilators, much less adenosine. The mere possibility that adenosine could cause heart block in human patients manifest from widespread reports of this effect in the literature would logically have counseled against its use for garden-variety vasodilator applications where other proven, safer drugs were available that did not carry this liability. 22

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4.

Sicor Has Not Demonstrated Any Reasonable Expectation of Success In Using Adenosine For Other Medical Applications

It has long been the law that in unpredictable arts, proof of obviousness requires proof of a reasonable expectation of success. See, e.g., In re Rinehart, 531 F.2d 1048, 1053-54 (C.C.P.A. 1976). The KSR decision did not change this aspect of the law of obviousness. While the Supreme Court found error in the Federal Circuit's conclusion that the patent claim in KSR could not be proved obvious merely by showing that the combination of elements was "obvious to try," that finding was in the context of a mechanical invention where there was "a design need or market pressure to solve a problem" and "a finite number of identified, predictable solutions," not an unpredictable pharmaceutical invention. See KSR, 127 S.Ct. at 1742, emphasis added. Numerous aspects of the patent law are applied differently in predictable mechanical technologies than they are in unpredictable technologies, like human medicine. See, e.g., In re Bowen, 492 F.2d 859, 862 (C.C.P.A. 1974); In re Cook, 439 F.2d 730, 734 (C.C.P.A. 1971); Capon v. Eshar, 418 F.3d 1349, 1358-59 (Fed. Cir. 2005). The requirement for a reasonable expectation of success is such a patent law principle that it is less easily satisfied where predictability is lacking, as it is here. See, e.g., In re Shetty, 556 F.2d 81, 86 (C.C.P.A. 1977); In re Kratz, 592 F.2d 1169, 1175 (C.C.P.A. 1979). Moreover, Sicor's reliance on the Supreme Court's reference to "common sense" in KSR as part of the broad obviousness inquiry is inappropriate here. (See DB 22.) The KSR Court noted only that in some fields, like the mechanical brake pedal there at issue, there might be "little discussion of obvious techniques or combinations" because market demand rather than scientific literature drives design considerations." KSR, 127 S.Ct. at 1741. The human medical use of vasodilators, however, is surely not such a field. Indeed, Sicor's expert, Dr. Strauss, identified 20,000 publications looking into the physiological effects of adenosine after

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Dr. Berne's 1963 publication on the "adenosine hypothesis." (Strauss 767:8-13.) This is not a field where the body of prior technical knowledge had not been reduced to writing and in which the dictates of unpublished "common sense" drive development decisions. Dr. Binkley offered opinions that "there was great interest" in vasodilating agents and that "adenosine would have appealed" to physicians treating congestive heart failure because of its short half-life, but he did not offer any basis by which a physician would reasonably expect that adenosine could be used successfully for that purpose. (See Binkley 1370:15-1371:24.) As discussed above, far from reasonably expecting success in patients with a history of coronary artery disease, the field eschewed use of adenosine as a vasodilator in humans for 50 years, and Dr. Sollevi, concerned about the effects of adenosine infusion in heart patients, excluded such patients from his study. (See TX-1170; Sollevi 441:16-442:2.) In the face of such contrary evidence, it is not enough for Dr. Binkley simply to assert that the use of adenosine would have "appealed" to those in the field or that those in the field would have been "interested" in knowing whether adenosine could be used as a vasodilator in congestive heart failure. Further demonstrating the disconnect between Dr. Binkley's general opinions about "interest" and an actual opinion about what would have been obvious, Dr. Binkley opined that one of ordinary skill might "consider" using adenosine for myocardial perfusion imaging in September 1985 based on knowledge that dipyridamole worked by influencing levels of endogenous adenosine. (See Binkley 1374:4-1375:7.) Yet, when pressed on cross examination as to whether he meant that that use would have been obvious, Dr. Binkley said no. (Binkley 1491:5-12.) While the Supreme Court in KSR directed that courts must not focus unduly on the problem the inventor was trying to solve where other needs or problems in the field might have

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suggested the claimed invention (see KSR, 127 S.Ct. at 1742), Sicor has failed to offer reliable evidence that one of ordinary skill in the art would have expected adenosine infusion to be successfully useable for any medical use other than controlled hypotension and then only with a dipyridamole pretreatment. III. SICOR FAILED TO PROVE OBVIOUSNESS IN VIEW OF THE FUKUNAGA PRIOR ART A. Sicor Ignores Direct Evidence of ATP's Direct Vasodilating Activity in Human Patients in Favor of Assumptions by Dr. Binkley

Sicor also asserts that the Fukunaga 1982 abstract would have rendered the claimed invention obvious because one of ordinary skill would know that adenosine, not ATP, was causing selective arterial vasodilation. (DB 29-30.) As an initial matter, the Fukunaga 1982 abstract says nothing about selective arterial vasodilation and the cardiac output data is too convoluted for one of ordinary skill to have drawn a meaningful conclusion that the vasodilation was primarily arterial. (TX-42; Klabunde 545:6-546:2, 548:9-20.) More importantly, direct evidence from human patients shows that ATP was having its own effect, wholly apart from any effect due to adenosine. As discussed in Plaintiffs' Opening Brief (PB 24-25), the Fukunaga 1984 abstract reported using a dose of 32 mcg/kg/min of ATP (alleged by Dr. Binkley to correspond to about 16 mcg/kg/min of adenosine) after pretreatment with dipyridamole to reduce blood pressure by about 40%. (Klabunde 549:4-550:24, 1044:5-25.) Dr. Sollevi needed approximately 140 mcg/kg/min to get the same effect with adenosine after pretreatment with dipyridamole. (Klabunde 549:4-550:24, 1044:5-25.) This requirement for significantly more adenosine than ATP to obtain the same effect was utterly inconsistent with the idea that ATP in humans was reducing blood pressure merely by acting as a precursor whose effects were being mediated primarily through adenosine. Prior art publications had shown that when ATP worked by being 25

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broken down into adenosine (as it did in the treatment of PSVT) ATP was less potent than adenosine, not more potent. (TX-36 at 1262; TX-152 at 198; Binkley 1459:20-1460:14; Klabunde 1211:20-1213:8.) That ATP was more potent than adenosine as a vasodilator in humans indicated a direct ATP-mediated vasodilator action. (Klabunde 551:20-552:3, 1044:5-25, 1117:5-1118:21.) This direct evidence is more compelling than Dr. Binkley's bare opinions