Free POST Trial Brief - District Court of Delaware - Delaware

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 1 of 45

IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

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

) ) ) ) ) ) ) ) ) ) ) ) ) )

Civil Action No. 05-337 SLR

DEFENDANTS SICOR INC. AND SICOR PHARMACEUTICALS INC.'S RESPONSIVE POST TRIAL BRIEF 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 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

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 2 of 45

TABLE OF CONTENTS Page

I. II.

INTRODUCTION .......................................................................................................... 1 RESPONSIVE ARGUMENT ......................................................................................... 3
A. THE ASSERTED CLAIMS WERE OBVIOUS IN LIGHT OF THE PRIOR ART............................................................................................................................... 3

1. 2.

The Law Of Obviousness......................................................................... 3 Sicor Has Shown Obviousness By Clear And Convincing Evidence ........ 4
a. b. c. d. e. The Underlying Facts Supporting Sicor's Prima Facie Case Of Obviousness Are Largely Undisputed.................................................... 4 There Is No Persuasive Evidence Of Teaching Away ............................ 4 The Field Of Pharmacologic Stress Agent Development For MPI Was Dormant For Several Years.......................................................... 13 The Prior Art Demonstrated The Speed And Safety Advantages Of Adenosine Over Dipyridamole ....................................................... 15 There Is Nothing Special About The Dose Of "About 140" Micrograms Per Kilogram Per Minute ................................................. 15

3.

The Secondary Considerations Argued By Plaintiff Do Not Rebut The Prima Facie Case ............................................................................ 19
a. b. c. No Credible Evidence Of Skepticism Or Surprise................................ 19 Copying Is Irrelevant In The ANDA Context....................................... 22 Any Commercial Success Enjoyed By Adenoscan® Does Not Rebut Obviousness Here ..................................................................... 23

i.

The Sales Levels of Adenoscan® Are Explained By the Interplay of Economic Factors................................... 23
(1) (2) (3) Adenoscan® Entered the Pharmacological Stressor Market at a Fortuitous Time .......................... 24 Fujisawa's Extensive Marketing and Promotion Drove The Adenoscan® Market Share Growth........... 25 Adenoscan®'s Increasing Sales Were Also Due to the General Growth of the Pharmacological Stress Market ............................................................. 26

ii.

Dr. Hay's Analysis Is Unsound and His Testimony Is Unreliable ................................................................... 28

B.

d. Lack Of Specific Suggestion Is Irrelevant............................................ 29 e. Simultaneous Invention Suggests Obviousness .................................... 30 THE ASSERTED CLAIMS ARE INVALID AS ANTICIPATED................................ 30

III. IV.

The `296 Patent Is Prior Art ................................................................... 30 The Karolinska Request Is Prior Art....................................................... 34 Claims 23(17) and 43 Are Anticipated By The `296 Patent And The Karolinska Request ......................................................................... 34 4. Claim 23(18) Is Anticipated By The `296 Patent .................................... 35 EVIDENTIARY ISSUES ............................................................................................. 35
A. B. RESPONSE TO PLAINTIFFS' EVIDENTIARY OBJECTIONS ................................. 35 OBJECTIONS TO EVIDENCE ON WHICH PLAINTIFFS HAVE RELIED............... 38

1. 2. 3.

CONCLUSION............................................................................................................. 39

-i-

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 3 of 45

TABLE OF AUTHORITIES CASES Page

Adams v. U.S., 330 F.2d 622 (Ct. Cl. 1964)........................................................................................................13, 20 Alpex Computer Corp. v. Nintendo Co., No. 86-1749, 1994 WL 681752 (S.D.N.Y. Dec. 5, 1994)................................................................. 21 Aventis Pharma Deutschland GmbH v. Lupin Ltd., 2006 WL 1008962 (E.D. Va. July 17, 2006)............................................................................... 22-23 Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001) ....................................................................................................... 35 Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223 (Fed. Cir. 1994) ......................................................................................................... 33 Cable Elec. Prods. v. Genmark, Inc., 770 F.2d 1015 (Fed. Cir. 1985) ....................................................................................................... 22 Comfort Silkie, Co. v. Seifert, 1998 U.S. Dist. LEXIS 22285 (C.D. Cal. May 26, 1998) ............................................................ 21-22 Friction Div. Prods., Inc. v. E. I. Du Pont de Nemours & Co., Inc., 693 F. Supp. 114 (D. Del. 1988)................................................................................................. 26-27 In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004) ................................................................................................... 5, 16 In re GPAC Inc., 57 F.3d 1573 (Fed. Cir. 1995) ......................................................................................................... 22 Graham v. John Deere Co., 383 U.S. 1 (1966)............................................................................................................................ 29 Hobbs v. Beach, 180 U.S. 383 (1901)........................................................................................................................ 29 ISCO Int'l, Inc. v. Conductus, Inc., 279 F. Supp. 2d 489 (D.Del. 2003).................................................................................................. 33 J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563 (Fed. Cir. 1997) ....................................................................................................... 23 In re Kahn, 441 F.3d 977 (Fed. Cir. 2006) ........................................................................................................... 5 In re Koller, 613 F.2d 819 (C.C.P.A. 1980)......................................................................................................... 11

- ii -

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 4 of 45

Kridl v. McCormick, 105 F.3d 1446 (Fed. Cir. 1997) ....................................................................................................... 31 KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727 (2007) ................................................................................................................. 5, 29 Leapfrog Enterprises, Inc. v. Fisher-Price, Inc., 485 F.3d 1157 (Fed. Cir. 2007) ......................................................................................................... 3 Lindemann Maschinenfabrik GmbH v. American Hoist & Derrick Co., 730 F.2d 1452 (Fed. Cir. 1984) ....................................................................................................... 30 Mahurkar v. C.R. Bard Inc., 79 F.3d 1572 (Fed. Cir. 1996) ......................................................................................................... 31 McNeil-PPC, Inc. v. L. Perrigo Co., 337 F.3d 1362 (Fed Cir. 2003) ........................................................................................................ 26 Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) ................................................................................................... 5, 12 Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804 (Fed. Cir. 1989) ......................................................................................................... 16 Merck & Co., Inc. v. Teva Pharms USA, Inc., 405 F.3d 1338 (Fed Cir. 2005) ........................................................................................................ 27 Optivus Tech., Inc. v. Ion Beam Apps. S.A., 469 F.3d 978 (Fed. Cir. 2006) ........................................................................................................... 5 Pacifica Technica Corp. v. U.S., 2 Cl. Ct. 170 (1983) ........................................................................................................................ 24 In re Petering, 301 F.2d 676 (C.C.P.A. 1962)......................................................................................................... 35 Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) ................................................................................................ Passim Pfizer Inc. v. Teva Pharms. USA, Inc., 461 F. Supp. 2d 271 (D.N.J. 2006) .................................................................................................. 23 Revlon, Inc. v. Carson Prods. Co., 602 F. Supp. 1071 (S.D.N.Y. 1985)................................................................................................. 26 Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476 (Fed. Cir. 1997) ......................................................................................................... 3 In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ....................................................................................................... 19

- iii -

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 5 of 45

In re Soni, 54 F.3d 746 (Fed. Cir. 1995) ........................................................................................................... 17 Speller v. U.S., 14 Cl. Ct. 170 (1988) ...................................................................................................................... 24 In re Stempel, 241 F.2d 755 (C.C.P.A. 1957).................................................................................................... 31-33 Syntex LLC v. Apotex, Inc., 407 F.3d 1371 (Fed. Cir. 2005) ......................................................................................................... 5 In re Tanczyn, 347 F.2d 830 (C.C.P.A. 1965).................................................................................................... 32-33 Tec Air, Inc. v. Denso Manuf. Mich., Inc., 192 F.3d 1353 (Fed. Cir. 1999) ......................................................................................................... 3 Tracinda Corp. v. DaimlerChrysler AG, 362 F.Supp.2d 487 (D. Del. 2005)................................................................................................... 36 U.S. v. Adams, 383 U.S. 39 (1966)..................................................................................................................... 19-20 Vandenberg v. Dairy Equip. Co., 740 F.2d 1560 (Fed. Cir. 1984) ....................................................................................................... 27 STATUTES 35 U.S.C. § 103................................................................................................................................14, 33 35 U.S.C. § 282..................................................................................................................................... 36 OTHER AUTHORITIES Fed. R. Evid. 402 .................................................................................................................................. 38 Fed. R. Evid. 703 .................................................................................................................................. 37 Fed. R. Evid. 802 .................................................................................................................................. 38

- iv -

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 6 of 45

I.

INTRODUCTION To be entitled to patent protection, an invention must be both novel and non-obvious. For all the

reasons set forth in detail in Sicor's Opening Brief, and those discussed below, the asserted claims of United States Patent 5,070,877 (the "`877 patent") are invalid as anticipated and obvious. The core of the obviousness analysis is the comparison of the prior art and the asserted claims. Here, Plaintiffs do not seriously dispute that the differences between the prior art and the actual language of the asserted claims are not substantial. Instead, Plaintiffs contest obviousness by creating new claim elements out of whole cloth and then arguing that the additional elements are missing from or not taught by the prior art. But these purported claim elements are nowhere to be found in the asserted claims. For example, Plaintiffs contend that a person of ordinary skill in the art at the time would not have known from the prior art what adenosine dose would cause "maximal" increase in coronary blood flow. D.I. 145 at 28-30. But causing a "maximal" increase in blood flow is not an element of any asserted claim. Instead, the asserted claims only require an adenosine infusion "sufficient to provide coronary artery dilation." See, e.g., TX 320, col. 8, lines 58-59. At trial Plaintiffs never seriously disputed that at the critical date the person of ordinary skill in the art would have reasonably expected that adenosine administered within the claimed range of doses was likely to cause coronary artery dilation. At trial Sicor proved that persons of skill in the art would have known that adenosine could provide sufficient arterial dilation for MPI based on knowledge in the art that MPI was already being performed with dipyridamole, which acted by increasing blood levels of endogenous adenosine. In like fashion, Plaintiffs focus on the "about 140 mcg/kg/min" limitation of claim 23 as read through claim 18 of the `877 patent. Plaintiffs argue that "about 140 mcg/kg/min" is a particularly good dose that provides unexpected results and would not have been obvious to the person of ordinary skill. Once again, Plaintiffs are wrong. There is no "optimal" or "best" dose claim limitation. The `877 patent does not disclose that the results from administering "about 140" are so substantially different from other doses within the claimed range such that 140 is an optimal or best dose. Nor does the `877 patent indicate that the dose of "about 140" causes a particular level of patient discomfort that is necessary to ensure

1

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 7 of 45

sufficient vasodilation, as Plaintiffs now argue. Notably, Plaintiffs do not cite anything from the trial record in support of their newly minted claim element. See D.I. 145 at 29-30. Further, the results of administering adenosine ­ vasodilation and side effects which were intolerable to some subjects ­ were known in the art and thus were not unexpected. Finally, even assuming arguendo that "about 140" were an optimized dose, optimization of a single variable such as dose is nothing more than routine experimentation and does not save claim 23(18) from obviousness. Plaintiffs also contend that the prior art taught away from the use of adenosine in patients as too dangerous. While older prior art using bolus injections of adenosine at higher doses in species other than humans might have discouraged medical use of adenosine in humans for a period of time, that era had ended by the mid-1980s. Before the `877 patent application was filed in 1988, adenosine was being safely administered to humans by continuous intravenous infusion at substantially lower doses. When the person of ordinary skill in the art is credited with common sense and average creativity in understanding and applying the prior art, as he or she must be, Plaintiffs' arguments fail. Finally, no secondary considerations raised by Plaintiffs overcome the obviousness of the asserted claims. For example, the alleged expressions of skepticism cited by Plaintiffs fall far short of expressions of disbelief that the claimed invention could or did work. In fact, the context of the statements reveals quite the opposite ­ the belief that the claimed invention would or did work. None of Plaintiffs' arguments demonstrate anything novel or non-obvious in 1987 about using the known coronary vasodilator, adenosine, as a pharmacologic stress agent. It is undisputed that the MPI procedures set forth in the asserted claims were already in use with the pharmacologic stress agent, dipyridamole, which was known to cause vasodilation through the action of adenosine. The evidence is clear and convincing that skilled artisans, taking into account all the relevant prior art and applying their ordinary creativity and common sense, would have reasonably expected that adenosine in the claimed ranges would work as a pharmacologic stress agent for MPI.

2

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 8 of 45

II.

RESPONSIVE ARGUMENT A. THE ASSERTED CLAIMS WERE OBVIOUS IN LIGHT OF THE PRIOR ART 1. The Law Of Obviousness

The legal standards for determining obviousness are set forth in detail in Sicor's Opening Brief and will not be repeated here in full. The law on the role of secondary factors, however, bears some repeating in view of Plaintiffs' discussion of secondary factors in their Opening Post-trial Brief. The relevant authority is clear that secondary considerations must be considered when they are present, but their existence alone does not control the obviousness determination. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007). Where the case for obviousness is strong, even substantial evidence of secondary factors cannot render the claims not obvious. See Leapfrog Enterprises, Inc. v. Fisher-Price, Inc., 485 F.3d 1157, 1162 (Fed. Cir. 2007) (finding that patentees' "substantial evidence of commercial success, praise and long-felt need" was insufficient to overcome the strong prima facie case of obviousness); Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476, 1484 (Fed. Cir. 1997) ("The unexpected results and commercial success of the claimed invention, although supported by substantial evidence, do not overcome the clear and convincing evidence that the subject matter sought to be patented is obvious."). Most important, while Plaintiffs are correct that the burden of persuasion remains on Sicor, Plaintiffs' discussion incorrectly suggests that Sicor has an affirmative duty to disprove the existence of certain secondary factors. D.I. 145 at 22-23. That is not the case. Rather, if Plaintiffs want the Court to consider any secondary factors, Plaintiffs should come forward with evidence of such factors. See Pfizer, 480 F.3d at 1360 (citations omitted) ("[O]nce a challenger has presented a prima facie case of invalidity, the patentee has the burden of going forward with rebuttal evidence."). The Court then 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." Id.; see also Tec Air, Inc. v. Denso Manuf. Mich., Inc., 192 F.3d 1353, 1360 (Fed. Cir. 1999) ("`Whether the evidence presented [by

3

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 9 of 45

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))). 2. Sicor Has Shown Obviousness By Clear And Convincing Evidence a. The Underlying Facts Supporting Sicor's Prima Facie Case Of Obviousness Are Largely Undisputed

The parties agree on several relevant factors. For example, there is no dispute that the person of ordinary skill in the art is a highly skilled medical doctor with a specialty in either cardiology or nuclear medicine and training in the other area. D.I. 145 at 23; D.I. 143 at 7. In addition, there is no dispute that the only difference between the prior art pharmacologic stress MPI procedures and the asserted claims of the `877 patent was the use of adenosine instead of dipyridamole. See D.I. 145 at 23; D.I. 143 at 24-25. Nor is there any dispute as to the scope and content of much of the prior art. For example, it is undisputed that (a) the mechanism of action of dipyridamole ­ specifically, that it acted by blocking adenosine uptake, thereby increasing levels of endogenous adenosine ­ was known in the prior art (see D.I. 145 at 15; D.I. 143 at 11-13); (b) adenosine was known in the prior art to be a potent vasodilator (see D.I. 145 at 1; D.I. 143 at 23); and (c) by mid-1987, adenosine had been administered to humans, both in the form of bolus injections and in the form of continuous intravenous infusions (see D.I. 145 at 12-15; D.I. 143 at 13-18). The critical dispute between the parties is whether, by mid to late 1987, the art as a whole taught toward or away from using the known, potent vasodilator adenosine as a pharmacologic stress agent for MPI. When the prior art is considered as a whole, as it must be, there can be no question that a person of ordinary skill in the art at the time would have been motivated to use adenosine for MPI, and that the asserted claims of the `877 patent were obvious. b. There Is No Persuasive Evidence Of Teaching Away

Plaintiffs' primary argument against Sicor's prima facie case of obviousness is that the prior art taught away from the use of adenosine in patients, particularly heart patients. In so arguing, however, Plaintiffs incorrectly fail to credit the person of ordinary skill in the art, a medical doctor with training in

4

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 10 of 45

cardiology and nuclear medicine, with even average common sense or creativity in understanding the significance of relevant art. See KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1742 (2007). Moreover, Plaintiffs' arguments run counter to the evidence of a surge in interest in adenosine that took place in the field during the early to mid 1980s. That increased interest taught toward adenosine use, including adenosine use for MPI, not away from it. A reference may teach away "`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" 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) ("The prior art must be considered as a whole for what it teaches.") (emphasis in original). 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). Although all teachings must be considered in context, the Federal Circuit has provided some guidance as to the types of things that do not "teach away." For example, disclosure in the prior art of a 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). Plaintiffs rely on a number of references, including some of the same references on which Sicor relies in establishing obviousness, for the proposition that the prior art would have taught away from using adenosine for MPI. Plaintiffs' analysis of this prior art is selective, and wrong, because it ignores the significance of the means of administration of adenosine and the doses used in the prior art references. See D.I. 145 at 6-14. When each reference is considered in its entirety, and in the context of the other

5

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 11 of 45

prior art, it becomes clear that nothing in any single reference, and nothing in the prior art as a whole, would have discouraged or led away from using adenosine for MPI as of the middle of 1987. One of the references on which Plaintiffs' rely is a 1983 article entitled "Adenosine, electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia" ("DiMarco 1983," TX 36). See D.I. 145 at 6. DiMarco 1983 describes the use of adenosine to treat heart arrhythmias by inducing AV block. TX 36. In DiMarco 1983 the adenosine was given by rapid bolus injection, not continuous intravenous infusion. Tr. 760:13-20; TX 36. DiMarco 1983 also described advantages associated with adenosine's rapid clearance from the system, including the lack of persistent drug effect and the fact that rapid clearance 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 in-process cardiac arrhythmia, and continuous intravenous infusion, which can be safely titrated up to a level that has a stable effect for the duration of the infusion. See Tr. 677:9-678:2. Further, DiMarco 1983 would have taught the skilled artisan that the rapid clearance of adenosine would facilitate a quick end to any undesired side effects. DiMarco 1983 would not have discouraged that person of ordinary skill in the art from using adenosine for MPI in 1987. Tr. 760:13-20. Plaintiffs also rely on a chapter from a 1983 book entitled "The Coronary Circulation In Health And Disease," by Dr. Melvin L. Marcus ("Marcus," TX 217) in an attempt to support their argument that a person of skill in the art would have been discouraged from using adenosine because of fear of hypotension. Notably, Marcus describes the use of adenosine in animals at very high doses. TX 217 at 430-31; Tr. 800:19-801:9. By the middle of 1987, several references in the art including Sollevi 1984, Sollevi 1986 and Owall disclosed the dose of adenosine necessary to achieve controlled hypotension in anesthetized humans. See TX 112, TX 1171; TX 1169. Each of those references describes doses of 200 mcg/kg/min of adenosine, or more, for controlled hypotension in humans. Id. A person of skill in the art in 1987 would not have been discouraged from using adenosine for MPI in humans at doses that were less

6

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 12 of 45

than those that produced hypotension in humans ­ doses which were far below those described in the 1983 Marcus reference. See Tr. 759:14-22.1 Still other references in the prior art made clear that adenosine could be safely, continuously infused to cause vasodilation at a dose less than the dose necessary for hypotension. For example, Biaggioni 1986 described continuous intravenous infusion of adenosine to conscious subjects at doses up to 140 mcg/kg/min without inducing hypotension, but with evidence of vasodilation. Tr. 718:4-719:2; TX 48 at 2234. In fact, none of the prior art references on which Sicor relies that describe continuous intravenous infusion to conscious humans identified hypotension. See TX 48; TX 220; TX 226; TX 1208. Accepting Plaintiffs' argument requires that this Court wrongly assume that the person of ordinary skill in the art in 1987 would have been discouraged by a 1983 caution about hypotension based on administration of high doses of adenosine to dogs, even though subsequent references provided clear guidance that lower doses of adenosine would not produce hypotension in humans. Plaintiffs attempt to use Biaggioni 1986 as support for the proposition that adenosine was thought to be too dangerous and short-lived to be a useful coronary vasodilator. D.I. 145 at 6 (citing TX 48). Plaintiffs, however, ignore a fact that would not be lost on persons of ordinary skill in the art. Biaggioni 1986 cites art from 1930 and 1933 concerning the effect of "large boluses of the drug." Compare D.I. 145 at 6 with 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 ­ in 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 generally, TX 48. The disclosures of the Biaggioni 1986 reference would have taught a person of

1

Likewise, a person of ordinary skill in the art in 1987 would not have been discouraged from using adenosine for MPI because of statements in a 1970 article discussing potential therapeutic, as opposed to diagnostic, use of adenosine. See D.I. 145 at 8 (citing TX 214). Tellingly, Plaintiffs did not question Dr. Wackers about this reference and have presented no evidence that this 1970 reference would have taught away from adenosine use as a diagnostic 17 years later.

7

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 13 of 45

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. Tr. 717:22-719:18; TX 48. In view of such disclosures, it is simply not credible to conclude that Biaggioni 1986 taught away from the use of adenosine as described in the asserted claims. Plaintiffs also ignore the clear statement in Biaggioni 1986 that intravenous infusion of adenosine had already been shown to be useful in inducing a "sustained" hypotensive effect. TX 48 at 2229. 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. Tr. 677:9-678:2. Other references in the art, such as Sollevi 1984, further demonstrate that it was known in the art before 1984 that continuous infusion of adenosine would result in a stable effect during the infusion. Tr. 692:12-694:7; TX 112. Biaggioni 1986 simply does not support Plaintiffs' teaching away argument. 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. Yet another of Plaintiffs' scattershot "teaching away" arguments is that a person of ordinary skill in the art would have been discouraged from using adenosine for MPI because of the possibility of ischemia. D.I. 145 at 7, 25. Once again, this argument does not stand up when viewed in the context of the actual teachings in the art. As discussed in Sicor's Opening Brief, the prior art pharmacologic stress MPI procedure used continuous intravenous infusion of dipyridamole. D.I. 143 at 9-11. Dipyridamole's vasodilating effect was known to be caused by endogenous adenosine. D.I. 143 at 11-13. A known possible side effect of dipyridamole stress MPI was ischemia. Tr. 673:15-674:11; Tr. 688:3-89:23; Tr. 1006:7-11; TX 93 at 758; TX 38 at 285-86. Indeed, a known effect of exercise stress was ischemia. Tr. 688:22-689:23; TX 38 at 285-86. As Dr. Strauss explained at trial: 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 that is the intent of stressing the person in that fashion.

8

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 14 of 45

Tr. 689:10-14. Yet, exercise stress remains the preferred method of stress testing, even today. Tr. 996:25-997:3. The prior art taught that ischemia was less likely with pharmacologic stress MPI with dipyridamole (which was acting through adenosine) than it was with exercise. TX 38 at 285-86. The known characteristics of adenosine, in particular its short half-life which enabled negative side effects to be terminated 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. Tr. 673:17-674:11; 688:22-690:9. Plaintiffs' reliance on Owall in their attempt to support their ischemia argument highlights Plaintiffs' failure to credit persons of skill in the art with any common sense. Owall describes doses of adenosine sufficient to cause controlled hypotension in anesthetized patients undergoing cerebral aneurysm surgery. Owall states that doses ranging from 88 up to 530 mcg/kg/min of adenosine were administered, and that a mean dose of 210 mcg/kg/min was required to induce controlled hypotension. TX 1169 at 230, 232. Owall describes two patients who had an earlier history with myocardial infarction who experienced disturbances of heart rhythm during the study. Id. at 231, 233. One of the two patients experienced the adverse event approximately five minutes after the induction of hypotension. Id. at 231. The second patient experienced an adverse event that was terminated during hypotension. Id. In other words, these adverse cardiac events occurred at doses sufficient to induce controlled hypotension ­ doses higher than what a person of ordinary skill in the art would reasonably expect to work for MPI. Tr. 725:12-726:6. Owall expressly states that "the use of adenosine hypotension should be carefully considered in patients with ischemic heart disease." TX 1169 at 233 (emphasis added). Owall would not have discouraged a person of skill in the art in 1987 from using adenosine for MPI because such a person would have avoided doses sufficient to induce hypotension. See Tr. 725:12-726:6; Tr. 910:8-17. Plaintiffs further argue that a person of skill in the art would have been discouraged from using adenosine for MPI because of concerns about "achieving sufficient efficacy." D.I. 145 at 25.2 Simple

2

Plaintiffs refer to TX 38 in support of their argument that Gould observed that a 400% increase in coronary blood flow was sufficient for reliable imaging. D.I. 145 at 25. Notably, Plaintiffs do not argue that a 400%

9

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 15 of 45

common sense dictates that a person of skill in the art would have understood from the prior art, including Gould 1978 and Albro, that there was necessarily an amount of adenosine that would be both safe and efficacious for MPI because dipyridamole, which caused vasodilation by increasing endogenous adenosine, was efficacious for MPI. The only question would have been what dose. Tr. 691:1-8. The prior art provided more than ample guidance as to the range of doses that would likely be successful. Tr. 708:10-709:20; Tr. 719:3-18; 738:16-740:18. Any optimization of this single variable ­ the dose of intravenously infused adenosine that would cause sufficient vasodilation for MPI ­ is precisely the type of routine work that is typically obvious. See Pfizer, 480 F.3d at 1368. The studies describing continuous, intravenous adenosine infusion to conscious, healthy volunteers provide information not only as to what doses would be safe and effective, but also as to the range of doses likely to be tolerated by conscious patients. With respect to these studies, the dose alone does not tell the complete story. Instead, additional factors such as the duration of the infusion must also be considered. As Dr. Strauss pointed out during his testimony, these studies described infusion of adenosine for much longer than the few minutes necessary to conduct an MPI test. See, e.g., Tr. 711:20712:13. In these prior art studies, adenosine was infused to a total of 29 healthy volunteers at doses that were increased stepwise during the infusion, resulting in total infusion times ranging from 37 minutes to 105 minutes. See TX 48; TX 220; TX 226; TX 1208. Even with these prolonged exposures to adenosine infusion, the maximum doses tolerated by the healthy volunteers ranged from 70 to 200 mcg/kg/min. See TX 48; TX 220; TX 226; TX 1208.3 The volunteers all tolerated doses of 70 mcg/kg/min or above, and the majority tolerated doses from 100 to 140 mcg/kg/min. Id. The references, alone and in combination

increase is necessary for reliable imaging, only that it is sufficient. See id. Figure 8 of Gould 1978 shows an average of a 400% increase in coronary blood flow, with a range from slightly less than a 300% increase to more than a 500% increase. TX 38 at 284. Gould 1978 does not state that a 400% increase is necessary for reliable imaging. TX 38. In the Protocol document, the named inventors of the `877 patent noted the results of various tests concerning increased blood flow after dipyridamole infusion, including an increase "up to 3.4 to 4.1 times baseline values" when studied by inert gas tracers. TX 52 at AST0009472.
3

There were other reported studies of adenosine in the prior art on which Sicor has not relied in its arguments. For example, a second article by Conradson, reports continuous adenosine infusion to an additional 6 healthy volunteers aged 23-40. See TX 1211.

10

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 16 of 45

with each other, would have encouraged, not discouraged, a person of ordinary skill in the art to use adenosine at doses within these ranges for MPI. See D.I. 147 at ¶¶ 68-106; 120-137. Plaintiffs' contention that this information from healthy volunteers would not be sufficiently instructive, or would even teach away, is contradicted by Plaintiffs' own research proposal. In their Protocol seeking permission from their internal review board, a Protocol that was ultimately submitted to the FDA in support of the investigational new drug application seeking to use adenosine for MPI in humans, the named inventors of the `877 patent proposed infusing adenosine to 20 healthy volunteers aged 19-39 before proceeding in patients. TX 52 at AST0009474; TX 57 at 000145. The fact that the named inventors were willing to proceed with infusion of adenosine to heart patients after conducting MPI with adenosine in 20 healthy volunteers aged 19-39 further supports Sicor's argument that the published results summarized above, showing safe infusion of adenosine to 29 healthy volunteers whose ages (when indicated) ranged from 23-40 would have been more than adequate to provide a reasonable expectation of at least the safety of these doses.4 It is also worth noting that the second protocol submitted as part of the IND seeking FDA approval to use adenosine in humans for MPI did not propose any additional studies in healthy volunteers, but instead proposed the use of adenosine in "[f]ifty patients with suspected coronary artery disease." TX 52 at AST0009465. Plaintiffs also rely on three publications that are not prior art in arguing that the prior art discouraged or taught away from the use of adenosine for MPI. See D.I. 145 at 7-8. Plaintiffs have not asserted that any of these references fit within any of the limited circumstances in which later publications may be used to show the state of the art at the relevant time. See, e.g., In re Koller, 613 F.2d 819, 824 (C.C.P.A. 1980). Nor have Plaintiffs established that any of these later references reflect the state of the art at the relevant time, and the references themselves do not purport to reflect the state of the art as of any particular date, let alone as of the relevant date. See TX 46, TX 47, TX 240. Accordingly, none of the later published references should be considered in assessing the obviousness of the asserted claims, which
4

Obviousness requires only a reasonable expectation of success, not absolute predictability or proof as Plaintiffs seem to demand. See Pfizer, 480 F.3d at 1364.

11

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 17 of 45

must be determined based upon what would have been obvious to a person of skill in the art at the time of invention. See Medichem, 437 F.3d at 1164. However, even if the three reference were considered, they do not show teaching away, discouragement or skepticism as of the relevant date. The first of these later publications is a 1995 chapter by Dr. Mario Verani in which Dr. Verani stated "it is interesting to speculate" as to why adenosine usage for MPI evolved as it did. TX 240 at 439; Tr. 953:17-24; 954:13-17. Dr. Verani's passing speculation in 1995 is hardly a persuasive assessment of the state of the art in 1987. More important, contemporaneous evidence from 1987 shows that Dr. Verani himself thought that, by 1987, adenosine had been shown to be safe enough for use with MPI. Dr. Verani stated in a research protocol that given "present knowledge" of adenosine by December 1987, the benefits from investigating adenosine for MPI "clearly outweigh the unlikely possibilities of side effects or complications." TX 52 at AST0009468; Tr. 1023:6-7; 1024:24-1025:11. The second of the three after-the-fact references cited by Plaintiffs is a 1990 article entitled "Effects of Adenosine on Human Coronary Arterial Circulation" by Robert F. Wilson and others ("Wilson," TX 46). D.I. 145 at 7. Although Wilson refers to concerns that he states "hampered" use of adenosine in humans, his comment is at best ambiguous as to when any such use was "hampered." TX 46 at 1596. The comment in Wilson does not establish that a person of skill in the art would have been discouraged from using adenosine in 1987. Neither does the comment show any continued skepticism about the use of adenosine when it is considered in the context of the full article, which describes continuous adenosine infusion to heart patients. TX 46. The third of the three later publications on which Plaintiffs rely is equally unpersuasive. That third publication is an Editorial Comment entitled "Adenosine, Renewed Interest in an Old Drug" (the "Editorial," TX 47). D.I. 145 at 7-8. Plaintiffs selectively cite the portion of the Editorial that states that adenosine "never achieved clinical usefulness . . ." D.I. 145 at 7. From context, "never" in the Editorial appears to mean the time from 1929 until some unspecified time before the date of the Editorial in 1990. TX 47 at 1854. The next sentence of the Editorial states "[h]owever, adenosine is now becoming a clinically relevant compound. There is increasing interest in 1) its application in the diagnosis and

12

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 18 of 45

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. Based on the other known uses of adenosine in the art prior to 1987, it is clear that "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 the art in 1987 taught away from using adenosine for MPI in humans. Plaintiffs' teaching away theory is also contradicted by their own arguments. On the one hand, Plaintiffs assert vigorously that anyone of skill in the art at the relevant time would have been afraid to use adenosine. On the other hand, Plaintiffs assert that Sicor's obviousness challenge is suspect because of the "sheer volume" of references. See D.I. 145 at 20. Unlike Adams v. U.S., 330 F.2d 622 (Ct. Cl. 1964), on which Plaintiffs' rely, this is not a situation where the obviousness challenge is based on multiple combinations of over 50 years worth of references. See id. at 624. Rather, the "volume" of the art here shows an increased interest in and use of adenosine from the early 1980s through the date of invention. Many of the references individually, and certainly the group of references taken together, show that the tide had turned by 1987, and that a person of ordinary skill in the art reasonably would have considered adenosine to be safe for use in human patients. These references also provide guidance as to doses of adenosine that likely would, and would not, work for MPI. c. The Field Of Pharmacologic Stress Agent Development For MPI Was Dormant For Several Years

Plaintiffs argue that adenosine was "passed over" as a potential pharmacologic stress agent and that the approach in the art was "anything but adenosine" for almost a decade. D.I. 145 at 11, 24. This argument suggests that adenosine was actively rejected, but there is no evidence in the record to support that interpretation. The evidence is that the MPI field was young and there was no particular interest in developing pharmacologic stress testing during much of that period, not that researchers in the field were actively searching for additional agents and had rejected or ignored adenosine.

13

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 19 of 45

Plaintiffs refer to Dr. Strauss's 1977 experiments with ethyl-adenosine as a pharmacologic stress agent in dogs. D.I. 145 at 9. This fact is inapposite. Dr. Strauss testified that he used ethyl-adenosine because it was made available to him by Abbott, not because anything in the prior art taught away from using adenosine. Tr. 654:3-10. Further, Dr. Strauss testified that Abbott chose to stop work with ethyladenosine and withdrew the supply. Tr. 654:11-16. Dr. Wackers confirmed that there was no particular push for a pharmacologic stress agent for MPI in the late 1970s. Tr. 997:4-14; Tr. 1002:7-9. In Dr. Wackers' words "the whole field was so new that you were still exploring" and only a "handful of laboratories" were involved with that exploration. Tr. 997:15-998:5. Shortly after Dr. Strauss's work with ethyl-adenosine, Gould 1978 described the first use of pharmacologic stress MPI in humans. TX 38. However, 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. Tr. 997:10-14.5 Notably, Plaintiffs do not point to any failed studies seeking other pharmacologic stress agents for MPI during this period. See generally, D.I. 145. Nor do Plaintiffs cite any evidence that adenosine had been considered and rejected. Id. This lack of mention is entirely consistent with the early stage of development of MPI and is not evidence that adenosine had been passed over as a pharmacologic stress agent option. More importantly, obviousness must be considered as of the time of the invention. 35 U.S.C. § 103(a) (subject matter not patentable if "subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art") (emphasis added). By 1987, a number of uses of adenosine in humans had been described in the art, and the use of adenosine for MPI was obvious.

5

In their background facts, Plaintiffs rely on information about the prevalence and need for pharmacologic stress MPI that was not available in the prior art and does not reflect the state of the art in 1987. D.I. 145 at 45, citing TX 138 (a chapter from the Fourth Edition of Diagnostic Nuclear Medicine, published in 2003); TX 103 (article dated February 1994); Tr. 986:21-23.

14

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 20 of 45

d.

The Prior Art Demonstrated The Speed And Safety Advantages Of Adenosine Over Dipyridamole

A person of ordinary skill in the art in 1987 would have known that dipyridamole had a longer duration of action than adenosine. Tr. 673:17-674:11. That person would have also understood that a longer duration of action means, among other things, a longer duration of negative side effects when they occur. Tr. 673:17-675:21. The prior art references describing continuous infusion of adenosine to humans established a number of facts about adenosine. Among those are (1) adenosine's action can be sustained for the duration of an infusion; and (2) adenosine's action can be terminated almost immediately upon termination of the infusion. For example, Sollevi 1984 describes a controlled, stable effect. Tr. 693:15694:7; TX 112. A person of ordinary skill in the art would have understood that continuous adenosine infusion, as opposed to rapid bolus, could be used to create a stable effect. Tr. 677:9-678:2. The art also taught that side effects, when they occurred, were fleeting. See, e.g., TX 220 at 389 (symptoms "completely vanished within 2 min after stopping the adenosine infusion"); TX 48 at 2233 (side effects "disappeared immediately after discontinuation of the infusion"); TX 1171 at 319 (adenosine's "effect is easy to control due to the extremely short plasma half-life"). A person of skill in the art in 1987 would have recognized the advantages of using a pharmacologic stress agent with an effect that did not last any longer than necessary for the procedure. Tr. 673:17-675:11. Adenosine was just such an agent. Indeed, Dr. Verani recognized this advantage prior to December of 1987 and noted it in his proposal that was submitted with Medco's IND. See TX 52 at AST0009465 ("The main advantage of using adenosine to provoke coronary vasodilation is the short duration of effect (10 to 20 seconds in humans."). e. There Is Nothing Special About The Dose Of "About 140" Micrograms Per Kilogram Per Minute

Plaintiffs argue that routine experimentation, particularly experimentation titrating to a tolerable dose, would not have resulted in the dose of about 140 mcg/kg/min. The evidence shows the opposite to be true. For example, in Biaggioni 1986, 5 out of 7 healthy volunteers tolerated a dose of 140 mcg/kg/min. TX 48 at 2231. In Biaggioni 1987, all 8 volunteers tolerated a dose of 140 mcg/kg/min.

15

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 21 of 45

TX 226 at 781-82. In Conradson, 3 of 8 volunteers tolerated a dose of 100 mcg/kg/min, the maximum dose administered in that study. TX 200 at 388. In Fuller, 6 volunteers tolerated a dose of 100 mcg/kg/min, 6 and two tolerated a dose of 200 mcg/kg/min for 1 and 2 minutes respectively. TX 1208 at 311. Fuller provided no additional information as to whether doses between 100 and 200 mcg/kg/min would be tolerated, as none were reported. TX 1208. Based on this data alone, a person of skill in the art would have expected that a substantial percentage of conscious humans would be able to tolerate an adenosine dose of 140 mcg/kg/min. In fact, the person of skill in the art would understand that volunteers often do not tolerate side effects as readily as patients do, because unlike volunteers who have no real incentive to tolerate even mild discomfort, patients have a vested interest in completing medical procedures. Tr. 714:7-715:3. The law does not require that "about 140" had to be the only obvious dose in order for the claim to have been obvious. The fact that a range of doses, including 140, was likely to work does not render "about 140" any less obvious. See Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 806-807 (Fed. Cir. 1989) ("A multitude of effective combinations does not render any particular formulation less obvious."); see also In re Fulton, 391 F.3d 1195, 1200 ("[A] finding that the prior art as a whole suggests the desirability of a particular combination need not be supported by a finding that the prior art suggests that the combination claimed by the patent applicant is the preferred, or most desirable, combination."). Plaintiffs' argument that a person of skill in the art would have tried to find a dose that resulted in no noticeable side effects (D.I. 145 at 27-28) is also belied by the prior art. Gould 1978 describes various side effects experienced by 43 patients given dipyridamole for MPI. TX 38 at 283. Those side effects included mild transient headache, mild transient facial flushing, mild transient nausea, and mild fleeting angina pectoris. Id. Similar types of side effects, including headache, flushing, nervousness and an urge to breathe deeply, were reported in prior art references, such as Biaggioni 1986 and Conradson, that described the results of adenosine infusion. Tr. 720:11-14; Tr. 728:10-14; TX 48 at 2233; TX 220 at 389.

6

One of the six volunteers in Fuller tolerated 100 mcg/kg/min for only 1 min. TX 1208 at 311.

16

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 22 of 45

These are precisely the types of side effects that a person of skill in the art in 1987 with even a modicum of common sense would have expected to see with adenosine in view of the known mechanism of action of dipyridamole. The prior art references that reported these as the side effects of adenosine infusion in conscious humans confirmed the expected result. It is also worth noting that the only reference on which Plaintiffs rely in support of their argument that a person of skill in the art in 1987 would have sought to accomplish pharmacologic stress without any side effects is the Karolinska Request, a document which Plaintiffs contend was not public and should not even be considered as prior art. See D.I. 145 at 39-40. Yet, another prior art publication by the same researcher, the `296 patent, expressly discloses that the effective dose of adenosine for MPI is likely to be in the range of 10 to 150. TX 275 at col. 21, ll. 59-61. In their attempt to salvage the most narrow claim of the `877 patent, Plaintiffs assert that the results of the dose of 140 mcg/kg/min of adenosine were "unpredictable." D.I. 145 at 27-30. Sicor assumes that Plaintiffs' intended argument is that the results of using the dose of 140 mcg/kg/min were unexpected. Plaintiffs were required to come forward with evidence of such unexpected results at trial. See Pfizer, 480 F.3d at 1371. Plaintiffs failed to do so. The evidence in the record does not show any surprising superior property or advantage to the dose of "about 140 mcg/kg/min." See In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (showing of unexpected results is "that the claimed invention exhibits some superior property or advantage that a person of ordinary skill in the art would have found surprising or unexpected"). Plaintiffs also never demonstrated what results were "expected," a failure that prevents this Court from properly considering what properties might be unexpected. See Pfizer, 480 F.3d at 1371 (finding that patentee's evidence of unexpected results "must fail because the record is devoid of any evidence of what the skilled artisan would have expected"). There is no evidence that the dose of "about 140 mcg/kg/min" as specified in claim 23(18) is actually better than other doses within the range that is disclosed in the prior art. Wilson, on which Plaintiffs rely, describes increases in coronary blood flow reserve at various doses of adenosine. TX 46. However, the Wilson study shows only a minor difference in coronary blood flow reserve between the

17

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 23 of 45

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 further highlighted in the textbook Clinical Nuclear Cardiology, in which the coronary flow reserve at 100 and 140 mcg/kg/min of adenosine is shown as equal -- based on the Wilson study. TX 5011 at 235, figure 14.1; Tr. 1030:4-12. 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. Nor does Wilson compare, describe or discuss the quality of myocardial perfusion images at any of these doses. Id. The most that Wilson shows is that coronary blood flow velocity rose and fell in a cyclic pattern at doses from 70 to 100 mcg/kg/min. TX 46 at 1600; Tr. 1031:17-1032:7. The Wilson study, and the depiction of the Wilson results in later publications, establish that the differences between the doses of 100 and 140 mcg/kg/min were insignificant at best. Wilson provides no evidence on whether doses of 120 or 160 mcg/kg/min are the same as or better than 100 and 140. Nothing in the record demonstrates anything special or unexpected about a dose of "about 140" mcg/kg/min of adenosine for MPI. There is also no evidence in the record that "about 140" mcg/kg/min results in better images or greater accuracy than any other dose between 60 and 120 mcg/kg/min. Referring to the results on which Plaintiffs rely as evidence of reduction to practice, Plaintiffs' expert, Dr. Wackers, testified that when the adenosine MPI results match up with the angiography results, the adenosine test was successful in that patient. Tr. 1016:9-17; 1017:14-21; TX 296 at AST0004357. Those study results show infusion of adenosine to 15 different patients at doses from 60 to 140 mcg/kg/min. TX 296 at AST0004357; Tr. 1018:2-17. The dose of 140 mcg/kg/min was used in only two of the 15 patients described in the study. Tr. 1018:13-17. The study results show that doses of 60, 100 and 120 mcg/kg/min resulted in successful identification of myocardial dysfunction in those patients, just as the 140 mcg/kg/min dose did. Tr. 1017:14-1018:12; TX 296 at 4357, 4364. In other words, the only evidence in the record concerning what doses of adenosine will work for MPI demonstrates that doses of any of 60, 100 or 120 mcg/kg/min will work. Thus, the evidence is that each of 60, 100, 120 and 140 work, not that "about 140" is unpredictably better.

18

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 24 of 45

Finally, Plaintiffs' "no pain no gain" argument is nothing more than a litigation construct without evidentiary support. See D.I. 145 at 29-30. Nothing in the asserted claims or the description of the invention in the `877 patent suggests that some amount of patient discomfort will be necessary in order to achieve sufficient vasodilation for MPI using the claimed invention. See, e.g., TX 320. More importantly, however, a person of ordinary skill in the art at the time would have expected some degree of patient discomfort during pharmacologic stress MPI procedures. See TX 38 at 283 (describing side effects during dipyridamole stress testing). The side effects of both dipyridamole and adenosine were known, and the manifestation of those side effects during MPI stress procedures was neither unpredictable or unexpected. TX 38 at 283; TX 48 at 2233; TX 220 at 389; TX 1171 at 319. 3. The Secondary Considerations Argued By Plaintiff Do Not Rebut The Prima Facie Case

Secondary considerations of nonobviousness may include any of (1) copying; (2) long-felt but unresolved need; (3) failure of others; (4) commercial success; (5) unexpected results; (6) unexpected properties of the claimed invention: (7) licensing showing industry respect for the invention; and (8) skepticism of skilled artisans before the invention. See In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1998). Plaintiffs argue that three of these secondary indicia ­ skepticism, commercial success, and copying ­ support non-obviousness in this case. D.I. 145 at 30-34. As set forth in more detail below, there is no persuasive evidence of skepticism; no nexus between any commercial success and any particular value of the claimed invention; and no relevance to an assertion of copying in the context of this ANDA case. a. No Credible Evidence Of Skepticism Or Surprise

As discussed above and in Sicor's Opening Brief, the prior art taught toward, not away from, the use of adenosine for MPI. The evidence presented by Plaintiffs also does not establish any skepticism in the art at or after the time of the invention. In U.S. v. Adams, 383 U.S. 39 (1966), on which Plaintiffs rely, the evidence showed skepticism by persons of skill in the art about the feasibility of the invention as well as continued disbelief that the

19

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 25 of 45

invention worked, even after the inventor had disclosed his discovery. See id. at 44. Specifically, the inventors in Adams gave demonstrations and provided graphical data showing characteristics of the invention to the government. Id. Even with this information, a government expert thought that the inventor was making "unusually large claims" about the characteristics and the expert found the evidence "far from convincing." Id. That is, the government expert did not think the invention actually worked as the inventor claimed it did. Here, the statements relied upon by Plaintiffs are a far cry from doubt as to feasibility or disbelief that adenosine worked for MPI. Plaintiffs rely on a smattering of out-of-context statements in their effort to show skepticism. First, Plaintiffs point to a statement in a December 31, 1987 letter ­ a letter that predates Plaintiffs' first use of adenosine for MPI ­ in which the author 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 with you further." TX 53. At most, this statement reflects a lack certainty as to the degree to which adenosine would be safe and effective for the purpose. It does not reflect doubt as to whether adenosine would work. Notably, the author here was sufficiently interested, and sufficiently convinced that adenosine was likely to be safe and effective, that he went on to state: 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 to adenosine. There are also other uses of intracoronary adenosine which we can envision that might also be of considerable interest to you. Id. This offer to work out a protocol and devote research time as of December 1987 contradicts Plaintiffs' contention that the author was skeptical about whether adenosine would work. Plaintiffs also rely on a letter to the editor published in a June 1990 journal. 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. Id. The letter further asks for more detail about the two instances, then expresses the need for more study and for caution during that study. Id. This letter raises questions, but does not express disbelief that adenosine worked as described. Moreover, Plaintiffs' expert witness, Dr. Wackers, did not know the author of the letter and thus could not say

20

Case 1:05-cv-00337-SLR

Document 152

Filed 06/19/2007

Page 26 of 45

whether the author was a person of skill in the art at the relevant time. Tr. 1026:5-14. For this reason alone, the letter should be given little weight. See Alpex Computer Corp. v. Nintendo Co., No. 86-1749, 1994 WL 681752, at *30 (S.D.N.Y. Dec. 5, 1994) ("[I]n the absence of a showing that the skeptics were people of ordinary skill in the art, evidence of their skepticism should be accorded little weight in the obviousness determination."), aff'd in rel. part, rev'd in part, 102 F.3d 1214 (Fed. Cir. 1996). Plaintiffs further suggest that the Wilson article, the Editorial, and the 1995 Verani chapter support skepticism. For the reasons discussed above, neither the two 1990 publications nor Dr. Verani's speculation in 1995 demonstrates any skepticism about the use of adenosine for MPI, either in 1990 or before. In fact, the Editorial concludes that "adenosine holds promise 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. Finally, Plaintiffs rely on hearsay testimony from one sales representative that some customers were concerned about the use of Adenoscan® when it was launched as a commercial product in 1995. See D.I. 145 at 17-18. Plaintiffs did not call any of these customers as witnesses, so Sicor could ask the customers whether they had any particular concern about adenosine or if instead they were content with dipyridamole and saw no particular reason to change. Plaintiffs relied on a sales representative to testify as to her uncorroborated memory of events within her small sales area more than ten years ago. See D.I. 145 at 17-18; Tr. 1535:11-1536:20. The probative value of that memory