Free POST Trial Brief - District Court of Delaware - Delaware

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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.

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Civil Action No. 05-336 SLR

DEFENDANTS SICOR'S RESPONSIVE POST-TRIAL BRIEF

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

Dated: June 19, 2007

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TABLE OF CONTENTS I. II. Introduction .............................................................................................................................. 1 The Asserted Claims Of The `296 Patent Are Invalid As Obvious ......................................... 4 A. The Sollevi Abstracts Render the Asserted Claims of the `296 Patent Obvious......................................................................................................................... 5 1. The Sollevi Abstracts Demonstrated That 140 µg/kg/min Adenosine Could Be Administered Safely To Humans By Continuous Intravenous Administration ............................................................................ 5

B.

The Fukunaga 1982 Abstract Renders the Asserted Claims of the `296 Patent Obvious ............................................................................................................. 7 The Dose Required to Produce a Desired Effect Could Have Been Determined Through Routine Experimentation ....................................................... 11 The Prior Art Uses of Adenosine and Other Vasodilators Did Not Teach Away from the Claimed Invention............................................................................. 12 1. The Use of Other Vasodilators During the Relevant Time Period Would Have Encouraged Persons of Ordinary Skill to Look to Adenosine....................................................................................................... 13 Research Concerning Adenosine for Various Medical Uses Exploded Following a 1980 Publication by Dr. Berne................................................... 14

C.

D.

2. III.

Secondary Considerations Do Not Support The Non-Obviousness Of The Asserted Claims ..................................................................................................................................... 16 A. Plaintiffs Have Not Demonstrated Unexpected Results ............................................ 16 1. The Occurrence of Selective Arterial Vasodilation at the Claimed Dosages Was Not Unexpected........................................................................ 17 The Lack of AV Block Was Not Unexpected ................................................ 18 The Lack of Uric Acid Build-Up Was Not Unexpected ................................ 19

2. 3. B.

Plaintiffs Have Failed to Provide Evidence of Skepticism ........................................ 19 1. 2. The Correspondence Is Not Probative Of Non Obviousness ........................ 20 The Correspondence Relied Upon by Plaintiffs is Not Admissible .............. 21

C.

Copying Is Irrelevant in the ANDA Context ............................................................. 22

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D.

Plaintiffs Have Failed to Show that the Alleged Commercial Success of Adenoscan® Has Any Nexus to the Asserted Claims ................................................ 23 1. The Sales Levels of Adenoscan® Are Explained By the Interplay of Economic Factors, Not The Product's Clinical Attributes ........................... 23 Dr. Hay's Analysis Is Unsound and His Testimony Is Unreliable ................ 28

2. IV. V.

The Asserted Claims Of The `296 Patent Are Inherently Anticipated.................................. 29 Expert Testimony Issues......................................................................................................... 30 A. Dr. Binkley is Highly Qualified to Serve as An Expert in This Case ........................ 30 1. Dr. Binkley's Opinions Were Well Within the Scope of His Expert Report ............................................................................................................ 31 Dr. Binkley Was Forced to Rebut Issues Raised by Plaintiffs for the First Time at Trial ......................................................................................... 32

2.

B. C.

Dr. Leffler is Highly Qualified to Testify As An Expert in This Case ...................... 34 The Expert Testimony Offered By Plaintiffs is Not Credible ................................... 36 1. Dr. Klabunde is a Physiologist Who Has Never Administered Any Vasodilator, Including Adenosine, To a Patient ........................................... 36 Plaintiffs' Last-Minute Decision Not To Call Dr. Zaret Unfairly Deprived Sicor of Favorable Admission........................................................ 37

2. VI.

Remaining Evidentiary Issues ................................................................................................ 38 A. B. Sicor's Designation of Dr. Zaret's Deposition Testimony is Admissible................... 38 Dr. Strauss's Testimony Cannot Be Properly Considered........................................ 39

VII.

Conclusion............................................................................................................................... 40

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TABLE OF AUTHORITIES CASES ABB Air Preheater Inc. v. Regenerative Envtl. Equip., 167 F.R.D. 668 (D.N.J. 1996).......................................................................................................... 34 Abbott Labs. v. Baxter Pharmaceutical Prods., Inc., 471 F.3d 1363 (Fed. Cir. 2006) ....................................................................................................... 29 Amazon.com, Inc. v. Barnesandnoble.com, Inc. et al., 239 F.3d 1343 (Fed. Cir. 2001) ..................................................................................................30, 40 Aventis Pharma Deutschland GmbH v. Lupin Ltd., 2006 WL 1008962 (E.D. Va. July 17, 2006).................................................................................... 22 Cable Elec. Prods. v. Genmark, Inc., 770 F.2d 1015 (Fed. Cir. 1985) ....................................................................................................... 22 Crowley v. Chait, 322 F. Supp. 2d 530 (D.N.J. 2004) .................................................................................................. 33 Eli Lilly & Co. v. Barr Labs, Inc., 251 F.3d 955 (Fed. Cir. 2001) ......................................................................................................... 29 eSpeed, Inc. et al. v. Brokertec USA, LLC, 404 F. Supp. 2d 575 (D. Del. 2005)................................................................................................. 31 Forest Labs., Inc. v Ivax Pharm., Inc., 237 F.R.D. 106 (D. Del. 2006) ........................................................................................................ 32 Friction Div. Prods., Inc. v. E. I. Du Pont de Nemours & Co., Inc., 693 F. Supp. 114 (D. Del. 1988)................................................................................................. 26-27 In re Fla. Microsoft Antitrust Litig., 2002 WL 31423620 (Fla. Cir. Ct. 2002) .......................................................................................... 34 In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004) ....................................................................................................... 13 In re GPAC Inc., 57 F.3d 1573 (Fed. Cir. 1995) ......................................................................................................... 22 J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563 (Fed. Cir. 1997) ....................................................................................................... 24 KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007) .........................................................................................................1, 4, 7, 13 Leapfrog Enters., Inc. v. Fisher-Price, Inc., 485 F.3d 1157 (Fed. Cir. 2007) ................................................................................................... 4, 16

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McNeil-PPC, Inc. v. L. Perrigo Co., 337 F.3d 1362 (Fed Cir. 2003) ........................................................................................................ 26 Merck & Co., Inc. v. Teva Pharms USA, Inc., 405 F.3d 1338 (Fed Cir. 2005) ........................................................................................................ 27 Ormco Corp. v. Align Tech., 463 F.3d 1299 (Fed. Cir. 2006) ......................................................................................................... 6 Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) .................................................................................................. 16-17 Pfizer Inc. v. Teva Pharms. USA, Inc., 461 F. Supp. 2d 271 (D.N.J. 2006) .......................................................................................23, 34, 36 Renishaw PLC v. Marposs Societa' Per Azioni, 158 F.3d 1243 (Fed. Cir. 1998) .................................................................................................. 16-17 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) ....................................................................................................... 16 Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373 (Fed. Cir. 2003) ....................................................................................................... 29 Sentex Sys., Inc. v. Elite Access Sys., Inc., 194 F.3d 1331 (Fed. Cir. 1999) (unpublished opinion)..................................................................... 23 Speller v. U.S., 14 Cl. Ct. 170 (1988) ...................................................................................................................... 24 Tracinda Corp. v. Daimlerchrysler AG, 362 F. Supp. 2d 487 (D. Del. 2005)............................................................................................ 38-39 U.S. v. Adams, 383 U.S. 39 (1966).......................................................................................................................... 20 Vandenberg v. Dairy Equip. Co., 740 F.2d 1560 (Fed. Cir. 1984) .................................................................................................. 27-28 Wash. Legal Found. v. Legal Found. of Wash., 271 F.3d 835 (9th Cir. 2001) ........................................................................................................... 34 STATUTES 35 U.S.C. § 282..................................................................................................................................... 33 OTHER AUTHORITIES Rule 26(a)(3), Fed. R. Civ. P. ................................................................................................................ 34

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I.

INTRODUCTION The case for the obviousness of the asserted `296 patent claims is not a figment of hindsight, as

Plaintiffs would have this Court believe. Here, the sole named inventor, Dr. Alf Sollevi, rendered the `296 patent obvious by publishing his work over one year before the patent's priority date. Dr. Sollevi's two abstracts ("the Sollevi abstracts") disclosed a method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation, comprising continuously administering adenosine at a rate of 140 µg/kg/min, using a pretreatment with dipyridamole. 1 There is no serious dispute that these abstracts disclosed every element of the asserted claims save one: the elimination of the dipyridamole pretreatment. At trial, Sicor demonstrated clearly and convincingly that everyday insights would have motivated a person of ordinary skill at the relevant time to take the single, obvious step of eliminating the dipyridamole pretreatment. The skilled artisan would have been moved to do so where her goal was to achieve selective arterial vasodilation at a level less than the maximal vasodilation required to induce controlled hypotension for the surgical patients in Dr. Sollevi's study. See KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1742 (2007) ("A person of ordinary skill is a person of ordinary creativity, not an automaton."). The skilled artisan would have known that dipyridamole acted indirectly by increasing the concentration of endogenous adenosine in the body and thus the dipyridamole pretreatment served only to reduce the amount of exogenously administered adenosine. As dipyridamole was just the middleman used to increase the adenosine concentration, it could be eliminated where the desired level of selective arterial vasodilatation required was less. The Sollevi abstracts are not the only invalidating prior art here. A 1982 abstract by Dr. Fukunaga ("Fukunaga 1982") disclosed a method of selectively vasodilating the arteries of a human

1

"The Sollevi abstracts" refers to the following two abstracts authored by Dr. Alf Sollevi, which were published over one year before the priority date of the `296 patent: A. Sollevi et al., Cardiovascular effects of adenosine during controlled hypotension in cerebral artery aneurysm surgery, Anesthesiology (Circulation II) 59(3): A9 (Sept. 1983) (TX 1170, "Sollevi I"); A. Sollevi et al., Cardiovascular effects of adenosine in man, Acta Physiol. Scan. 120(2): 11A (Feb. 1984) (TX 37, "Sollevi II").

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patient without inducing significant venous dilation and without pretreatment with dipyridamole, comprising continuously administering adenosine triphosphate ("ATP") at a rate equivalent to the range of adenosine claimed in the `296 patent. The ATP administered by Dr. Fukunaga would have been rapidly and virtually completely converted to adenosine, a fact that persons of skill would have readily understood based a number of relevant prior art publications, among them a Sollevi publication. Dr. Fukunaga's 1984 abstract ("Fukunaga 1984"), in which the amount of ATP required to induce controlled hypotension was reduced by a dipyridamole pretreatment, confirmed that the selective arterial vasodilatation observed in Fukunaga 1982 was caused by the adenosine liberated by the rapid metabolism of the infused ATP, and not by the direct action of the ATP itself. Plaintiffs' response to Sicor's strong prima facie case of invalidity is threefold. First, Plaintiffs dispute that skilled artisans would have reasonably expected that selective arterial vasodilatation would result from the intravenous administration of adenosine alone in the claimed ranges. In support, Plaintiffs' expert opined that skilled artisans would have determined that amounts of adenosine far higher than the claimed range would be required. But Plaintiffs' expert's calculations both ignored the teaching of the Fukunaga 1982 and 1984 abstracts and incorrectly assumed that the skilled artisan's only goal was the maximal selective arterial vasodilatation induced by Dr. Sollevi and Dr. Fukunaga for surgical patients. Second, Plaintiffs contend that the only medical use of adenosine disclosed in the prior art was controlled hypotension, and thus that skilled artisans would not consider adenosine for other uses, e.g., those uses calling for less selective arterial vasodilatation and less adenosine, which would suggest the elimination of dipyridamole pretreatment. Dr. Binkley, however, testified that such uses would have been of interest to a person of skill at the time, and Plaintiffs have not shown otherwise. More important, Plaintiffs' argument is inapposite because even if the asserted claims did require that the selective arterial vasodilatation be employed for a specific medical use ­ which they do not ­ there is no legal requirement that the prior art have expressly disclosed such use for these claims to be obvious. As the Supreme Court made clear in KSR, a finding of obviousness does not require precise teachings directed to the specific

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subject matter of the claim. 127 S. Ct. at 1741. In this case, the `296 patent claims only selective vasodilation without qualification as to the level or medical purpose. And it is not disputed that selective arterial vasodilatation can occur at levels below the extreme level achieved in controlled hypotension ­ a basic scientific principle that was confirmed by both Plaintiffs' expert (Tr. 1059:19-22) and Sicor's expert, Dr. Binkley (Tr. 1367:7-1368:2). Finally, Plaintiffs also raise a number of so-called "secondary considerations" in an attempt to rebut Sicor's prima facie obviousness case, including unexpected results, skepticism of experts, and commercial success. But the purported "unexpected results" ­ no AV block and no increase in uric acid levels ­ were not unexpected based on Dr. Sollevi's own prior art. The Sollevi abstracts do not report any concern regarding AV block or uric acid. Moreover, Dr. Sollevi testified that he had the means to monitor for AV block and uric acid build-up, and he did not observe any sign of either of them. (Tr. 479:5-23; Tr. 482:11-16.) Whatever concerns may have existed in the older prior art, Dr. Sollevi's own work obviated them before the critical date. In similar fashion, the purported skepticism of experts that adenosine could be safely administered to patients is just smoke and mirrors. Plaintiffs cannot point to a single publication ­ peer-reviewed or otherwise ­ that demonstrates this purported skepticism. There are none. The private correspondence on which Plaintiffs rely is not the discourse of experts written to withstand public scrutiny, but merely letters congratulating Dr. Sollevi for achieving a result which the authors do not doubt was feasible or was in fact accomplished. Plaintiffs have also failed to demonstrate a nexus between the asserted claims of the `296 patent and the alleged commercial success of the Adenoscan® product. Adenoscan® was marketed on the basis of its short half life and the concomitant short duration of side effects, not on the basis of its ability to selectively vasodilate arteries rather than veins. Moreover, the sales levels for Adenoscan® do not suggest any non-obviousness and are instead explained by the confluence and interaction of four economic factors.

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For these reasons, and as explained in more detail below, as well as in Sicor's May 9, 2007 Opening Post-Trial Brief, Sicor asks this Court to find that the asserted `296 patent claims are invalid and enter judgment in Sicor's favor.

II.

THE ASSERTED CLAIMS OF THE `296 PATENT ARE INVALID AS OBVIOUS Plaintiffs attack Sicor's case for obviousness by challenging the lack of motivation to modify the

prior art. In the face of the evidence and the recent Supreme Court and Federal Circuit decisions concerning obviousness, Plaintiffs' challenge must fail. See generally KSR, 127 S. Ct. 1727; Leapfrog Enters., Inc. v. Fisher-Price, Inc., 485 F.3d 1157 (Fed. Cir. 2007). In their brief, Plaintiffs repeatedly claim that Sicor has not provided evidence of motivation to modify the prior art. But the rigid "teaching-suggestion-motivation" test upon which Plaintiffs rely is not the legal standard for an obviousness analysis. The Supreme Court could not have been more clear: a "expansive and flexible" approach should be used in assessing obviousness: As our precedents make clear, however, the analysis need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill can employ. See KSR, 127 S. Ct at 1739-41. While recognizing the need to guard against hindsight bias, the Supreme Court cautioned against adopting a wooden approach that takes common sense out of the obviousness analysis: The Court of Appeals, finally, drew the wrong conclusion from the risk of courts and patent examiners falling prey to hindsight bias. A factfinder should be aware, of course, of the distortion caused by hindsight bias and must be cautious of arguments reliant upon ex post reasoning. Rigid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it. See KSR, 127 S. Ct. at 1742-43 (emphasis added; citations omitted). The Supreme Court was cautioning against just the sort of trap that Plaintiffs' arguments have set for the Court here. By contrast, the correct analysis employs a broader conception of the suggestion test, taking into account the common knowledge in the field of art and allowing for the skilled artisan's use of her common sense and ordinary innovation. Id. at 1742. Here, the application of common knowledge and common sense renders these claims obvious.

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A.

The Sollevi Abstracts Render the Asserted Claims of the `296 Patent Obvious

Plaintiffs repeatedly describe Dr. Sollevi as a "pioneer" in the adenosine field. (D.I 151 at 8.) Even if that description were correct and Dr. Sollevi's continuous intravenous administration of adenosine were "pioneering," the problem for Plaintiffs is that Dr. Sollevi placed his "pioneering" work in the public domain in two abstracts (TX 37 and TX 1170) published more than a year before the priority date of the `296 patent (September 24, 1985). The Sollevi abstracts describe a human clinical study which disclosed nearly each and every element of the asserted claims: a method of selectively dilating the arteries of a human patient without inducing significant venous dilation, comprising administering adenosine intravenously at a rate of 140 µg/kg/min. (D.I. 150 at 17-19.) There is no dispute that these elements are disclosed in the Sollevi abstracts. (Tr. 1941:18-1942:6.) As a consequence of Dr. Sollevi's disclosures, persons of ordinary skill, employing their knowledge of the prior art, their common sense, and their ordinary creativity, would have understood that the dipyridamole pretreatment in the Sollevi abstracts could be eliminated and that the continuous intravenous administration of adenosine to humans in the claimed range could be done safely and would be reasonably likely to cause selective arterial vasodilation.

1.

The Sollevi Abstracts Demonstrated That 140 µg/kg/min Of Adenosine Could Be Administered Safely To Humans By Continuous Intravenous Administration

Plaintiffs claim that Dr. Sollevi administered a dipyridamole pretreatment before adenosine due to his "concern[] about adenosine's effect on the heart and its capacity to form the toxic uric acid metabolite" and that Dr. Sollevi considered the infusion of adenosine without dipyridamole "unthinkable, as the much higher doses thought to be required . . . would surely have lead to serious side effects." (D.I. 151 at 2.) Plaintiffs' argument and the Sollevi testimony upon which Plaintiffs rely should be discounted as a litigation-inspired gloss lacking credibility. The contemporaneous documents, the Sollevi abstracts, are silent on Dr. Sollevi's reasons for the use of dipyridamole except to say that dipyridamole was an "adenosine uptake inhibitor" (TX 37) and "reduced the required ADO dose" (TX 1170). Furthermore, Dr. Sollevi made no mention of such serious

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concerns when he disclosed his own experiments using adenosine without dipyridamole pretreatment. (TX 112 at 403 fn.). Nor were any of the purported serious side effects observed in Fukunaga 1982 (TX 42), a study that Dr. Sollevi cited in his contemporaneous publications. In view of Dr. Sollevi's silence in the contemporaneous record, his litigation-inspired after-the-fact testimony should carry no weight. Dr. Sollevi has acknowledged his financial interest in the outcome of this case. (Tr. 473:19-474:8.) And even if he were entirely free of bias ­ and he is not ­ Dr. Sollevi's testimony as an purported inventor is not relevant to the obviousness analysis because, according to Plaintiffs, Dr. Sollevi was an innovator and thus not a person of ordinary skill in the art in 1985. Moreover, the reasons that Dr. Sollevi now asserts for using the dipyridamole pretreatment were not expressed contemporaneously by him in the public domain and thus could not even have influenced the thinking of persons of ordinary skill at the time. The standard for obviousness is the understanding of a person of ordinary skill ­ not the understanding of the inventor ­ based on what is in the public domain. Ormco Corp. v. Align Tech., 463 F.3d 1299, 1306 (Fed. Cir. 2006). Other circumstantial evidence discounts Plaintiffs' and Dr. Sollevi's assertions that adenosine was perceived as too dangerous to be used without dipyridamole. The Sollevi abstracts conclude by recommending the use of intravenous adenosine for controlled hypotension ­ with no reference to the need for dipyridamole. (D.I. 150 at 18-19.) If Dr. Sollevi believed that it was dangerous to administer adenosine without dipyridamole, as Plaintiffs claim, a person of ordinary skill would have expected the Sollevi abstracts to stress the importance of the dipyridamole pretreatment ­ but the Sollevi abstracts never do so. By contrast, the last sentences of the Sollevi abstracts state that the "hemodynamic and metabolic properties of adenosine make it a suitable agent for CH in man." (Id. (emphasis added).) There is no mention that dipyridamole must always be used. Because adenosine and dipyridamole have very different metabolic properties, in particular half life,2 this statement focusing on the advantageous

2

For example, the metabolism of adenosine in human blood is 10 to 30 seconds, whereas the half life of dipyridamole is approximately 30 to 40 minutes. (D.I. 150 at 11.)

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metabolic properties of adenosine would not indicate to skilled artisans that it was unthinkable to administer adenosine without a dipyridamole pretreatment. Further, the specter of danger from the use of adenosine is belied by Dr. Sollevi's decision to conduct the first ever human trial on the intravenous administration of adenosine (with or without dipyridamole) on surgical patients suffering from cerebral aneurysms (i.e., "a `bulb' or bubble on a blood vessel in the brain that could rupture, causing bleeding and death"). (D.I. 151 at 8.) As a physician desiring to do no harm to his patients, Dr. Sollevi's decision to forego the accepted protocol within the medical community to first conduct clinical trials in healthy volunteers strongly suggests that his contemporaneous concerns regarding the danger of adenosine were far less than he and Plaintiffs now assert.

B.

The Fukunaga 1982 Abstract Renders The Asserted Claims Of The `296 Patent Obvious

Plaintiffs argue that persons of ordinary skill would not have understood that the controlled hypotension reported in the Fukunaga Abstracts following the intravenous administration of adenosine triphosphate ("ATP") was the result of the action of adenosine. Plaintiffs' argument fails because it incorrectly presumes that persons of ordinary skill would view the prior art robotically instead of using their expertise and common sense (see KSR, 127 S. Ct. at 1742), and would ignore the teachings of more relevant and recent prior art in favor of the less relevant and older prior art cited by Plaintiffs. Plaintiffs rely primarily on the testimony of Dr. Klabunde, who on the ATP-adenosine conversion issue, focused almost exclusively on references from the 1970s (TX 151; TX 199). These references do not contradict Sicor's evidence, and at any rate were outdated by the `296 patent priority date. Dr. Klabunde and Plaintiffs turn a blind eye to the evidence existing at the relevant time that the vasodilative effects of ATP were due to its rapid and complete conversion to adenosine. (D.I. 150 at 11-13.) For example, a contemporaneous publication co-authored by Dr. Sollevi expressly stated that ATP that is intravenously administered is degraded "entirely to adenosine" during the transpulmonary passage. (TX 236 at 547.)

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Plaintiffs assert that a study by Moir and Downs published in the early 1970s ("Moir and Downs," TX 199) would have led skilled artisans to believe that ATP was a more potent vasodilator than adenosine and thus that ATP, not adenosine, was the direct-acting agent for the selective arterial vasodilatation in Fukunaga 1982. Plaintiffs' analysis is wrong. Even Dr. Klabunde admitted that by the relevant time, the Moir and Downs study was old news, and a person of ordinary skill would have looked to more recent publications to understand the relationship between ATP and adenosine in vasodilation. (Tr. 1118:8-12.) The later publications would lead the skilled artisan to understand that adenosine, not ATP, was the direct-acting agent in Fukunaga 1982. Moreover, the data in Moir and Downs do not even support Plaintiffs' position that skilled artisans would have viewed ATP as more potent than adenosine. As Dr. Binkley testified, "there really is not a great difference" in coronary blood flow when comparing data from the dogs who had received ATP and the dogs who had received adenosine (Tr. 1422:18-1425:25), nor were p-values calculated to allow a proper statistical analysis of the data comparison (Tr. 1450:7-24).3 Importantly, Dr. Binkley noted a key difference in the manner of ATP administration in TX 199 and the manner of ATP administration in the Fukunaga abstract that undermines Plaintiffs' characterization of the results. (Tr. 1426:19-1427:15.) In TX 199, ATP was administered directly into the artery to be dilated and did not cross the transpulmonary passage. In Fukunaga 1982, ATP was administered intravenously, and thus necessarily flowed through the transpulmonary passage. A person of ordinary skill would have understood that intravenously administered ATP would be degraded entirely to adenosine during the transpulmonary passage (see, e.g., TX 236), and also would have understood that the ATP administered in TX 199 (which reflected intra-arterial administration) bypassed the transpulmonary passage. (Tr. 1426:19-1427:15.) Therefore, a person of ordinary skill would have known the data in TX 199 did not represent the effects that would be expected if ATP was intravenously, because the conversion of adenosine to ATP in the transpulmonary passage could not occur.
3

Dr. Binkley did not believe that the difference in the amount of adenosine and ATP that was administered to the dogs in TX 199 was relevant.

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Based on a correct and complete understanding of the prior art, the asserted claims would have been obvious to a person of ordinary skill in the art in view of Fukunaga 1982 (TX 42). Fukunaga 1982 disclosed the intravenous administration of 200 to 600 ug/kg/min of ATP, which a person of ordinary skill would have understood to be equivalent to about 97 to 290 µg/kg/min of adenosine.4 (D.I. 150 at 19.) Fukunaga 1982 also disclosed that the administration of ATP in this dosage range lead to controlled hypotension, coupled with "well-maintained" cardiac output, which indicates that selective arterial vasodilation occurred. (Tr. 163:9-166:7.) Dr. Sollevi himself expressly addressed Fukunaga 1982 in a 1984 publication that discussed the same results set forth in the Sollevi abstracts. (TX 112.) In that discussion, Dr. Sollevi described what was known to persons of ordinary skill at that time ­ that degradation of ATP to adenosine was rapid, complete, and resulted in "considerable phosphate formation" in the bloodstream. (Id. at 403.) Relying on a 1982 reference in support of the statement that "high levels of phosphate could cause arrhythmia," Dr. Sollevi stated that "we consider it more appropriate to use adenosine in preference to ATP to induce controlled hypotension." (Id.) The substitution of adenosine for ATP was therefore not inventive ­ it was based on the disclosure in Fukunaga 1982 coupled with the knowledge of a person of ordinary skill in the art at the relevant time. A person of ordinary skill would have understood, based on a number of relevant publications, that ATP breaks down to adenosine almost immediately following intravenous administration. (See, e.g., TX 236 at 547; TX 51 at A39; TX 228 at 807-08; TX 5000 at 1196.) A 1984 publication co-authored by Dr. Sollevi himself disclosed that "the arterial plasma adenosine concentration during ATP infusions was similar to that found during an equimolar infusion of adenosine." (TX 88 at 174-75.) This publication

4

Plaintiffs challenge the simplifying assumptions that Dr. Binkley made in calculating this conversion. (D.I. 151 at 23-24.) But plaintiffs never actually contest that this conversion is precisely the sort of calculation that a person of ordinary skill would have replied upon to estimate the amount of adenosine to administer to achieve the same result. (Tr. 167:20-168:18.) The person of ordinary skill has been defined as a physician, not a pharmacokineticist.

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contradicts Plaintiffs' argument that skilled artisans would not have understood that the ATP administered in Fukunaga 1982 was being rapidly converted to adenosine. Most important, the results in Fukunaga (TX 51, "Fukunaga 1984") convincingly demonstrated that in Fukunaga 1982 adenosine was the direct-acting agent of the selective arterial vasodilation, not ATP. The pretreatment with dipyridamole in Fukunaga 1984 reduced the amount of ATP that was required to induce controlled hypotension. Because dipyridamole blocks the uptake of adenosine, but not ATP, the result in Fukunaga 1984 meant that the vasodilatation was caused by adenosine that accumulated after its rapid conversion from the ATP. (Tr. 178:14-18; Tr. 179:13-181:22.) Thus Fukunaga 1984 would confirm to a person of ordinary skill that adenosine ­ not ATP ­ was responsible for the vasodilation. Rather than discourage a skilled artisan from using adenosine without dipyridamole, as Plaintiffs claim, Fukunaga 1984 would simply teach that dipyridamole could be a "potentially useful added agent," and is not a requirement for safe and effective selective arterial vasodilation. (D.I. 150 at 28-29.) Plaintiffs are also wrong in contending that skilled artisans would not understand the direct-acting effect of adenosine in Fukunaga 1982 based on a publication by Dr. Burnstock concerning the different cellular receptors for adenosine and ATP (TX 151). The opposite is true. Dr. Burnstock's research showed that the receptors for adenosine (P1) are predominant in sites where arterial vasodilatation can occur, e.g., "in most cardiovascular beds" (like arteries), whereas the receptors for ATP (P2) are predominant in sites that play no role in arterial vasodilatation, e.g., the gastrointestinal tract and the urinogenital system. (TX 151 at 110; D.I. 150 at 13; Tr. 1172:6-18.) Dr. Klabunde confirmed that a subsequent 1985 publication (also by Burnstock) would teach a person of ordinary skill that P1 receptors were associated with vasodilation. (Tr. 1174:25-1177:2; TX 152 at 195.) Given that adenosine receptors are present predominantly in arteries and ATP receptors are not, a person of ordinary would understand that the arterial vasodilation that was observed following that administration of ATP was due to its conversion to adenosine. (Tr. 1437:11-1438:2.) And the rapid conversion of ATP to adenosine would

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have suggested to the skilled artisan that little (if any) ATP would remain to bind to any ATP receptors that were present in the arterial vasculature. (Tr. 1107:3-12; TX 5000 at 1196; TX 51 at A39.)

C.

The Dose Required to Produce a Desired Effect Could Have Been Determined Through Routine Experimentation

In response to Sicor's evidence that the Sollevi abstracts and Fukunaga 1982 disclose that a dose of 140 µg/kg/min of intravenous adenosine is safe, Plaintiffs contend that a person of ordinary skill would not have been able to determine the dose of adenosine needed to cause vasodilation. (D.I. 151 at 9-10.) This argument fails, too. First, Plaintiffs rely primarily on in vitro studies or studies in non-human species. Not one of the studies cited by Plaintiffs concern a dose titration of adenosine in humans, even though such studies had been published during the same time period. (TX 36; TX 45.) Based on these studies in humans, a person of ordinary skill would have understood that the dose of adenosine administered could be readily titrated until the desired level of vasodilation were achieved. Dr. Klabunde confirmed that such a dose titration would have been routine experimentation for a person of ordinary skill in the art at that time. (Tr. 1132:21-1133:1; see also TX 36 at 1261.) Second, selective arterial vasodilation is not an all or nothing phenomenon. Different degrees of vasodilation may occur depending upon the dose of vasodilator that is administered. Importantly, the asserted claims of the `296 patent do not claim a specific degree of vasodilation, and are directed to a method of selective arterial vasodilation generally. Yet Plaintiffs' argument assumes that the only goal of a person of ordinary skill in the art is the maximal selective arterial vasodilatation required to induce controlled hypotension in surgical patients. Dr. Binkley explained that skilled artisans would also be interested in medical uses of adenosine calling for less than maximal selective arterial vasodilatation. (Tr. 1370:15-1372:10; Tr. 1372:25-1374:3.) Plaintiffs cannot defeat the case for obviousness by conjuring new claim limitations, such as an implied requirement for a certain level of vasodilation, particularly where their litigation position has been that no claim construction is needed. The limitation

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that Plaintiffs would have this Court now read into the asserted claims is a far cry from their plain and ordinary meaning. And in fact, as Dr. Klabunde confirmed, a person of ordinary skill could have used the amount of adenosine administered in the Sollevi abstracts as a guide and easily conducted a dose titration to determine the required dose. (D.I. 150 at 23.) A person of ordinary skill would have had a reasonable expectation that such a titration would be successful, given that publications at the relevant time concerning administration of adenosine in humans stated that "rapid uptake and metabolism of adenosine allow easy dose titration." (TX 45 at 423.) Plaintiffs also cite an abstract by Biaggioni ("Biaggioni," TX 1187) in support of their argument that a person of ordinary skill would not believe that a dose of 140 µg/kg/min would be sufficient to cause "hypotension." (D.I. 151 at 9.) But again, Plaintiffs have ignored the plain language of the asserted claims. None of the asserted claims set forth a specific medical use for adenosine, let alone hypotension. Instead, the claims recite only a method of causing selective arterial vasodilation. As confirmed by Dr. Klabunde at trial, controlled hypotension for surgery is the result of near-maximal vasodilation. (Tr. at 1059:15-1060:4.) A person ordinary skill at the relevant time would have known that lower levels of vasodilation would have been necessary for other medical uses, like cardiac diagnostics. By contrast, the Biaggioni study cited by Plaintiffs demonstrated that 140 µg/kg/min adenosine could be safely administered to humans without dipyridamole pretreatment and without causing AV block or excessive build up of uric acid. And the pattern of side effects (e.g., flushing) observed in Biaggioni also confirmed that adenosine doses in the claimed range had a systemic effect.

D.

The Prior Art Uses of Adenosine and Other Vasodilators Did Not Teach Away from the Claimed Invention

Plaintiffs contend that certain problems historically associated with adenosine would have taught away from its intravenous administration at the critical time. (D.I. 151 at 5-7.) For example, Plaintiffs cite a publication from the early 1970s which notes that adenosine's use in cardiovascular therapy has

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been hampered due to its short-term action and its effects on the heart.5 (TX 214) But skilled artisans would not view the prior art wearing Plaintiffs' blinders. The Sollevi abstracts, which were published much closer to the date that the `296 patent was filed, disclosed the safe and effective use of intravenous adenosine in humans with dipyridamole, whereas Fukunaga 1982 and Biaggioni demonstrated the same without dipyridamole pretreatment.

1.

The Use of Other Vasodilators During the Relevant Time Period Would Have Encouraged Persons of Ordinary Skill to Look to Adenosine

Plaintiffs also claim that the use of other known vasodilators, specifically dipyridamole and ATP, would have taught away from adenosine administration. (D.I. 151 at 6-7.) Plaintiffs' argument is wrong both legally and factually. Importantly, the 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. In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). And rather than teach away from the use of adenosine, the use of dipyridamole and ATP, in view of the knowledge of their mechanism of action through adenosine, would have motivated a person of ordinary skill to "cut out the middleman" and administer adenosine for the same purpose. Far from teaching away, the use of dipyridamole as a vasodilator would have taught a person of ordinary skill in the art that adenosine could be used for the very same purpose. Dipyridamole had long been known in the art as a vasodilator, and its mechanism of action had been understood since at least the late 1970s. (D.I. 150 at 10-11.) As Dr. Klabunde confirmed, persons of ordinary skill would have understood not only dipyridamole's mechanism of action but also that the use of dipyridamole had several drawbacks, including a slower onset and a longer duration. (D.I. 150 at 11.) Based on these drawbacks, a person of ordinary skill would have been motivated to administer adenosine alone to effect vasodilation. See KSR, 127 S. Ct. at 1742 ("When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options with his or her technical grasp.").
5

This publication was not cited in Dr. Klabunde's expert report (TX 119) and was first introduced at trial.

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Similarly, prior art publications about the use of ATP for vasodilation would have encouraged a person of ordinary skill to use adenosine for the very same purpose. As discussed supra, such a person would have understood that ATP that is intravenously administered rapidly and completely degrades to adenosine, and this adenosine ­ not its ATP parent ­ causes selective arterial vasodilation. And as Dr. Sollevi's own writings make clear (TX 112 at 403), a person of ordinary skill would have understood that the administration of ATP would result in an increase in phosphate, which would be formed during ATP's conversion to adenosine, and thus would be motivated to administer adenosine directly. As with dipyridamole, a person of ordinary skill would have been motivated by common sense to remove the middleman and administer adenosine directly to effect vasodilation. But at the relevant time, pharmaceutical-grade adenosine was not readily available for intravenous administration. (Tr. 331:21-332:2.) Therefore, a person of ordinary skill would have used dipyridamole and ATP as indirect-acting surrogates for what such a person would have understood to be the direct action of adenosine.

2.

Research Concerning Adenosine for Various Medical Uses Exploded Following a 1980 Publication by Dr. Berne

In December 1980, long before the priority date of the `296 patent and well after the outdated prior art cited by Plaintiffs, Dr. Robert Berne published an article in Circulation Research entitled "The Role of Adenosine in the Regulation of Coronary Blood Flow" (TX 228). Dr. Berne described adenosine as one of the "principle contenders that can serve as a mediator of coronary blood flow (CBF) regulation." (Id. at 807 (emphasis added).) Soon thereafter, the field of adenosine research exploded, as scientists and physicians searched for new uses for this "principle contender" in the field of vasodilation. As Dr. Binkley testified, selective arterial vasodilators were considered for many different uses during the relevant time period, including treatment of hypertension, treatment of congestive heart failure, treatment of limb ischemia, diagnosis of coronary artery disease, and (last but not least) controlled hypotension. (D.I. 150 at 21.)

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Plaintiffs' assertion that Dr. Berne disclosed the "first human medical use" of adenosine in December 1983 as a treatment for paroxysmal supraventricular tachycardia ("PSVT") is simply wrong. (D.I. 151 at 18.) By September 1983, the Sollevi abstracts had disclosed the intravenous administration of adenosine to surgical patients (TX 1170), and shown that a dose of 140 µg/kg/min of intravenous adenosine was safe. Plaintiffs are wrong that Dr. Berne's December 1983 publication would have discouraged a person of ordinary skill from using intravenous adenosine administration.6 By that time, Dr. Sollevi had already done so, Dr. Fukunaga had used its equivalent (TX 42), and Biaggioni's work with adenosine (TX 1187) was not far behind. Moreover, the Sollevi abstracts would have encouraged interest in the intravenous infusion of adenosine. For example, Dr. Klabunde testified that the goal of one of his own publications (dated 1982) about the effects of adenosine in vitro was to stimulate others to find practical medical applications for adenosine. (Tr. 1078:21-1080:2.) If in vitro experiments could stimulate this level of interest, then the in vivo clinical testing in humans at the relevant time, as published in the Sollevi abstracts, would place even more focus on this area of research. Even before the Sollevi abstracts were published, the use of adenosine to induce controlled hypotension in humans was also an area of interest. Other contemporaneous scientists suggested that adenosine could be administered to humans without dipyridamole to induce controlled hypotension: [W]e speculate that adenosine alone, without the potentiating effects of dipyridamole, may be sufficient to produce hypotension in higher primates and man without involving excessive volumes of fluid. See TX 40 at 73; see also Tr. 1197:13-1198:5.

6

Similarly, Plaintiffs also cite a number of additional publications in which adenosine is administered as a bolus injection for treatment of PSVT. (D.I. 151 at 5.) But rather than discourage persons of ordinary skill, these publications would, if anything, motivate a person of ordinary skill in the art to seek additional medical uses for adenosine, including diagnostic uses. (TX 36 at 1261.) And notably, plaintiff Astellas markets an injectable form of adenosine, sold under the brand name Adenocard®, for this treatment of PSVT.

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III.

SECONDARY CONSIDERATIONS DO NOT SUPPORT THE NON-OBVIOUSNESS OF THE ASSERTED CLAIMS Plaintiffs devote a substantial portion of their attack on Sicor's prima facie obviousness case to

secondary indicia of non-obviousness ("secondary considerations"). But where, as here, the case for obviousness is strong, even substantial evidence of secondary indicia will fail. See, e.g., 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."); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) (holding that even if patentee showed unexpectedly superior results, "this secondary consideration does not overcome the strong showing of obviousness in this case"). Even if the secondary considerations evidence here were as compelling as Plaintiffs claim ­ and it is not ­ nevertheless it falls short of the not obvious mark. See Leapfrog, 485 F.3d at 1162 (affirming that a patent was invalid where the "district court explicitly stated in its opinion that Leapfrog had provided substantial evidence of commercial success, praise, and long-felt need, but that, given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion that claim 25 would have been obvious").

A.

Plaintiffs Have Not Demonstrated Unexpected Results

Plaintiffs' argument for unexpected results makes no sense because it ignores the language of the asserted claims. As discussed supra, the claims of the `296 patent are directed to a method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation, and without pretreatment with dipyridamole, through the continuous intravenous administration of adenosine at certain rates. (D.I. 150 at 6.) There is no requirement in the claims that a specific degree of vasodilation be achieved, nor a "functional" requirement that AV block or increases in uric acid levels do not occur. See Renishaw PLC v. Marposs Societa' Per Azioni, 158 F.3d 1243, 1252 (Fed. Cir. 1998) (declining to "plac[e] a functional limitation" in a claim, on the basis that "this limitation appear[ed] nowhere in the claims; rather it c[a]me[] from a concept of operability").

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1.

The Occurrence of Selective Arterial Vasodilation at the Claimed Dosages Was Not Unexpected

Plaintiffs assert that "the clear teaching of the prior art was that unacceptably high doses of adenosine would be required in the absence of dipyridamole pretreatment." (D.I. 151 at 34-35.) Plaintiffs' contention is wrong for at least two reasons. First, Fukunaga 1982, viewed in the light of Fukunaga 1984, confirmed that the intravenous administration of adenosine in the claimed range, without dipyridamole pretreatment, caused maximal selective arterial vasodilation sufficient to induce controlled hypotension in surgical patients. For this reason alone, the occurrence of selective arterial vasodilatation would not be unexpected. Second, Plaintiffs' contention is improperly limited to the consideration of controlled hypotension for surgery, whereas the claims are not. The only "purpose" actually claimed in asserted claims of the `296 patent is "selectively vasodilating the arteries of a human patient without inducing significant venous dilation." (TX 275 at col. 22, ll. 20-21.) Contrary to Plaintiffs' suggestions, the asserted claims do not claim "a safe and effective dose [of adenosine] that would induce hypotension in the absence of [dipyridamole] pretreatment." (See, e.g., D.I. 151 at 9.) Plaintiffs' attempt to interject additional "functional" elements into the asserted claims is legally improper and must fail. See Renishaw, 158 F.3d at 1248-49 ("`We know of no principle of law which would authorize us to read into a claim an element which is not present, for the purpose of making out a case of novelty or infringement.'" (quoting McCarty v. Lehigh Val. R.R., 160 U.S. 110, 116 (1895))). To evaluate whether a given result is unexpected, the court should consider what result was expected. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). The evidence is that a person of ordinary skill in the art at the relevant time would have expected the intravenous administration of adenosine to cause at least some selective arterial vasodilation at the claimed dose range and in the absence of dipyridamole pretreatment. (Tr. 355:16-356:8; TX 37; TX 42; TX 1170.) Plaintiffs' "unexpected results" argument is also specious to the extent that it relies on the Sollevi testimony. (D.I. 151 at 8-10, 34-35.) Dr. Sollevi's statements at trial must be considered against the

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backdrop of several important facts: he is not a person of ordinary skill in the art (the proper standard for an invalidity analysis) (Tr. 475:10-24), and he has a strong financial interest in the outcome of this litigation (Tr. 473:19-474:8, 475:2-9). Further, Dr. Sollevi's contemporaneous publications concerning the intravenous administration of adenosine without dipyridamole do not raise as concerns the prospect of increases in uric acid levels and AV block as associated concerns. Presumably, if Dr. Sollevi were so concerned about these issues, he would have addressed them in his publications at the time. (See, e.g., TX 112.) Finally, Plaintiffs' argument suffers from a serious credibility issue. Dr. Sollevi would have this Court believe that he decided to conduct an experiment eliminating the dipyridamole pretreatment for 20 surgical patients and expecting to use amounts of adenosine that he deemed at the time to be "unthinkable" and likely to cause AV block and serious risk of uric acid build-up, yet at the same time relegated his report of the results of this "unthinkable" experiment to a footnote in TX 112 that failed to mention any of the surprise at the results that he now asserts. There is no reason to believe that Dr. Sollevi or the Karolinska Institute Hospital would have permitted such risk taking with patients. Dr. Sollevi's expression of surprise at the "unexpected result" rings hollow and should be discounted in its entirety.

2.

The Lack of AV Block Was Not Unexpected

Plaintiffs also assert that the lack of AV block observed following the claimed administration of adenosine was unexpected. (D.I. 151 at 7.) But Plaintiffs' contention is not supported by the record, and makes no logical sense. The Sollevi abstracts do not report AV block and thus directly contradict Plaintiffs' argument that a person of ordinary skill in the art would have expected the intravenous adenosine administration of adenosine in the claimed range to cause AV block. Dr. Sollevi "carefully monitor[ed] the electrocardiograms" when he administered adenosine with dipyridamole, and he did not observe any evidence of AV block. (D.I. 151 at 8; Tr. 479:5-23.) Therefore, a person of ordinary skill would understand that the Sollevi abstracts proved that continuous intravenous infusion of adenosine at a

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rate of 140 ug/kg/min was not likely to cause AV block, particularly if the same dose of adenosine was administered in the absence of dipyridamole. The person of ordinary skill would also understand that AV block is a transient effect that would be much more easily resolved in the absence of dipyridamole pretreatment, given that dipyridamole causes an additional increase in the adenosine concentration that lasts for a relatively longer period of time. (D.I. 150 at 31-32.) If dipyridamole and adenosine are administered together, their combined effects cannot be terminated by the flick of a switch ­ but the effects of adenosine alone can be.

3.

The Lack of Uric Acid Build-Up Was Not Unexpected

Plaintiffs further suggest that the lack of uric acid build-up observed following the intravenous administration of adenosine was an unexpected result. (See, e.g., D.I. 151 at 16, 18.) But again, a person of ordinary skill would actually understand that the side effects that might be associated with adenosine, including a transient increase in uric acid levels, would be much less likely to occur if dipyridamole were not administered with adenosine. (D.I. 150 at 32-33.) And, as discussed above, the Sollevi abstracts also would have relieved any concerns that a person of ordinary skill in the would have had regarding the risk of uric acid build-up from intravenous adenosine administration. Dr. Sollevi "carefully . . . test[ed] the metabolite levels" when he administered adenosine with dipyridamole, but he did not observe any evidence of prohibitive increases in uric acid levels.7 (D.I. 151 at 8; Tr. 482:11-16.) Importantly, a person or ordinary skill at the relevant time would have understood that the net increase in adenosine concentration would have been greater ­ and that any side effects were more likely to occur ­ if dipyridamole were also intravenously administered along with adenosine, as compared to the increase when the same dose of adenosine was administered alone.

B.

Plaintiffs Have Failed to Provide Evidence of Skepticism

The keystone of Plaintiffs' evidence of skepticism in the field is personal, non-public correspondence between the inventor, Dr. Sollevi, and others in the field who may or may not be experts.
7

And contrary to Plaintiffs' assertions (D.I. 151 at 7), adenosine is much more likely to be recycled into AMP than degraded to inosine (the precursor to uric acid). (TX 228 at 808.)

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Even if admissible, which Sicor does not concede, the correspondence here is not probative and should be given no weight.

1.

The Correspondence Is Not Probative Of Non-Obviousness

As "evidence" of skepticism in the field, Plaintiffs rely entirely on personal correspondence between Dr. Sollevi and Dr. Berne (Tr. 1201:7-10, 13-16; Tr. 1974:12-14, 18-19), and other correspondence between and among Dr. Sollevi, a journal editor, and Dr. Francis Robicsek8 (Tr. 1201:11-16; Tr. 363:14-364:4). The correspondence relied upon by Plaintiffs is far too unspecific to be probative, let alone to be persuasive evidence that experts were skeptical that adenosine could be administered without causing AV block or uric acid build-up. The correspondence does not describe (1) the study subjects (e.g., humans or animals), (2) the dose of adenosine used, (3) the manner in which adenosine was administered (e.g., bolus or intravenous infusion), (4) the purposes of the study (e.g., vasodilation or platelet aggregation), and (5) whether a dipyridamole pretreatment was administered. Each of these factors represents a piece of information that must be known to determine whether the correspondence is even relevant to skepticism of experts, or whether the expert may have may have, in fact, been expressing skepticism about a completely different discovery. (D.I. 150 at 34.) Plaintiffs cite U.S. v. Adams, 383 U.S. 39 (1966), in support of the argument that the correspondence proved skepticism of experts. (D.I. 151 at 28-30.) Adams does not help Plaintiffs because important distinctions exist between the two cases. Unlike this case, private correspondence was not the only evidence available to the Court in Adams. Instead, as the Adams briefs cited by Plaintiffs make clear (D.I. 151, Appendix at 76-78), an issued patent and a published article served as primary evidence of skepticism of experts. Thus, in Adams, the totality of the evidence, not just private correspondence, supported a finding of skepticism of experts. Furthermore, in Adams, the Court emphasized that the proffered evidence showed continued skepticism that the inventor had accomplished what he claimed to have accomplished, even after the
8

Plaintiffs have provided no evidence that Dr. Robicsek ever conducted a clinical study administering adenosine to a human, making his purported "expertise" in the field dubious at best.

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inventor disclosed his discovery. See Adams, 383 U.S. at 44. The letters here evidence no such disbelief. Rather, the correspondence congratulates Dr. Sollevi for accomplishing exactly what he said he had accomplished (the specific nature of the accomplishment cannot be discerned from the correspondence). Certainly, congratulations from one colleague to another does not mean that scientific work is patentable. Second, as discussed supra, the inventor's alleged subjective disbelief that adenosine could be administered intravenously in the relevant ranges without encountering certain adverse events runs counter to evidence in the prior art at the time. (D.I. 150 at 30-33.) Similarly, Dr. Sollevi's secondhand testimony that others in the field considered him "a crazy Swede" is hardly the sort of evidence of skepticism that supports a finding of non-obviousness. For these reasons, Plaintiffs' ill-considered attempt to use a few ambiguous private letters as evidence of widespread skepticism in the field must be rejected.

2.

The Correspondence Relied Upon by Plaintiffs is Not Admissible

The correspondence here was private and thus not publicly available to persons of ordinary skill in the art, not subject to public scrutiny or comment, and therefore could not have influenced (much less discouraged) persons of ordinary skill in the art at the relevant time. (Tr. 1201:7-10, 13-16; Tr. 363:14-364:4.) As Plaintiffs note, the Court questioned at trial whether this correspondence should be considered. (D.I. 151 at 3.) In response to Plaintiffs' argument that the letters should be admitted because of the ancient documents exception to the hearsay rule, the Court observed: [T]he keystone to the hearsay rule is reliability, and I can't imagine that letters, not publications that appear at someplace in a public context, but personal letters, not signed, not authenticated, can possibly be deemed reliable, and making them old doesn't make [me] more comfortable that they are reliable sources of evidence. (Tr. 415:9-15.) In addition, the Court pointed out that [S]omeone is more apt to be skeptical in a private fashion, which is not necessarily tested by any scientific thought than they are in published materials. . . . what I write in an e-mail to my Law Clerk I would never want published as my view on a matter. It is not my view on a matter until it is published, and I think that's why prior art is defined the way it is.

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(Tr. 417:5-11.) Sicor shares the Court's view that "when scientists don't express the same skepticism in public, [the Court is] concerned that a letter just like e-mails was written without scientific thought and was a transitory thought and not a reliable scientific thought." (Tr. 421:9-13.) Tellingly, the editor of the journal that published the study at the heart of correspondence between Dr. Sollevi and Dr. Robicsek concluded that this correspondence did not merit publication. (TX 412.) This corroborates Sicor's view that this correspondence does not raise genuine scientific issues. As such, it could not be probative of the non-obviousness of the asserted claims.

C.

Copying Is Irrelevant in the ANDA Context

Plaintiffs assert that the filing of Sicor's ANDA is evidence of copying of the invention. (D.I. 151 at 35.) However, the Federal Circuit has stated "`more than the mere fact of copying by an accused infringer is needed to make that action significant to a determination of the obviousness issue.'" In re GPAC Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995) (quoting Cable Elec. Prods. v. Genmark, Inc., 770 F.2d 1015 (Fed. Cir. 1985)). Indeed, copying may occur for reasons that are unrelated to any purported nonobviousness of the invention. See Cable Elec. Prods., 770 F.2d at 1028, overruled on other grounds by Midwest Indus., Inc. v. Karavan Trailers, Inc., 175 F.3d 1356 (Fed. Cir. 1999). The Eastern District of Virginia has explained why copying is particularly weak evidence of non-obviousness in the ANDA litigation context. See Aventis Pharma Deutschland GmbH v. Lupin Ltd., 2006 WL 1008962, at *45 (E.D. Va. July 17, 2006). Like the defendant in A