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

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

ITEM DEVELOPMENT AB, ASTELLAS US LLC, and ASTELLAS PHARMA US, INC. Plaintiffs, v. SICOR INC. and SICOR PHARMACEUTICALS, INC. Defendants.

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

Civil Action No. 05-336 SLR

DEFENDANTS SICOR'S RESPONSIVE PROPOSED FINDINGS OF FACT AND CONCLUSIONS OF LAW

Josy W. Ingersoll (No. 1088) John W. Shaw (No. 3362) Karen E. Keller (No. 4489) YOUNG CONAWAY STARGATT & TAYLOR, LLP The Brandywine Building 1000 West Street, 17th Floor Wilmington, DE 19801 (302) 571-6600 [email protected] Of Counsel: David M. Hashmall, P.C. Annemarie Hassett GOODWIN PROCTER LLP 599 Lexington Avenue New York, NY 10022 (212) 813-8800 Dated: June 19, 2007 Attorneys for Defendants Sicor Inc. and Sicor Pharmaceuticals, Inc.

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TABLE OF CONTENTS Page I. PROPOSED RESPONSIVE FINDINGS OF FACT...................................................... 1 A. The Asserted Claims of the `296 Patent are Invalid As Obvious....................... 1 1. 2. The Asserted Claims of the `296 Patent...................................................... 1 The Sollevi Abstracts Render the Asserted Claims of the `296 Patent Obvious ..................................................................................................... 2 a. The Sollevi Abstracts Demonstrated That 140 µg/kg/min of Adenosine Could Be Administered Safely To Humans By Continuous Intravenous Administration Without Dipyridamole Pretreatment ................................................................................... 3

3.

The Fukunaga 1982 Abstract Renders the Asserted Claims of the `296 Patent Obvious........................................................................................... 4 a. The Study Reported in the Fukunaga 1982 Abstract, Coupled with the Knowledge of a Person of Ordinary Skill at the Relevant Time, Would Have Led to the Use of Adenosine Infusion Without Dipyridamole Pretreatment ............................................... 5 (i) (ii) (iii) Fukunaga 1984 (TX 51)...................................................... 6 Moir and Downs (TX 199).................................................. 7 Burnstock (TX 151, TX 152) .............................................. 8

4. 5.

The Dose Required to Produce a Desired Effect Could Have Been Determined Through Routine Experimentation .......................................... 9 The Prior Art Uses of Adenosine and Other Vasodilators Would Not Have Taught Away from the Claimed Invention ........................................ 11 a. The Use of Other Vasodilators During the Relevant Time Period Would Have Encouraged Persons of Ordinary Skill to Look to Adenosine ...................................................................................... 11 Research Concerning Adenosine for Various Medical Uses Exploded Following a 1980 Publication by Dr. Berne .................... 12

b. B.

Secondary Considerations Do Not Support the Non-Obviousness of the Asserted Claims ................................................................................................... 14 1. Plaintiffs Have Not Demonstrated Unexpected Results .............................. 14 a. The Occurrence of Selective Arterial Vasodilation at the Claimed Dosages Was Not Unexpected.......................................... 14

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b. c. 2. 3.

The Lack of AV Block Was Not Unexpected ................................. 15 The Lack of Uric Acid Build-Up Was Not Unexpected .................. 16

Plaintiffs Have Failed to Provide Evidence of Skepticism .......................... 17 Plaintiffs Have Failed to Show that the Alleged Commercial Success of Adenoscan® Has Any Nexus to the Asserted Claims .................................. 18 a. The Sales Levels of Adenoscan® Are Explained By the Interplay of Economic Factors, Not the Product's Clinical Attributes ............ 19 (i) (ii) Adenoscan® Entered the Pharmacological Stress Market at a Fortuitous Time............................................................ 19 Fujisawa's Extensive Marketing and Promotion Drove Adenoscan®`s Market Share Growth Pharmacological Stressor............................................................................... 20 Adenoscan®'s Increasing Sales Were Also Due to the General Growth of the Pharmacological Stress Market ....... 22

(iii) b. C. D.

Dr. Hay's Analysis is Unsound and His Testimony Is Unreliable.... 23

The Asserted Claims of the `296 Patent are Inherently Anticipated................. 24 Expert Testimony Issues ..................................................................................... 25 1. Dr. Binkley is Highly Qualified to Serve as an Expert in this Case............. 25 a. b. 2. 3. Dr. Binkley's Opinions Were Well Within the Scope of His Expert Report ................................................................................. 26 Dr. Binkley Was Forced to Rebut Issues Raised by Plaintiffs for the First Time at Trial..................................................................... 28

Dr. Leffler is Highly Qualified to Serve as an Expert in this Case .............. 28 The Expert Testimony Offered By Plaintiffs is Not Credible...................... 31 a. b. Dr. Klabunde is a Physiologist Who Has Never Administered Any Vasodilator, Including Adenosine, To a Patient....................... 31 Plaintiffs' Last-Minute Decision Not to Call Their Only Expert Physician Witness Was Designed to Deprive Sicor of Favorable Admissions..................................................................................... 32

II.

PROPOSED RESPONSIVE CONCLUSIONS OF LAW ............................................. 33 A. Claims 1, 3, 7, and 9 of the `296 Patent Are Invalid As Obvious ....................... 33 1. The Rigid "Teaching Suggestion Motivation" Test Relied Upon By Plaintiffs is Not the Proper Legal Standard for an Obviousness Analysis.... 33 ii

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2.

Sicor Has Shown Obviousness By Clear and Convincing Evidence............ 34 a. b. c. d. The Sollevi Abstracts Render the Asserted Claims Obvious ........... 34 The Fukunaga 1982 Abstract Renders the Asserted Claims Obvious.......................................................................................... 35 The Dose Required to Produce a Desired Effect Could Have Been Determined Through Routine Experimentation...................... 36 The Prior Art Uses of Adenosine and Other Vasodilators Would Not Have Taught Away from the Claimed Invention........... 37

3.

The Secondary Considerations Argued by Plaintiff Do Not Rebut Sicor's Strong Prima Facie Case of Obviousness ....................................... 39 a. Plaintiffs Have Not Demonstrated Unexpected Results................... 40 (1) (2) (3) b. c. d. The Occurrence of Selective Arterial Vasodilation at the Claimed Dosages was Not Unexpected ............................... 41 The Lack of AV Block Was Not Unexpected...................... 42 The Lack of Uric Acid Build-Up Was Not Unexpected....... 42

Plaintiffs Have Failed to Provide Credible Evidence of Skepticism or Surprise.................................................................... 42 Copying, Even If Shown, Is Irrelevant in the ANDA Context ......... 44 Any Commercial Success Enjoyed By Adenoscan® Does Not Rebut Sicor's Case of Obviousness ................................................ 45 (i) The Sales Levels of Adenoscan® Are Explained By the Interplay of Economic Factors, Not the Product's Clinical Attributes............................................................................ 45 (1) Adenoscan® Entered the Pharmacological Stressor Market at a Fortuitous Time ............................................ 46 (2) Fujisawa's Extensive Marketing and Promotion Drove Adenoscan®'s Market Share Growth.............................. 46 (3) Adenoscan®'s Increasing Sales Were Also Due to the General Growth of the Pharmacological Stress Market.... 47 (ii) Dr. Hay's Analysis Is Unsound and His Testimony Is Unreliable ........................................................................... 49

B.

Claims 1, 3, 7, and 9 of the `296 Patent Are Invalid As Inherently Anticipated........................................................................................................... 49 1. The Asserted Claims are Inherently Anticipated by the Fukunaga Abstract ..................................................................................................... 49 iii

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C.

Expert Testimony Issues ..................................................................................... 50 1. Dr. Binkley is Highly Qualified to Serve as an Expert in This Case............ 50 a. b. 2. 3. Dr. Binkley's Opinions Were Well Within the Scope of His Expert Report ................................................................................. 51 Dr. Binkley Was Improperly Forced to Rebut Issues Raised by Plaintiffs for the First Time at Trial ................................................ 51

Dr. Leffler is Highly Qualified to Serve as an Expert in This Case ............. 52 The Expert Testimony Offered by Plaintiffs is Not Credible ...................... 53

III.

CONCLUSION................................................................................................................. 55

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TABLE OF AUTHORITIES CASES Page ABB Air Preheater Inc. v. Regenerative Envtl. Equip., 167 F.R.D. 668 (D.N.J. 1996) ............................................................................................. 52 Abbott Labs. v. Baxter Pharmaceutical Prods., Inc., 471 F.3d 1363 (Fed. Cir. 2006) ........................................................................................... 49 Alpex Computer Corp. v. Nintendo Co., No. 86-1749, 1994 WL 681752 (S.D.N.Y. Dec. 5, 1994) .................................................... 43 Amazon.com, Inc. v. Barnesandnoble.com, Inc. et al., 239 F.3d 1343 (Fed. Cir. 2001) ........................................................................................... 50 Aventis Pharms. Deutschland GmbH v. Lupin Ltd., 2006 WL 1008962 (E.D. Va. July 17, 2006) ....................................................................... 44 Cable Elec. Prods., Inc. v. Genmark, Inc., 770 F.2d 1015 (Fed. Cir. 1985) ........................................................................................... 44 Crowley v. Chait, 322 F. Supp. 2d 530 (D.N.J. 2004)................................................................................. 51-52 Eli Lilly & Co. v. Barr Labs, Inc., 251 F.3d 955 (Fed. Cir. 2001)............................................................................................. 49 Endress + Hauser, Inc. v. Hawk Measurement Sys. Pty. Ltd., 122 F.3d 1040 (Fed. Cir. 1997) ........................................................................................... 50 eSpeed, Inc. et al. v. Brokertec USA, LLC, 404 F. Supp. 2d 575 (D. Del. 2005) .................................................................................... 50 Friction Div. Prods., Inc. v. E. I. Du Pont de Nemours & Co., Inc., 693 F. Supp. 114 (D. Del. 1988) .................................................................................... 47-48 In re Fla. Microsoft Antitrust Litig., 2002 WL 31423620 (Fla. Cir. Ct. 2002).........................................................................29, 53 In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004) ...................................................................................... 37-38 In re GPAC Inc., 57 F.3d 1573 (Fed. Cir. 1995)............................................................................................. 44

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KSR Int'l Co. v. Teleflex, Inc., 127 S. Ct. 1727 (2007)........................................................................................33-34, 36, 38 J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563 (Fed. Cir. 1997) ........................................................................................... 45 In re Kahn, 441 F.3d 977 (Fed. Cir. 2006)............................................................................................. 37 In re Koller, 613 F.2d 819 (C.C.P.A. 1980)............................................................................................. 38 Leapfrog Enters., Inc. v. Fisher-Price, Inc., 485 F.3d 1157 (Fed. Cir. 2007) ......................................................................................33, 40 McCarty v. Lehigh Val. R.R., 160 U.S. 110 (1895)............................................................................................................ 41 McNeil-PPC, Inc. v. L. Perrigo Co., 337 F.3d 1362 (Fed Cir. 2003) ............................................................................................ 47 Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) ........................................................................................... 37 Merck & Co., Inc. v. Teva Pharms USA, Inc., 405 F.3d 1338 (Fed Cir. 2005) ............................................................................................ 48 Midwest Indus. v. Karavan Trailers, Inc., 175 F.3d 1356 (Fed. Cir. 1999) ........................................................................................... 44 Optivus Tech., Inc. v. Ion Beam Apps. S.A., 469 F.3d 978 (Fed. Cir. 2006)............................................................................................. 37 Ormco Corp. v. Align Tech., 463 F.3d 1299 (Fed. Cir. 2006) ........................................................................................... 35 Pacifica Technica Corp. v. U.S., 2 Cl. Ct. 170 (1983) ............................................................................................................ 46 Pfizer, Inc. v. Apotex, Inc. 480 F.3d 1348 (Fed. Cir. 2007) ................................................................................ 33, 39-40 Pfizer Inc. v. Teva Pharms. USA, Inc., 461 F. Supp. 2d 271 (D.N.J. 2006)...........................................................................29, 45, 53 Renishaw PLC v. Marposs Societa' Per Azioni, 158 F.3d 1243 (Fed. Cir. 1998) ...................................................................................... 40-41

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Revlon, Inc. v. Carson Prods. Co., 602 F. Supp. 1071 (S.D.N.Y. 1985) .................................................................................... 47 Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476 (Fed. Cir. 1997) ........................................................................................... 39 In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ........................................................................................... 39 Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373 (Fed. Cir. 2003) ........................................................................................... 49 Sentex Sys., Inc. v. Elite Access Sys., Inc., 194 F.3d 1331 (Fed. Cir. 1999) ........................................................................................... 45 In re Soni, 54 F.3d 746 (Fed. Cir. 1995)............................................................................................... 40 Speller v. U.S., 14 Cl. Ct. 170 (1988) .......................................................................................................... 46 Syntex LLC v. Apotex, Inc., 407 F.3d 1371 (Fed. Cir. 2005) ........................................................................................... 38 Tec Air, Inc. v. Denso Mfg. Mich., Inc., 192 F.3d 1353 (Fed. Cir. 1999) ........................................................................................... 33 U.S. v. Adams, 383 U.S. 39 (1966) ........................................................................................................ 42-44 Vandenberg v. Dairy Equip. Co., 740 F.2d 1560 (Fed. Cir. 1984) ........................................................................................... 48 Wash. Legal Found. v. Legal Found. of Wash., 271 F.3d 835 (9th Cir. 2001).................................................................................... 29, 52-53

STATUTES 35 U.S.C. § 282 ........................................................................................................................ 51

OTHER AUTHORITIES Rule 26(a)(3), Fed. R. Civ. P. ................................................................................................... 52

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Defendants Sicor Inc. and Sicor Pharmaceuticals, Inc. (collectively "Sicor") submit the following Responsive Proposed Findings of Fact and Conclusions of Law in response to Plaintiffs' Post-Trial Proposed Findings of Fact And Conclusions of Law Concerning U.S. Patent No. 5,731,296 ("Plaintiffs' Proposed Findings"). These Responsive Proposed Findings of Fact and Conclusions of Law Supplement Sicor's Proposed Findings of Fact ("D.I. 149 FOF") and Conclusions of Law ("D.I. 149 COL") (collectively "Sicor's Proposed Findings"), dated May 9, 2007. To the extent that any of the findings of fact set forth below or in Sicor's Proposed Findings is a conclusion of law, Sicor requests that it be adopted as such. To the extent that any of the proposed conclusions of law set forth below or in Sicor's Proposed Findings is a finding of fact, Sicor requests that it be adopted as such. I. PROPOSED RESPONSIVE FINDINGS OF FACT A. The Asserted Claims of the `296 Patent are Invalid As Obvious 1. 1. The Asserted Claims of the `296 Patent

At trial, Plaintiffs asserted four claims of the `296 patent: claims 1, 3, 7, and 9.

(D.I. 127, Ex. 10; D.I. 149 FOF at ¶¶ 21-26.) 2. None of the asserted claims recites a specific medical use for the claimed

invention. (See TX 275.) 3. None of the asserted claims recites a specific degree of selective arterial

vasodilation. (See TX 275.) 4. 5. None of the asserted claims recites an optimal level of vasodilation. (See id.) None of the asserted claims recites a functional requirement that atrioventricular

block or increases in uric acid levels do not occur. (See id.)

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6.

The asserted claims of the `296 patent claim "selectively vasodilating the arteries

of a human patient without inducing significant venous dilation." (TX 275.) 7. The asserted claims of the `296 patent do not claim a "safe and effective dose [of

adenosine] that would induce hypotension in the absence of [dipyridamole] pretreatment." (Compare, e.g., D.I. 151 at 9 with TX 275.) 2. 8. The Sollevi Abstracts Render the Asserted Claims of the `296 Patent Obvious

The Sollevi abstracts (TX 37, "Sollevi I" and TX 1170, "Sollevi II") 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. 149 FOF at ¶¶ 96-123.) 9. There is no dispute that the Sollevi abstracts disclose nearly all elements of the

asserted claims. (Zaret, Tr. 1941:18-1942:6.) 10. 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. (D.I. 149 FOF at ¶¶ 96-123.)

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a.

The Sollevi Abstracts Demonstrated That 140 µg/kg/min of Adenosine Could Be Administered Safely To Humans By Continuous Intravenous Administration Without Dipyridamole Pretreatment

11.

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). 12. The Sollevi abstracts each conclude by recommending the use of intravenous

adenosine for controlled hypotension and do not expressly state the need for pretreatment with dipyridamole. (D.I. 149 FOF at ¶¶ 110-12, 122-23.) The last sentence of Sollevi I states that the "hemodynamic and metabolic properties of adenosine make it a suitable agent for CH in man." (TX 1170 at A9 (emphasis added).) The last sentence of Sollevi I states that the "adenosine may be used to achieve controlled hypotension in man since it acts as a rather pure arteriolar vasodilator with rapid onset, sustained action and rapid elimination." (TX 37 at 11A:C16 (emphasis added).) There is no mention in either Sollevi I or Sollevi II that dipyridamole must be used. (See TX 37 and TX 1170.) 13. If Dr. Sollevi believed that dangerous side effects could occur if adenosine were

administered without dipyridamole, a person of ordinary skill would have expected him to stress the importance of the dipyridamole pretreatment in the Sollevi abstracts. (See TX 37 and TX 1170.) 14. Dr. Sollevi did not mention that he had serious concerns about adenosine's safety

when he disclosed his own experiments using adenosine without dipyridamole pretreatment. (TX 112 at fn.). 15. No serious side effects were reported in Fukunaga 1982, a study that Dr. Sollevi

cited in his contemporaneous publications. (See TX 37 and TX 1170.)

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16.

The reasons that Dr. Sollevi now asserts for his use of the dipyridamole

pretreatment in the Sollevi abstracts were not expressed contemporaneously by him in the public domain and would not have influenced the thinking of persons of ordinary skill at the time. (Binkley, Tr. 201:21-203:3, 224:6-226:7.) 17. Dr. Sollevi purportedly conducted the first human trial concerning the intravenous

administration of adenosine (with and without dipyridamole) on surgical patients suffering from cerebral aneurysms (e.g., "a `bulb' or bubble on a blood vessel in the brain that could rupture, causing bleeding and death"). (D.I. 151 at 8.) 18. Dr. Sollevi's decision to forego the accepted protocol within the medical

community to first conduct clinical trials in healthy volunteers, and instead conduct these trials on seriously ill patients, suggests that his contemporaneous concerns regarding the danger of adenosine were less serious than he now asserts. (D.I. 149 FOF at ¶¶ 154-70.) 19. Dr. Sollevi has an acknowledged financial interest in the outcome of this

litigation. (Sollevi, Tr. 473:19-474:8, 475:2-9.) 20. Dr. Sollevi's testimony is not relevant to the Court's obviousness analysis because

as the named inventor Dr. Sollevi claims to be an innovator and thus not a person of ordinary skill in the art in 1985. (Sollevi, Tr. 475:10-24.) 3. 21. The Fukunaga 1982 Abstract Renders the Asserted Claims of the `296 Patent Obvious

The Fukunaga 1982 Abstract (TX 42) discloses the intravenous administration of

adenosine triphosphate ("ATP") at a dose of 200 to 600 µg/kg/min without dipyridamole pretreatment to induce controlled hypotension in anesthetized human patients undergoing surgery. (Binkley, Tr. 162:6-13; TX 42 at A65; D.I. 150 at 19; D.I. 149 FOF at ¶¶ 124-28.) The

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dosage range overlaps each of the ranges recited in the asserted claims of the `296 patent. (Binkley, Tr. 171:6-15; TX 275; D.I. 149 FOF at ¶ 129.) 22. The teachings of the Fukunaga 1982 Abstract would lead a person of ordinary

skill in the art in 1985 to conclude that selective arterial dilation without significant venous dilation had occurred. (D.I. 149 FOF at ¶¶ 130-33.) 23. The substitution of adenosine for ATP was not inventive ­ it was based on the

disclosure in the Fukunaga 1982 Abstract coupled with the knowledge of a person of ordinary skill in the art. (D.I. 149 FOF at ¶¶ 124-38.) a. The Study Reported in the Fukunaga 1982 Abstract, Coupled with the Knowledge of a Person of Ordinary Skill at the Relevant Time, Would Have Led to the Use of Adenosine Infusion Without Dipyridamole Pretreatment

24.

Plaintiffs primarily rely on the testimony of Dr. Klabunde, who focused almost

exclusively on references from the 1970s (TX 151; TX 199) in an attempt to prove that the selective arterial vasodilation reported in the Fukunaga 1982 Abstract was not due to the actions of adenosine. By the critical date, these references were nearly two decades old and had been superseded by more recent publications (see, e.g., TX 36; TX 51; TX 88; TX 236; TX 228; TX 5000) by the `296 patent priority date. 25. Persons of ordinary skill would have understood that the controlled hypotension

reported in the Fukunaga 1982 Abstract following the intravenous administration of ATP was the result of the action of adenosine. (See D.I. 149 FOF at ¶¶ 71-83, 134.) 26. The evidence at the relevant time showed that the vasodilative effects of ATP

were due to its rapid and complete conversion to adenosine. (Id.) 27. 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

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administration. (See, e.g., TX 236 at 547; TX 51 at A39; TX 228 at 807-08; TX 5000 at 1196; D.I. 149 FOF at ¶¶ 71-83). 28. For example, contemporaneous publications co-authored by Dr. Sollevi expressly

stated that ATP that is intravenously administered is degraded "entirely to adenosine" during the transpulmonary passage. (See, e.g., TX 236 at 547.) 29. A 1984 publication, also co-authored by Dr. Sollevi, 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; D.I. 149 FOF at ¶¶ 80-81.) 30. Dr. Sollevi expressly discussed the Fukunaga 1982 Abstract in another 1984

publication that discussed the same results set forth in the Sollevi abstracts. (TX 112.) 31. In TX 112, 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. (TX 112 at 403.) Dr. Sollevi then cited another 1982 reference in support of the statement that "high levels of phosphate could cause arrhythmia" and concluded that "we consider it more appropriate to use adenosine in preference to ATP to induce hypotension." (TX 112 at 403.) 32. Dr. Sollevi's contemporaneous statements (see paragraphs 28-31 above)

contradict Plaintiffs' assertions that skilled artisans would not have understood that in Fukunaga 1982 adenosine converted from ATP was the direct cause of controlled hypotension. (i) 33. Fukunaga 1984 (TX 51)

The results in Fukunaga 1984 (TX 51) also demonstrated that adenosine (not

ATP) was the direct-acting agent in Fukunaga 1982. (D.I. 149 FOF at ¶ 134.) 34. The pretreatment with dipyridamole in Fukunaga 1984 reduced the amount of

ATP that was required to induce controlled hypotension. (TX 51; D.I. 149 FOF at ¶¶ 136-38.) 6

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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. (Binkley, Tr. 178:14-15, 179:13-181:22; D.I. 149 FOF at ¶¶ 136-38.) 35. Fukunaga 1984 would confirm to a person of ordinary skill that adenosine ­ not

ATP ­ was responsible for the vasodilation. (D.I. 149 FOF at ¶ 137.) Rather than discourage a skilled artisan from using adenosine without dipyridamole, 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. 149 FOF at ¶ 136.) (ii) 36. Moir and Downs (TX 199)

A study authored by Moir and Downs published in the early 1970s would not

have led a person of ordinary skill to believe that ATP was a more potent vasodilator than adenosine. ("Moir and Downs," TX 199.) 37. Dr. Klabunde admitted that by the relevant time, a person of ordinary skill would

have looked to more recent publications than Moir and Downs to understand the relationship between ATP and adenosine in vasodilation. (Klabunde, Tr. at 1118:8-12.) 38. Later publications (see, e.g., TX 36; TX 51; TX 88; TX 236; TX 228; TX 5000)

would have led the skilled artisan to understand that adenosine, not ATP, was the direct-acting agent in Fukunaga 1982. (See D.I. 149 FOF at ¶¶ 71-83.) 39. The data in Moir and Downs do not support Plaintiffs' position that a person of

ordinary skill at the relevant time would have viewed ATP as more potent than adenosine. (TX 199.) "There was really 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. (Binkley, Tr. 1422:18-1425:25.) In addition, p-values were not calculated, so a proper statistical analysis of the data was not available to a person of ordinary skill. (Binkley, Tr. 1450:7-24.) 7

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40.

There is a key difference in the manner of ATP administration in TX 199 and the

manner of ATP administration in the Fukunaga 1982 Abstract. (Binkley, 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. (Binkley, Tr. 1426:19-24; TX 199.) In the Fukunaga 1982 Abstract, ATP was administered intravenously, and thus necessarily flowed through the transpulmonary passage. (TX 42.) 41. 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.) Such a person also would have understood that the ATP administered in TX 199 (which reflected intra-arterial administration) bypassed the transpulmonary passage. (Binkley, Tr. 1426:19-1427:15.) 42. 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 administered intravenously, because the conversion of adenosine to ATP in the transpulmonary passage could not occur. (Binkley, Tr. 1427:4-10.) (iii) 43. Burnstock (TX 151, TX 152)

Skilled artisans would understand that adenosine was the direct-acting agent in

the Fukunaga 1982 Abstract based on a publication by Dr. Burnstock concerning the different cellular receptors for adenosine and ATP. (TX 151; D.I. 149 FOF at ¶¶ 82-83.) 44. 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; Klabunde, Tr. 1172:6-18.) 8

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45.

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. (Klabunde, Tr. 1174:25-1177:2; TX 152 at 195.) 46. 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 the administration of ATP was due to its conversion to adenosine. (Klabunde, Tr. 1437:11-1438:2; D.I. 149 FOF at ¶¶ 71-83.) 47. The rapid conversion of ATP to adenosine would have suggested to a person of

ordinary skill at the relevant time that little (if any) ATP would remain to bind to any ATP receptors that were present in the arterial vasculature. (Klabunde, Tr. 1107:3-12; TX 5000 at 1196; TX 51 at A39.) 4. 48. The Dose Required to Produce a Desired Effect Could Have Been Determined Through Routine Experimentation

Plaintiffs rely primarily on in vitro studies or studies in animals in support of their

contention 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.) None 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.) 49. Selective arterial vasodilation is not an all or nothing phenomenon. (Binkley, Tr.

137:20-138:9.) Different degrees of vasodilation may occur depending upon the dose of vasodilator that is administered. (D.I. 149 FOF at ¶ 141.) 50. 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. (See TX 275.)

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51.

Based on these human clinical studies, 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. (D.I. 149 FOF at ¶¶ 150-51.) 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. (Klabunde, Tr. 1132:21-1133:1; see also TX 36 at 1261.) 52. Persons of ordinary skill at the relevant time would also be interested in medical

uses of adenosine calling for less than maximal selective arterial vasodilatation. (Binkley, Tr. 1370:15-1372:10, 1372:25-1374:3; D.I. 149 FOF at ¶¶ 139-46.) 53. 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. 149 FOF at ¶¶ 147-52.) 54. 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 for easy dose titration." (TX 45 at 423.) 55. Plaintiffs cite an abstract by 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.) 56. However, none of the asserted claims set forth any specific medical use for

adenosine. (See TX 275.) The claims recite only a method of causing selective arterial vasodilation. (See id.) 57. Hypotension is the result of near-maximal vasodilation. (Klabunde, Tr. at

1059:15-1060:4). A person of ordinary skill at the relevant time would have known that lower

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levels of vasodilation would have been necessary for other medical uses, like myocardial perfusion imaging. (D.I. 149 FOF at ¶ 142.) 58. The Biaggioni abstract (TX 1187) 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. (D.I. 149 FOF at ¶ 146.) 59. The pattern of side effects observed in Biaggioni (e.g., flushing) confirmed that

adenosine doses in the claimed range had a systemic effect. (See TX 1187.) 5. 60. The Prior Art Uses of Adenosine and Other Vasodilators Would Not Have Taught Away from the Claimed Invention

Plaintiffs allege that problems that were historically associated with adenosine

would have taught away from its intravenous administration at the relevant time. (D.I. 151 at 5-7.) However, the Sollevi abstracts each disclosed the safe and effective use of intravenous adenosine in humans with dipyridamole. Fukunaga 1982 and Biaggioni (TX 1187) effectively demonstrated the same without dipyridamole pretreatment. (D.I. 149 FOF at ¶¶ 96-138, 144-52.) a. The Use of Other Vasodilators During the Relevant Time Period Would Have Encouraged Persons of Ordinary Skill to Look to Adenosine

61.

The use of other known vasodilators, dipyridamole and ATP, would not have

taught away from adenosine administration. Instead, the prior art use of dipyridamole and ATP, in view of the knowledge of a person of ordinary skill in the art concerning 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. (D.I. 149 FOF at ¶¶ 71-95, 147-52.) 62. 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. 149 FOF at ¶¶ 84-95.)

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63.

Persons of ordinary skill would have further understood that the use of

dipyridamole had several drawbacks, including a slower onset and a longer duration, as compared to adenosine. (D.I. 149 FOF at ¶¶ 84-95; Binkley, Tr. 133:21-134:9; Klabunde, Tr. 1096:11-25.) Based on these drawbacks, a person of ordinary skill would have been motivated to administer adenosine alone to effect vasodilation. (D.I. 149 FOF at ¶¶ 147-52.) 64. 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. (D.I. 149 FOF at ¶¶ 80-83.) 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. (D.I. 149 FOF at ¶¶ 71-83.) 65. Dr. Sollevi's own work makes clear that 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. (TX 112 at 403.) 66. At the relevant time, pharmaceutical adenosine was not readily available for

intravenous administration, and a person of ordinary skill would have been forced to use dipyridamole and ATP as indirect-acting surrogates for what such a person would have understood to be the direct actions of adenosine. (Binkley, Tr. 331:22-332:2; D.I. 149 FOF ¶¶ 78, 87.) b. 67. Research Concerning Adenosine for Various Medical Uses Exploded Following a 1980 Publication by Dr. Berne

In December 1980, Dr. Robert Berne published an article in Circulation Research

entitled "The Role of Adenosine in the Regulation of Coronary Blood Flow" (TX 228; D.I. 149 FOF at ¶¶ 69-70.)

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68.

Dr. Berne described adenosine as one of the "principle contenders that can serve

as a mediator of coronary blood flow (CBF) regulation." (TX 228 at 807; emphasis added.) 69. Soon after the publication of TX 228, the field of adenosine research exploded, as

scientists and physicians searched for new uses for this "principle contender" in the field of vasodilation. (D.I. 149 FOF at ¶ 70.) 70. 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 controlled hypotension. (D.I. 149 FOF at ¶¶ 70, 142.) 71. Plaintiffs assert that Dr. Berne disclosed the "first human medical use" of

adenosine in December 1983. (TX 36.) But by September 1983, Sollevi I had already disclosed the intravenous administration of adenosine to surgical patients, and shown that a dose of 140 µg/kg/min of intravenous adenosine was safe. (TX 1170.) Plaintiffs are therefore incorrect. 72. Moreover, Dr. Berne's December 1983 publication (TX 36) would not have

discouraged a person of ordinary skill from using intravenous adenosine administration. By December 1983, Dr. Sollevi had administered adenosine intravenously, Dr. Fukunaga had used its equivalent, and Biaggioni's work with adenosine was likely already underway. (TX 1170; TX 42; TX 1187.) 73. The Sollevi abstracts would also have given rise to additional interest in the

intravenous infusion of adenosine. (D.I. 149 FOF at ¶¶ 110-12, 122-23.) As Dr. Klabunde testified, 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. (Klabunde, Tr. 1079:21 1080:2.) If in vitro experiments could stimulate this level of interest, then the in vivo

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clinical testing in humans at the relevant time (as disclosed in the Sollevi abstracts), would also increase interest in this area of research. (Id.) 74. Even before the Sollevi abstracts were published, the use of adenosine to induce

controlled hypotension in humans was an area of interest to persons of ordinary skill in the art. (D.I. 149 FOF at ¶ 152.) For example, other scientists suggested at the relevant time 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 Klabunde, Tr. 1197:13-1198:5.) B. Secondary Considerations Do Not Support the Non-Obviousness of the Asserted Claims 1. 75. Plaintiffs Have Not Demonstrated Unexpected Results

There is no requirement in the asserted claims of the `296 patent 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 TX 275.) a. 76. The Occurrence of Selective Arterial Vasodilation at the Claimed Dosages Was Not Unexpected

Plaintiffs' contention 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) is limited to the consideration of controlled hypotension for surgery, whereas the claims are not so limited. (TX 275.) 77. The asserted claims do not claim "a safe and effective dose [of adenosine] that

would induce hypotension in the absence of [dipyridamole] pretreatment." (Compare D.I. 151 at 9 with TX 275.) The only "purpose" actually claimed in asserted claims of the `296 patent is

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"selectively vasodilating the arteries of a human patient without inducing significant venous dilation." (TX 275.) 78. The evidence shows 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. (Binkley, Tr. 355:16-356:8; TX 37; TX 42; TX 1170.) 79. Fukunaga 1982 (TX 42), viewed in the light of Fukunaga 1984 (TX 51),

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. (D.I. 149 FOF at ¶¶ 124-38.) 80. Plaintiffs' reliance on Dr. Sollevi's testimony in support of their "unexpected

results" argument (D.I. 151 8-10, 34-35) is misplaced. Dr. Sollevi is not a person of ordinary skill in the art (the proper standard for an invalidity analysis) (Sollevi, Tr. 475:10-24) and he has a strong financial interest in the outcome of this litigation (Sollevi, Tr. 473:19-474:8, 475:2-9). b. 81. The Lack of AV Block Was Not Unexpected

A person of ordinary skill at the relevant time would understand that continuous

intravenous infusion of adenosine at a rate of 140 ·g/kg/min was not likely to cause AV block, particularly if the same dose of adenosine was administered in the absence of dipyridamole. (D.I. 149 FOF at ¶¶ 156-164.) 82. A person of ordinary skill would see that the Sollevi abstracts did not report any

AV block. (D.I. 149 FOF at ¶¶ 160, 162-63.) The Sollevi abstracts would have taught a person of ordinary skill in the art that the intravenous adenosine administration of adenosine in the claimed range would not cause AV block, as Dr. Sollevi "carefully monitor[ed] the

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electrocardiograms" when he administered adenosine with dipyridamole, and did not observe any evidence of AV block. (Sollevi, Tr. 479:5-23; D.I. 149 FOF at ¶¶ 160, 162-63.) 83. A 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. 149 FOF at ¶ 155.) 84. Dr. Sollevi's contemporaneous publications concerning the intravenous

administration of adenosine without dipyridamole do not raise the possibility of AV block as a concern. (See, e.g., TX 37, 1170; D.I. 149 FOF at ¶¶ 162-63, 170.) If Dr. Sollevi were so concerned about this issue, he would have addressed it in his publications at the time, but he did not. (See, e.g., TX 112.) 85. In addition, Dr. Sollevi's testimony that he was surprised by the results is not

credible because he relegated his report of his allegedly "unthinkable" experiment (eliminating dipyridamole pretreatment when administering adenosine to induce controlled hypotension) to a footnote to TX 112, which failed to mention any of the surprise at the results that he now asserts. (TX 112 at fn.). 86. Dr. Sollevi's testimony concerning his belief at the time of the alleged dangers of

adenosine and his surprise at the results is also not credible because there is no reason to believe that the Karolinska Institute Hospital would permit such risk-taking by Dr. Sollevi with surgical patients. c. 87. The Lack of Uric Acid Build-Up Was Not Unexpected

A person of ordinary skill would understand that the side effects that might be

associated with adenosine, including a transient increase in uric acid levels, would be much less

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likely to occur if dipyridamole were not administered with adenosine. (D.I. 149 FOF at ¶ 155, 165-170.) 88. The Sollevi abstracts do not report any uric acid build-up. The Sollevi abstracts

would have relieved any concerns that a person of ordinary skill in the would have had concerning the risk of uric acid build-up from intravenous adenosine administration because Dr. Sollevi "carefully . . . test[ed] the metabolite levels" when he administered adenosine with dipyridamole, but did not observe any evidence of prohibitive increases in uric acid levels. (Sollevi, Tr. 482:11-16; D.I. 149 FOF at ¶¶ 170.) 89. Dr. Sollevi's contemporaneous publications concerning the intravenous

administration of adenosine without dipyridamole do not state the risk of uric acid build-up as a concern. (See, e.g., TX 37; TX 1170; D.I. 149 FOF at ¶¶ 162-63, 170.) If Dr. Sollevi were so concerned about this issue, he would have addressed it in his publications at the time, but he did not. (See, e.g., TX 112.) 2. 90. Plaintiffs Have Failed to Provide Evidence of Skepticism

As "evidence" of skepticism in the field, Plaintiffs rely entirely on personal

correspondence between Dr. Sollevi and Dr. Berne (Klabunde, Tr. 1201:7-10, 13-16; Zaret, Tr. 1974:12-14, 18-19), and other correspondence between and among Dr. Sollevi, a journal editor, and Dr. Francis Robicsek (Klabunde, Tr. 1201:11-16; Binkley, Tr. 363:14-364:4). 91. The correspondence relied upon by Plaintiffs is not probative, let alone

persuasive, evidence that experts were skeptical that adenosine could be administered without causing AV block or uric acid build-up. (D.I. 149 FOF at ¶¶ 174-75.) 92. The correspondence was private and therefore not publicly available to persons of

ordinary skill in the art, not subject to public scrutiny or comment, and could not have influenced

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(much less discouraged) persons of ordinary skill in the art at the relevant time. (Klabunde, Tr. 1201:7-10, 13-16; Binkley, Tr. 363:14-364:4.) 93. The editor of the journal that published the study at the heart of the

correspondence between Dr. Sollevi and Dr. Robicsek concluded that this correspondence did not merit publication, corroborating the view that this correspondence does not raise genuine scientific issues. (TX 412.) 94. Dr. Sollevi'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. 149 FOF at ¶¶ 153-73.) 95. Dr. Sollevi's secondhand testimony that another scientist in the field considered

him "a crazy Swede" is not evidence of skepticism that supports a finding of non-obviousness. (Sollevi, Tr. 453:13-454:1.) 3. 96. Plaintiffs Have Failed to Show that the Alleged Commercial Success of Adenoscan® Has Any Nexus to the Asserted Claims

Plaintiffs have failed to demonstrate the requisite nexus between the claimed

invention of the `296 patent and the alleged commercial success of the Adenoscan® product. (See, generally, D.I. 149 FOF at ¶¶ 184-242.) 97. None of Plaintiffs' experts testified at trial that the requisite nexus existed.

Plaintiffs' economic expert, Dr. Hay, devoted just one conclusory sentence of his expert report to the issue, stating in the penultimate paragraph that the sales of Adenoscan® are connected to the attributes of the product. (Hay, Tr. 1790:11-1792:15, 1793:7-14.) Dr. Hay otherwise ignored the issue in favor of describing the sales performance of Adenoscan®. (Id.)

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a.

The Sales Levels of Adenoscan® Are Explained By the Interplay of Economic Factors, Not the Product's Clinical Attributes

98.

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

economic factors: (1) There was only one other FDA-approved competitor in the pharmacological stress-testing market at the time of Adenoscan® entry; Adenoscan® became the only promoted product in the pharmacological stress testing market shortly after its entry; Extensive marketing and promotion of Adenoscan® by Fujisawa; and Growth in demand for pharmacological stress testing unrelated to the asserted inventions.

(2)

(3)

(4)

(See D.I. 149 FOF at ¶¶ 184-242.) 99. The sales levels achieved by Adenoscan® are not explained not by any asserted

innovation in the `296 patent. (See D.I. 149 FOF at ¶¶ 224-25.) Adenoscan® was marketed not on the basis of its ability to selectively dilate arteries rather than veins without pretreatment with dipyridamole (i.e., the claimed `296 patent invention), but on the basis of its short half life and the concomitant rapid cessation of side effects. (See id.) (i) 100. Adenoscan® Entered the Pharmacological Stress Market at a Fortuitous Time

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

Adenoscan. (See, e.g., TX 1226 at AST0065726-727.) In that time, the company developed countless strategic relationships with physician advocates and sponsored the activities of the American Society of Nuclear Cardiology ("ASNC"). (Leffler, Tr. 1611:10-15, 1612:9-1613:4;

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White, Tr. 1252:17-25, 1339:4-15; TX 1078 at AST006674.) Fujisawa was hardly the "new kid on the block." (See generally D.I. 149 FOF at ¶¶ 197-225.) 101. Fujisawa launched Adenoscan® in the pharmacological stressor market at a

propitious time. (D.I. 149 FOF at ¶¶ 185-196.) Because the manufacturer of Persantine®, the only other directly-competing product, ceased promotion spending after Persantine® went generic in late 1996, Adenoscan® had the good fortune, not long after its launch, to become the only product being advertised to the prescribers of pharmacological stress tests. (See id.) 102. Furthermore, the audience for the Adenoscan® marketing message was relatively

price insensitive. The prescribing physicians do not themselves pay for the product and expect that their patients will be covered by federal or private health insurance. (Leffler, Tr. 1694:18-1695:9.) (ii) Fujisawa's Extensive Marketing and Promotion Drove Adenoscan®`s Market Share Growth Pharmacological Stressor

103.

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

the industry. (See D.I. 149 FOF at ¶¶ 197-225.) Fujisawa's spending was devoted to extensive traditional and non-traditional marketing activities, including substantial detailing efforts; support of the American Society of Nuclear Cardiology ("ASNC"); support of physician advocates; provision of financial incentives such as trial product and pumps to prospective customers; sole sponsorship of industry "educational initiatives"; and promotion of Adenoscan® for new uses and user populations. (See id.) 104. On cross-examination, Dr. Hay admitted that the 6% industry-standard average

promotion-to-sales ratio that he relied on for his testimony that Fujisawa's spending was

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"typical" was essentially a concocted number and inappropriately applied to the pharmacological stress market. (Hay, Tr. 1760:19-24, 1761:3-9, 1763:15-18, 1764:1-1765:6.) 105. Dr. Hay's 6% was not based on reliable data; without any basis in fact, Dr. Hay

"calculated" this 6% ratio as the "midpoint" between two other numbers that are based on reliable data: the 12% industry average for drugs sold primarily in retail pharmacies and the 3.1% industry average for drugs sold primarily in hospitals. (Hay, Tr. 1761:12-1762:6.) 106. Dr. Hay admitted that the appropriate average promotion-to-sales ratio for

Adenoscan® is 3.1% because pharmacological stress products are sold primarily in hospitals and clinics, and not in retail pharmacies. (Hay, Tr. 1760:19-24; Tr. 1761:3-9, 1763:15-18, 1764:11765:6.) 107. Dr. Hay also admitted that if a line were drawn at the 3% mark on the misleading

demonstrative used to illustrate his testimony, it would be clear that Fujisawa's marketing and promotional spending would exceed the average in every single year from 1995 through 2005. (Hay, Tr. 1766:18-1777:12; DTX 2041.) 108. Fujisawa's advertising and promotional spending in at least the years 1996, 1999

and 2001 was in fact roughly twice as high as the average promotional spending for hospitaldominated products in those years. (Hay, Tr. 1766:18-1777:12; DTX 2041.) This is especially remarkable given that the pharmacological stress market is very concentrated, requiring fewer resources to reach the marketing audience. (D.I. 149 FOF at ¶¶ 198-201.) It is also remarkable in a market in which, as Plaintiffs argue, the consumers are "expert," and therefore "not swayed" by product promotion. (D.I. 151 at 33.)

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(iii) 109.

Adenoscan's Increasing Sales Were Also Due to the General Growth of the Pharmacological Stress Market

Despite Plaintiffs' representations concerning relative market shares, Adenoscan®

did not grow market share at the expense of dipyridamole, the incumbent product in the pharmacological stress market. (Leffler, Tr. 1600:6-16, 1632:4-7; DTX 3132; D.I. 149 FOF at ¶ 237.) 110. Although the market was ripe for a new entrant when Fujisawa launched

Adenoscan®, it took over six years for the sales of Adenoscan® to overtake dipyridamole, even with the differential in the prices of the products. (D.I. 149 FOF at ¶¶ 229-230.) 111. Dipyridamole retained significant usage after the launch of Adenoscan® and has

experienced continuous growth since that time. (Leffler, Tr. 1599:12-1600:16; TX 21; DTX 3132; DTX 3134.) 112. The higher overall level of growth achieved by Adenoscan® can be attributed to

the company's extensive marketing and promotion investment in creating and capturing additional user populations for the product. (D.I. 149 FOF at ¶¶ 214-218.) 113. The higher overall growth level is also attributable to a general growth in demand

for pharmacological stress testing unrelated to the asserted invention, and due instead to demographic phenomena such as the increased aging of the American population and the rise in American obesity. (D.I. 149 FOF at ¶¶ 226-238.) As Plaintiffs' witness Mr. White pointed out, "rising water raises all the boats"--i.e., dipyridamole as well as Adenoscan®. (White, Tr. 1257:11-12.) 114. Adenoscan®`s success is thus based on a fortuitous market occurrence and is not

probative of non-obviousness. (See also D.I. 149 FOF at ¶¶ 184-242.)

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b. 115.

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

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

and his analysis of the economic issues in this case was inaccurate. 116. A discussed supra, Dr. Hay relied on a concocted industry average that is

inappropriate for the niche market of pharmacological stress agents. 117. In addition, Dr. Hay did not conduct his analysis based on the actual facts in this

case. For example, in response to questions about Fujisawa's 86-member sales force, which Dr. Hay had earlier disagreed was twice the size of the sales force of its competitor, DuPont, Dr. Hay admitted when pressed that he "[didn't] know exactly what DuPont was doing." (Hay, Tr. 1774:24-1776:19.) Despite this lack of knowledge, Dr. Hay testified on direct to an opinion on the relative detailing efforts of Fujisawa and DuPont. (Id.) 118. Dr. Hay also used dollar-based market share as a preferred measure of the relative

success of Adenoscan® and dipyridamole (Hay, Tr. 1777:11-1778:3) even though Astellas's own Senior Vice President of Marketing, Richard White, testified that the preferred measure used internally by Astellas to gauge the success of its products is market share of procedures performed. (White, Tr. 1286:23-1287:9.) 119. Market share of procedures performed is a more appropriate measure of relative

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

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120.

Dr. Hay also inappropriately chose to use gross sales to calculate market shares

and promotion-to-sales ratios, even though he admitted on cross examination that gross sales is an "inflated number" and that Mr. White testified that net sales "represents the money that the company actually takes in for the sales of its product" because it factors out "certain returns and allowances." (White, Tr. 1236:21-1237:3; Hay, Tr. 1788:2-15.) 121. At several points throughout his testimony, Dr. Hay was intent on criticizing Dr.

Leffler's testimony even though he had either incorrectly heard the testimony or had failed to listen to it altogether. (Hay, Tr. 1767:13-1768:14.) In one instance, Dr. Hay was forced to admit that his criticism on direct examination of Dr. Leffler's calculation of a promotion-to-sales ratio was based on a calculation that Dr. Leffler had revised since his opening report and had not presented to the Court at trial. (Hay, Tr. 1773:25-1774:23.) Dr. Hay's apparent personal bias against Dr. Leffler and his disregard of the facts make him an unreliable source for this Court to rely on. (See id.) C. 122. The Asserted Claims of the `296 Patent are Inherently Anticipated As discussed supra, the Fukunaga 1982 abstract disclosed the administration of

ATP (without dipyridamole) to patients to cause controlled hypotension, one of the medical applications of selective arterial vasodilation. (TX 42.) The dose of ATP administered was equivalent to a dose of adenosine that falls within each of the claimed ranges of the asserted claims, and a person of ordinary skill would have made this common sense calculation in determining the amount of adenosine to administer for the same purpose. (See id.) 123. While Fukunaga 1982 admittedly does not expressly disclose the administration

of adenosine, a person of ordinary skill in the art at the relevant time would understand that "the natural result flowing from" the administration of ATP would be the rapid and virtually complete conversion of ATP to adenosine, as discussed supra. (See D.I. 149 FOF at ¶¶ 71-83.) 24

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124.

As also discussed supra, the immediate and complete conversion of ATP to

adenosine was, in fact, appreciated at the time, and repeatedly acknowledged by Dr. Sollevi. (See D.I. 149 FOF at ¶¶ 71-83.) 125. Therefore, each and every element of the asserted claims was inherently disclosed

in Fukunaga 1982. (See D.I. 149 FOF at ¶¶ 243-246.) D. Expert Testimony Issues 1. 126. Dr. Binkley is Highly Qualified to Serve as an Expert in this Case

As demonstrated infra, the record contradicts Plaintiffs' attempt to characterize

Dr. Binkley as anything less than a highly qualified and credible expert witness in this case. 127. Dr. Binkley is a highly-regarded cardiologist who has been a practicing physician

for over 22 years and serves as Ohio State University's Wilson Professor of Medicine in Cardiology, Director of Cardiovascular Research in the Division of Cardiology, and Director of Clinical Programs in the Dorothy M. Davis Heart and Research Institute. (Binkley, Tr. 72:16-73:23.) 128. Unlike Plaintiffs' only testifying expert on validity, Dr. Binkley treats patients

and has administered or supervised the administration of adenosine for the purpose of pharmacologic stress testing. (Binkley, Tr. 74:23-75:3.) 129. Dr. Binkley also serves on the editorial board of the American Heart Journal and

is a peer-reviewer for a number of other well-known journals in the field of cardiology, including Circulation. (Binkley, Tr. 76:25-77:8.) 130. Dr. Binkley has authored over 140 peer-evaluated publications and several book

chapters related to his cardiovascular research, and has earned several honors for his work in the field of cardiology. (Binkley, Tr. 75:5-76:24, 77:9-17.)

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131.

Unlike Plaintiffs' expert, Dr. Klabunde (the only validity expert proffered by

Plaintiffs at trial), Dr. Binkley is a cardiologist who was in practice at the relevant time, so he squarely qualified as a person of ordinary skill in the art at the time of the alleged invention. (Binkley, Tr. 73:23-74:4, 75:23-76:4.) 132. The parties have agreed that a person of ordinary skill in the art to which the `296

patent pertains is a cardiologist with a residency in internal medicine and two years of a cardiology fellowship, whose experience could also include nuclear cardiology imaging. (Binkley, Tr. 95:25-96:7; Klabunde, Tr. 515:15-25.) 133. Dr. Binkley is a cardiologist and completed both a residency in internal medicine

and a fellowship in cardiology in the mid 1980s. (Binkley, Tr. 73:23-74:4, 75:23-76:4.) Dr. Klabunde lacks these qualifications. (Klabunde, Tr. 1057:4-19.) 134. Having been a practicing cardiologist at the time, Dr. Binkley has much more

relevant insight about what skilled artisans would have understood as compared to Dr. Klabunde, who is not a cardiologist, not a physician, was not teaching physicians at the relevant time, and only later came to teach at a school of osteopathy. (Binkley, Tr. 73:23-74:4, 75:23-76:4; Klabunde, Tr. 1056:12-1057:19.) a. 135. Dr. Binkley's Opinions Were Well Within the Scope of His Expert Report

Plaintiffs' assertion that Dr. Binkley offered new theories of invalidity that were

not previously disclosed in his expert reports is not borne out by the record. 136. Dr. Binkley opined in his expert report that a person of ordinary skill would be

motivated to administer adenosine without pretreatment by dipyridamole, in part because of the properties resulting from the difference in the half lives of dipyridamole and adenosine. (TX 26,