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

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 1 of 115

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

PLAINTIFFS' PROPOSED COUNTERFINDINGS OF FACT AND COUNTERCONCLUSIONS OF LAW
Richard K. Herrmann #405 Mary B. Matterer #2696 MORRIS JAMES LLP 500 Delaware Avenue, Suite 1500 Wilmington, DE 19801 (302) 888-6800 [email protected] Charles E. Lipsey FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP Two Freedom Square 11955 Freedom Drive Reston, VA 20190-5675 (571) 203-2700 Susan H. Griffen David P. Frazier FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP 901 New York Avenue Washington, D.C. 20001-4413 (202) 408-4000 Attorneys for Plaintiffs Astellas US LLC and Astellas Pharma US, Inc. Paul M Lukoff #96 David E. Brand #201 PRICKETT JONES & ELLIOTT, P.A. 1310 King Street Wilmington, DE 19801 (302) 888-6520 [email protected] John Scheibeler WHITE & CASE LLP 1155 Avenue of the Americas New York, NY 10036 (212) 819-8200 Attorneys for Plaintiff Item Development AB

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 2 of 115

TABLE OF CONTENTS I. PLAINTIFF'S COUNTERFINDINGS TO DEFENDANTS' PROPOSED FINDINGS OF FACT..........................................................................................................1 A. B. Counterfindings Regarding the `296 Patent.............................................................2 Counterfindings Regarding the Background ...........................................................3 1. 2. 3. 4. 5. 6. 7. C. 1. 2. Counterfindings Regarding the State of the Art ..........................................3 Counterfindings Regarding the Level of Ordinary Skill in the Art ..........................................................................................................3 Counterfindings Regarding Vasodilators Generally....................................3 Counterfindings Regarding Hemodynamic Parameters...............................5 Counterfindings Regarding Adenosine........................................................6 Counterfindings Regarding ATP ...............................................................10 Counterfindings Regarding Dipyridamole.................................................20 Counterfindings Regarding the Scope and Content of the Prior Art .....................................................................................................24 Counterfindings Regarding Motiviation to Administer Adenosine for Any Medical Use Other Than Inducing Controlled Hypotension .............................................................................40 Counterfindings Regarding Motivation to Administer Adenosine Without Dipyridamole Pretreatment........................................44 Counterfindings Regarding Secondary Factors .........................................48

Counterfindings Regarding Obviousness in View of the Prior Art .......................24

3. 4. D. II.

Counterfindings Regarding Anticipation...............................................................78

PLAINTIFFS' COUNTERCONCLUSIONS TO DEFENDANTS' PROPOSED CONCLUSIONS OF LAW..........................................................................81 A. Counterconclusions Regarding Obviousness.........................................................81 1. 2. 3. Counterconclusions Regarding Legal Standard.........................................81 Counterconclusions Regarding Differences Between the Claimed Invention Of the `296 Patent and the Prior Art ...........................92 Counterconclusions Regarding the Sollevi Prior Art In Combination with the Knowledge of a Person of Ordinary Skill in the Art............................................................................................94 Counterconclusions Regarding Fukunaga 1982 In Combination with the Knowledge of a Person of Ordinary Skill in the Art............................................................................................98 Counterconclusions Regarding Secondary Factors .................................102

4.

5.

i

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 3 of 115

B.

Counterconclusions Regarding Anticipation .......................................................106 1. 2. Counterconclusions Regarding Legal Standard.......................................106 Counterconclusions Regarding Fukunaga 1982......................................108

III.

CONCLUSION................................................................................................................111

ii

Case 1:05-cv-00336-SLR I.

Document 157

Filed 06/19/2007

Page 4 of 115

PLAINTIFF'S COUNTERFINDINGS TO DEFENDANTS' PROPOSED FINDINGS OF FACT As an aid to the Court, Plaintiffs have prepared responses and counterfindings with an

emphasis on issues believed to be most pertinent to this case. Each response and counterfinding is in bold text immediately following the finding to which it pertains. While each response and counterfinding indicates specific reasons for Plaintiffs' disagreement with Sicor's proposed finding, such responses and counterfindings do not necessarily encompass all of the bases for Plaintiffs' disagreement. Moreover, the absence of a response or counterfinding to any specific proposed finding or part thereof does not constitute an admission that Plaintiffs agree with or concede that the proposed finding or any part thereof is correct as stated. Additionaly, Plaintffs provide the following glossary of abbreviations used herein to refer to the various post-trial filings: "PB" refers to Plaintiffs' Opening Post Trial Brief, as filed on May 9, 2007, (D.I. 151); "DB" refers to Defendants Sicor's Post-Trial Brief, as filed on May 9, 2007, (D.I. 150); "POB" refers to Plaintiffs' Opposition to Defendants' Post Trial Brief, as filed on June 19, 2007; "PFF" refers to Plaintiffs' Proposed Findings of Fact, as filed on May 9, 2007, (D.I. 152); "DFF" refers to Defendants' Proposed Findings of Fact, as filed on May 16, 2007, (D.I. 153); "PCF" refers to Plaintiffs' Counterfindings of Fact corresponding to the DFF of the same number, as filed on June 19, 2007; "PCL" refers to Plaintiffs' Proposed Conclusions of Law, as filed on May 9, 2007, (D.I. 152); "DCL" refers to Defendants' Proposed Conclusions of Law, as filed on May 16, 2007, (D.I. 153); and "PCC" refers to Plaintiffs' Counterconclusions of Law corresponding to the DCL of the same number, as filed on June 19, 2007.

1

Case 1:05-cv-00336-SLR A.

Document 157

Filed 06/19/2007

Page 5 of 115

Counterfindings Regarding the `296 Patent

DFF18. The `296 patent has a priority date of September 24, 1985, and therefore the relevant time for prior art is on or before September 24, 1985. (Binkley, Tr. 192:2-193:2; TX 275; DTX 3063.) PCF18. The `296 patent has an effective filing date pursuant to 35 U.S.C. §

120 for the subject matter of the asserted claims of September 24, 1985. (TX-275.) While generally the relevant time for assessing the state of the art with respect to the `296 patent would be on or before September 24, 1985, publications describing Dr. Sollevi's own work cannot be relied upon to defeat patentability unless published before September 24, 1984. (See 35 U.S.C. §§ 102(a), (b).) DFF24. Claim 7 of the `296 patent reads as follows:

A method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation and without pretreatment with dipyridamole, comprising continuously administering into the blood stream of said patient by intravenous administration about 0.01 milligrams to about 0.15 milligrams of adenosine per kilogram body weight per minute. (TX 275, col. 22, ll. 41-47; DTX 3048.) PCF24. Claim 7 of the `296 patent reads as follows:

A method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation and without pretreatment with dipyridamole, comprising continuously administering into the blood stream of said patient adenosine at a rate of administration of 0.01 to 0.15 milligrams of adenosine per kilogram body weight per minute. DFF26. The specification of the `296 patent uses the term "preload" as equivalent to dilating veins and the term "afterload" as equivalent to dilating arteries. (TX 275, col. 2, ll. 39-42.) RESPONSE: Plaintiffs object to this finding as immaterial to any issue in dispute at trial. Whether couched in terms of selective arterial vasodilation without inducing significant venous dilation or inducing a reduced afterload without reducing the preload, all claims require selective arterial vasodilation by adenosine, the hallmarks of which were a very clear-cut reduction in vascular resistance combined with essentially unaffected 2

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 6 of 115

filling pressures of the heart, and without exception, an increase in cardiac output (the rate of blood flow pumping through the heart). (Sollevi 433:23-434:11.) B. Counterfindings Regarding the Background 1. Counterfindings Regarding the State of the Art

DFF27. The field of art relevant to the `296 patent can be described broadly as the field of vasodilators and the related hemodynamic parameters, with a focus on the medical uses of vasodilators. (Binkley, Tr. 95:9-24.) RESPONSE: Plaintiffs object to the proposed finding as irrelevant because the only theory of invalidity disclosed in Sicor's expert reports was invalidity in view of prior art concerning inducing controlled hypotension in surgical patients, not other uses of vasodilation. 2. Counterfindings Regarding the Level of Ordinary Skill in the Art

DFF28. The 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.) PCF28. (See PFF160.) A person of ordinary skill in the art would be a

cardiologist whose training would have included medical school, a residency in internal medicine, and fellowship in cardiology. (Klabunde 515:11-25; Binkley 95:25-96:7.) 3. Counterfindings Regarding Vasodilators Generally

DFF38. Vasodilators that act primarily to dilate arteries include adenosine, dipyridamole, and hydralazine. (Binkley, Tr. 85:10-15; DTX 3004-I.) RESPONSE: The portion of the transcript cited by Sicor (Binkley at 85:10-15) does not support this statement. Thus, the following counterfinding, which is supported by the cited testimony, is proposed: PCF38. Nitro compounds are classic examples of venodilators that dilate

primarily the veins. (Binkley 85:10-15.) DFF41. Vasodilators have been used in medicine since the early 1950s, when they were used in medication to treat hypertension (i.e., high blood pressure) by "relaxing" the blood

3

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 7 of 115

vessels. (Binkley, Tr. 86:17-21.) For example, a vasodilator like hydralazine would be used to relax the arteries, and therefore reduce the patient's blood pressure. (Binkley, Tr. 86:17-87:12.) RESPONSE: Plaintiffs object to this finding as irrelevant because Defendants' expert reports did not disclose any theory of invalidity based on use of hydralazine in the 1950s to lower blood pressure. The only prior art medical use relied on in Sicor's expert reports concerned induction of controlled hypotension in surgical patients. PCF41. Not all vasodilators work interchangeably to lower the blood pressure.

For instance, dipyridamole did not produce hypotension in Dr. Sollevi's studies, whereas adenosine did. (Klabunde 1166:4-20.) Moreover, adenosine did not lower mean arterial blood pressure in the Biaggioni 1985 study of normal conscious volunteers. (See TX-1187; Klabunde 554:14-555:2.) DFF42. Later, in the 1970s and early 1980s, vasodilators were also used in the treatment of congestive heart failure and to lower blood pressure during surgical procedures. (Binkley, Tr. 87:13-24.) In the case of congestive heart failure, doctors began using vasodilators to reduce blood pressure in order to allow the weakened heart muscle to function more efficiently. (Binkley, Tr. 87:16-21.) Doctors also began using vasodilators to reduce blood pressure during surgery in order to reduce the risk of bleeding. (Binkley, Tr. 87:22-24.) RESPONSE: Though Dr. Binkley suggested at trial that adenosine infusions would have been considered for the treatment of congestive heart failure, that assertion is nowhere in his expert reports. (See TX-26, TX-43.) Moreover, Dr. Binkley, a heart failure specialist, admits that to this day he has never continuously infused adenosine to treat a heart failure patient. (Binkley 1490:5-11.) As discussed above, Plaintiffs object to this finding as irrelevant because the only theory of invalidity disclosed in Sicor's expert reports was invalidity in view of prior art concerning inducing controlled hypotension in surgical patients, not other uses of vasodilators. Plaintiffs' response to Sicor's specific allegations concerning alternative uses of vasodilators is set forth in Plaintiffs' Opposition Brief at Section II(B).

4

Case 1:05-cv-00336-SLR 4.

Document 157

Filed 06/19/2007

Page 8 of 115

Counterfindings Regarding Hemodynamic Parameters

DFF55. For example, if MABP (i.e., pressure) decreases and CO (i.e., flow) increases or remains the same, then resistance in the arteries, i.e., SVR, must have also decreased. (Binkley, Tr. 94:17-95:7; DTX 3011-B-C.) This relationship between the hemodynamic parameters is summarized by the following equation: Pressure (P) · = Blood Flow (F) · * Resistance (R) ·. (Binkley, Tr. 94:6-95:7; DTX 3011-B.) From such information, i.e., if MABP decreases and CO increases or remains the same, a person of ordinary skill in the art would conclude that arterial vasodilation had occurred. (Binkley, Tr. 94:17-95:13.) RESPONSE: While Dr. Binkley describes in general the theory that attempts to explain the hemodynamics of blood pressure, Dr. Sollevi specifically addressed the changes in hemodynamic properties observed in actual patients that indicate selective arterial vasodilation. Thus, the following, more relevant, counterfinding is proposed: PCF55. (See PFF146) Dr. Sollevi described the hallmarks of selective arterial

vasodilation following an adenosine infusion as involving a clear cut reduction in vascular resistance combined with essentially unaffected filling pressures to the heart and, without exception, an increase in cardiac output (the rate of blood flow pumping through the heart). (Sollevi 433:23-434:11.) Indeed, he observed such a decrease in vascular resistance, maintained filling pressure, and an increase in cardiac output in patients administered adenosine infusions. (TX-37; TX-1170; TX-1169 at 232; Sollevi 433:23-434:11.) DFF56. In the same example as the one described in paragraph 55, since CO did not decrease, a person of ordinary skill would conclude that there was little or no venous dilation. (Binkley, Tr. 95:5-13.) If venous dilation had occurred, a decrease in flow would be expected. (Binkley, Tr. 95:11-13.) PCF56. See PCF55.

DFF57. All of the facts recited supra in paragraphs 30-56 would have been known to a person of ordinary skill in the art at the beginning of September 1985. (Binkley, Tr. 96:1418.) PCF57. As discussed above, Plaintiffs object to this finding as irrelevant

because the only theory of invalidity disclosed in Sicor's expert reports was invalidity in 5

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 9 of 115

view of prior art concerning inducing controlled hypotension in surgical patients, not other uses of vasodilators. (See Responses and Proposed Counterfindings to DFF38, 41, 42, and 55.) 5. Counterfindings Regarding Adenosine

DFF61. Molecules of adenosine in the bloodstream can either be metabolized, i.e., eliminated through a process of converting adenosine to another substance, or bound to receptors in the artery wall through which the adenosine will act. (Binkley, Tr. 102:4-103:24; DTX 3014A-C, see white "cones.") RESPONSE: This finding does not completely explain the complex set of chemical reactions that occur in the body when adenosine is metabolized. Thus, the following counterfinding is proposed: PCF61. Adenosine does not simply "pool" in the body, it is rapidly converted

into other substances. (Binkley 274:6-9.) When adenosine is metabolized, it is taken up by the red blood cells or certain sites on the artery wall and acted on by an enzyme called adenosine deaminase, which breaks the adenosine down into molecules such as hypoxanthine, inosine, and ultimately the end product, uric acid . (Binkley 103:7-18, 274:1-4.) However, adenosine is a part of a more complex metabolic pathway in the body. In that pathway, adenosine is created, inter alia, by the breakdown of ATP. The ATP pathway can also work in reverse, taking available adenosine in the body and using it to build AMP, ADP, and ATP. (Binkley 272:15-25.) Thus, adenosine can either be reformed into AMP, ADP or ATP, or broken down into other metabolites including hypoxanthine, inosine, and ultimately the end product, uric acid (Binkley 272:15-274:9.) (See also PFF64, 65, 144.) DFF62. When adenosine is metabolized, it is taken up by the red blood cell or certain sites on the artery wall and acted on by an enzyme called adenosine deaminase, which breaks the adenosine down into molecules such as hypoxanthine and inosine. (Binkley, Tr. 103:7-18; DTX 3014-A-C, see green "pacmen.") PCF62. See PCF61. 6

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 10 of 115

DFF65. The increase in adenosine in the bloodstream necessarily results in an increase of the amount of adenosine binding to the receptors in the arterial wall; the effect is an increase in the relative degree of arterial vasodilation. (Binkley, Tr. 105:13-106:13; DTX 3014C-E.) The more adenosine that is produced, the greater the magnitude of arterial vasodilation. (Binkley, Tr. 103:25-104:13.) PCF65. While prior art studies concerning the "Adenosine Hypothesis"

identified endogenous adenosine as a vasodilator capable of regulating blood flow in the coronary arteries, those studies on adenosine physiology did not identify it as a selective arterial vasodilator, nor did they describe adenosine as playing the same role in regulating blood flow in other parts of the circulatory system outside of the heart. (See, e.g., Klabunde 1077:21-1078:19, 1085:20-1087:9.) DFF66. All of the facts recited supra in paragraphs 58-65 would have been known to a person of ordinary skill in the art at the beginning of September 1985. (Binkley, Tr. 99:4-7, 106:23-107:4.) PCF66. See Responses and Proposed Counterfindings to DFF61 and 65.

DFF67. Adenosine's potent vasodilator effects were recognized in the art as early as 1929, when Drs. A.N. Drury and A. Szent-Gyorgy published an article in the Journal of Physiology entitled "Physiological Activity of Adenine Compounds with Especial Reference to their Action Upon the Mammalian Heart." (Binkley, Tr. 99:4-22; TX 35.) In this foundation article, Drs. Drury and Szent-Gyorgy observed that adenosine and adenosine nucleotides "lower general arterial pressure. This is due in part to the cardiac slowing and in part to a general arterial dilation." (Binkley, Tr. 99:23-101:17; TX 35 at 236; DTX 3055.) RESPONSE: This finding is only a partial description what the Drury and SzentGyorgyi article (TX-35) would have conveyed to one of ordinary skill in the art. For completeness, the following counterfinding is proposed: PCF67. (See PFF21) Although demonstrating that adenosine was a

vasodilator, the studies published by Drury and Szent-Gyorgyi also revealed adenosine's ability to slow or stop electrical conduction in the heart, resulting in "AV block."(TX-35) "AV block" is the interruption of conduction in the AV node of the heart, which was known to coordinate the beating of the upper chambers of the heart (the atria) and the

7

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 11 of 115

lower chambers (the ventricles). (TX-35 at 236; TX-36 at 1254; Binkley 244:13-245:17; Klabunde 517:6-17, 519:8-520:18.) DFF68. As discussed supra in paragraph 42, during the time period from the early 1970s to the 1980s, there was an increasing focus on the use of selective arterial vasodilators (like adenosine) to treat a number of cardiovascular conditions, including congestive heart failure and hypertension. (Binkley, Tr. 86:17-87:24.) RESPONSE: Though Dr. Binkley suggested at trial that adenosine infusions would have been considered for uses such as the treatment of congestive heart failure, hypertension, or "limb ischemia," those assertions were nowhere in his expert reports. (See TX-26; TX-43.) Plaintiffs object to this finding as irrelevant because the only theory of invalidity disclosed in Sicor's expert reports was invalidity in view of prior art concerning inducing controlled hypotension in surgical patients, not other uses of vasodilators. Indeed, prior to Sollevi's invention, the continuous infusion of adenosine alone was not considered a viable option for any medical condition. (See generally Plaintiffs' Proposed Findings of Fact at § III(A).) Thus, the following counterfinding is proposed: PCF68. Concerns existed about administering a compound such as adenosine,

known to be capable of inducing slowing of the heartbeat (bradycardia), temporary cardiac arrest, and extreme hypotension, to patients with heart disease. Indeed, Dr. Sollevi was sufficiently concerned about the effects of adenosine in heart patients that he excluded such patients from his studies. (TX-1170; Sollevi 441:16-42:2.) Tellingly, Dr. Binkley, a heart failure specialist, admitted that even today he has never used adenosine to treat heart failure as he proposed would have been obvious to one of ordinary skill in the art in 1985. (See Binkley 1490:5-11.) Moreover, none of the prior art relied on by Sicor refers to a medical use for infusing adenosine other than inducing controlled hypotension during surgery. (See Binkley 256:7-17.) While adenosine had been known since the 1920s and vasodilators had been used to treat hypertension in the 1950s, adenosine infusions were not

8

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 12 of 115

used for any medical purpose prior to Dr. Sollevi's studies in the 1980s. (Sollevi 438:1-7; Strauss 765:17-767:18.) DFF69. A seminal publication in Circulation Research by Dr. Robert Berne in 1980, "The Role of Adenosine in the Regulation of Coronary Blood Flow," observed that "adenosine is a very active vasodilator." (Binkley, Tr. 110:21-111:3; TX 228 at 807; DTX 3056.) RESPONSE: Nowhere in the cited testimony does Dr. Binkley call Dr. Berne's 1980 article (TX-228) a "seminal publication." Indeed, on cross-examination Dr. Binkley referred to a paper published seventeen years earlier by Dr. Berne as a "famous paper from that era." (See Binkley 247:4-12.) Thus, the following counterfinding is proposed: PCF69. The seminal publication on adenosine was not Dr. Berne's 1980

publication, but instead his 1963 publication. (See TX-113) It was this "classic" paper in which Dr. Berne proposed that endogenous adenosine might be the physiological molecule responsible for coronary vasodilation in response to low oxygen levels (hypoxia) in cardiac tissue. (TX-113 at 317, 321; see Klabunde 1071:25-1072:25; Binkley 247:4-12.) Dr. Berne's proposition set forth in this 1963 paper became known as the "Adenosine Hypothesis." (Binkley 247:4-12.) (See also PFF30-33.) DFF70. Dr. Berne's article resulted in numerous animal and clinical studies to explore adenosine's medical uses. (See, e.g., TX 36, TX 37, TX 40, TX 45, TX 88, TX 236, TX 1170, TX 1187, TX 5000.) RESPONSE: Plaintiffs object to this finding to the extent that it relies on documents not discussed in Dr. Binkley's expert reports (TX-88, TX-236, TX-5000; Binkley 1442:16-1443:24, 1505:6-1505:20) or not disclosed at all prior to trial (TX-5000). (See PB at 37-38.) The following counterfinding is proposed: PCF70. Sicor contends that renewed interest in adenosine was spurred by a

"seminal publication in 1980 in Circulation Research (TX-228)," referring to a review article by Dr. Berne concerning the "Adenosine Hypothesis" (DB at 10), which identified adenosine as a mediator of vasodilation in the coronary arteries. Notably, Sicor cites no 9

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 13 of 115

testimony to support its contention. In fact, the record does not support Sicor's assertion that the 1980 article "placed adenosine squarely at the forefront" of research on vasodilators. (DB at 10.) Both Dr. Klabunde and Dr. Binkley agreed that the real seminal paper on the adenosine hypothesis was published seventeen years earlier, in 1963. (See Binkley 247:4-12; Klabunde 1071:25-1072:25.) That no one between 1963 and the early 1980s tested or suggested the use of an adenosine infusion as a selective arterial vasodilator is compelling evidence that the recognition of adenosine as an endogenous vasodilator simply did not lead to the further recognition that it might be useful as an exogenously administered pharmaceutical. (See also PFF30-33.) 6. Counterfindings Regarding ATP

DFF71. Adenosine triphosphate ("ATP") is a substance that is found in the human body and is composed of an adenosine molecule bound to a "tail" composed of three phosphate molecules. (Binkley, Tr. 106:14-18, 107:22-108:24; TX 228; DTX 3016-A, see blue triangles.) RESPONSE: This finding minimizes the chemical importance of the three phosphate groups present in ATP. As is not uncommon with chemical molecules, the presence of these additional atoms of phosphorus and oxygen gives ATP important biological properties that adenosine lacks. (Klabunde 505:17-506:18, 1117:5-1118:21.) The following counterfinding is proposed: PCF71. (See PFF56) ATP (adenosine triphosphate) is a high energy molecule

with a chemical structure that includes three "phosphate groups" (collections of phosphorous and oxygen atoms) not found in adenosine itself. (Klabunde 505:17-506:18.) (See also PFF56-59.) The presence of these phosphate groups confers important properties on ATP that adenosine lacks. For example, ATP is the primary energy source in all cells and is particularly present in the muscular tissue of the heart. (Klabunde 506:7-10, 1102:6-1103:7; TX-113 at 317.) Adenosine and ATP were also known to bind to different receptors in the body. (Klabunde 510:8-513:24; TX-151; see also PFF58.) 10

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 14 of 115

DFF72. Within the body, ATP is constantly converted to adenosine by a reaction that is fundamental to human metabolism. (Binkley, Tr. 108:1-109:9; DTX 3016-A-H.) An enzyme called 5'-nucleotidase sequentially clips each of the phosphates off of the "tail," first converting the adenosine triphosphate to adenosine diphosphate, then to adenosine monophosphate, and then ultimately to adenosine. (Binkley Tr. 108:1-109:9, 113:17-114:3; Klabunde, Tr. 1083:9-16, 1107:3-7; DTX 3016-A-H.) RESPONSE: This proposed finding does not fully reflect the cited testimony. Specifically, Dr. Binkley describes that this reaction can continue to form further metabolites, mentioning hypoxanthine and inosine, or that the phosphate groups can be added back on to reform ATP. (Binkley 108:25-109:9.) Thus, the following counterfinding is proposed: PCF72. In addition to recognizing ATP as a direct acting vasodilator, prior

art investigators knew that it could be broken down by enzymes in the bloodstream into more than six different metabolites. (TX-126 at 612; Binkley 272:15-274:9.) Furthermore, the adenosine that is formed as a breakdown product of ATP does not simply "pool" in the body, it is rapidly converted into other substances. It can either be reformed into AMP, ADP, or ATP, or broken down into other metabolites including hypoxanthine, inosine, or ultimately the end product, uric acid. (Binkley 108:1-109:9, 274:1-9; see also PPF64, 65, 144.) DFF73. This conversion is nearly immediate, as noted in several references published in the early 1980s, including one co-authored in 1984 by Dr. Sollevi. (Binkley, Tr. 109:10-15, 111:8-112:17, 1418:21-1419:5; TX 228 at 807-08; TX 236 at 547; TX 5000 at 1196.) In 1980, Dr. Berne observed that "it is virtually impossible to make accurate measurements of ATP in venous blood since the nucleotide is rapidly degraded in blood and also can be released from the cellular elements of the blood." (TX 228 at 807 (emphasis added); see also Binkley, Tr. 111:23-112:17.) In 1984, Dr. Sollevi wrote that ATP was nearly immediately converted to adenosine following administration: Using a quantitative HPLC method for purine determination, we recently have demonstrated that ATP given by the iv route is degraded entirely to adenosine and its breakdown products during the transpulmonary passage. (TX 236 at 547; see also Binkley, Tr. 109:10-15, 111:8-112:17, 1418:21-1419:5; TX 228 at 80708; TX 5000 at 1196.)

11

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 15 of 115

RESPONSE: Plaintiffs object to this finding as relying on documents and testimony not disclosed in Dr. Binkley's expert reports (TX-88, TX-236, TX-5000; Binkley 1442:161443:24, 1505:6-1505:20) or not disclosed at all prior to trial (TX-5000; Binkley 1505:6-20). (See PB at 37-38.) This proposed finding is contradictory to other testimony at the trial, including, inter alia, testimony from Dr. Binkley. For instance, testimony indicated that metabolism of ATP differed in prior art studies of different species. PCF73. Prior art investigators knew that effects of ATP and its degree of

metabolism would be different in different species. (See, e.g., Klabunde 1215:19-1216:25; Binkley 1465:5-1466:15; TX-126 at 613-614.) Moreover, Sicor cited a study in dogs in which ATP apparently acted by being completely metabolized to adenosine. (TX-88; Binkley 396:4-397:17.) A different study by Fukunaga in rabbits, however, showed ATP to be the more potent vasodilator, demonstrating that, in rabbits, ATP was having a direct effect. (Binkley 267:9-269:6, 1465:5-1466:15; TX-87 at 275.) Indeed, Fukunaga commented in that rabbit study that "[a]lthough much information about the extracellular, especially cardiovascular, effects of the adenine nucleotides has been accumulated, clinical uses will require more information in different species and under a variety of conditions." (TX-87 at 277.) (See also PFF71-74.) DFF74. The reaction that causes ATP to be constantly converted to adenosine would have been known to a person of ordinary skill in the art in 1985. (Binkley, Tr. 107:22109:20, 109:25-110:10, 111:8-22; Klabunde, Tr. 1043:21-23.) PCF74. While a person of ordinary skill would have understood the general

nature of ATP's metabolism, it would have been impossible to predict the specific amount of each of ATP's various metabolites that would be formed or to separate their individual effects because they rapidly interconverted with each other and several of the interconverted molecules, including ATP, ADP, AMP, and adenosine, caused vasodilation

12

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 16 of 115

in their own right. (Klabunde 507:8-508:3, 1116:5-1117:4, 1220:19-1221:10; Binkley 272:15-274:9.) DFF75. The conversion of ATP to adenosine is equimolar. (Binkley, Tr. 1415:191416:9; TX 88 at 174.) "Equimolar" means that a certain number of ATP molecules are converted to the same number of molecules of adenosine. (Binkley, Tr. 1416:4-9.) RESPONSE: Plaintiffs object to this finding as relying on information not properly disclosed in Dr. Binkley's expert reports. (See Binkley 1412:2-1417:21, particularly at 1412:2-15 and 1417:14-21, see also PB37-38.) Thus, the following counterfinding proposed: PCF75. See PCF74.

DFF76. A number of references disclosed that exogenous ATP is converted rapidly and completely to adenosine following the administration of ATP. In 1984, Dr. Sollevi wrote as follows: The arterial plasma adenosine concentration during ATP infusions was similar to that found during an equimolar infusion of adenosine. Moreover, similar arterial plasma concentrations of adenosine were found at similar hypotensive levels, whether adenosine or ATP was given . . . (TX 88 at 173-175; see also Binkley, Tr. 1409:15-19, 1411:17-1414:6; Klabunde, Tr. 1125:231126:13; TX 36 at 1262; TX 236 at 547.) RESPONSE: Plaintiffs object to this finding as relying on exhibits (TX-88; TX-236) and testimony not properly disclosed in Dr. Sollevi's expert reports. (See PB37-38.) This finding is misleading as it does not specify the species studied in TX-88 or TX-236, which was canine. However, the testimony was that ATP metabolism differs between mammalian species and that the rate of ATP breakdown in humans was low compared to other species. (See, e.g., TX-126 at 613; Klabunde 1215:2-1216:25.) The cited portion of TX-36 also refers to studies in rats. While there is a discussion of human studies in TX-36, it concerns ATP's effect on electrical conduction in the heart in treating PSVT, not its vasodilating activity, which involves different receptors altogether. (Klabunde 1210:1-1211:19.) The evidence showed that in humans, ATP had independent activity as a vasodilator that was

13

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 17 of 115

not solely dependent on being broken down into adenosine. (See, e.g., Klabunde 1117:13-1118:21.) (See also PFF71-74.) Thus, the following counterfinding is proposed: PCF76. (See PFF71.) Metabolism of ATP differed in prior art studies of

different mammalian species. Consequently, prior art investigators knew that effects of ATP and its degree of metabolism would be different in different species. (See, e.g., Klabunde 1216:18-25; TX-126 at 613.) DFF77. Like adenosine, ATP causes selective arterial vasodilation when administered intravenously. (Binkley, Tr. 396:20-24, 397:3-17. This property led to the use of ATP to induce controlled hypotension in surgical patients. (Binkley, Tr. 161:24-162:9.; TX 42.) RESPONSE: This proposed finding is contrary to the evidence, which indicated that the hallmarks of selective arterial vasodilation, i.e., consistent increased cardiac output together with clear-cut reduction in vascular resistance and maintained filling pressures (see, e.g., TX-37; TX-1170; TX-1169 at 232; Sollevi 433:23-434:11; PFF146), were not shown when ATP was administered to humans according to TX-42. (See, e.g., Klabunde 544:8-546:2; TX-42.) Thus, the following counterfinding is proposed: PCF77. The Fukunaga 1982 abstract on ATP infusion does not report the

consistent increase in cardiac output together with maintained filling pressure observed upon administration of adenosine to surgical patients indicative of selective arterial vasodilation. The abstract does not even report measurement of filling pressures, such as right atrial pressure. (Klabunde 544:8-546:2; TX-42.) Moreover, the cardiac output data in Fukunaga 1982 is flawed and would not have allowed one of ordinary skill in the art to conclude that selective arterial vasodilation occurred in patients administered an ATP infusion. (Klabunde 548:9-20.) (See also PFF147-149.) DFF78. By the early 1980s, it was known that the vasodilative effects of ATP are due to its breakdown to adenosine ­ not the actions of the ATP itself. In June 1984, Dr. Berne wrote: In the guinea pig heart the AV conduction delay and block caused by adenosine triphosphate is due to its degradative product, adenosine. Thus, it is probable that 14

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 18 of 115

in humans, as in the case of the guinea pig, adenosine triphosphate must be hydrolyzed to adenosine to exert its effect. Hence, it is adenosine that is the active agent. (TX 5000 at 1196 (emphasis added); see also Binkley, Tr. 112:22-113:16, 115:2-116:3, 166:12167:1, 179:13-180:6, 396:16-397:17, 1410:2-21, 1412:17-1413:11, 1414:23-1416:22, 1420:61421:10; Klabunde, Tr. 1107:3-12; TX 51 at A39; TX 88 at 174-175; TX 228 at 807; TX 236 at 547 n.6.) RESPONSE: Plaintiffs object to this finding as relying on exhibits (TX-88, TX-236, and TX-5000) and testimony not properly disclosed in Dr. Binkley's expert reports. (See PB at 37-38.) The exhibit which is the subject of and quoted in this proposed finding (TX-5000), and which was proffered by Sicor's expert at trial, was never disclosed in discovery and was neither discussed in Dr. Binkley's expert report nor cited in Sicor's 35 U.S.C. § 282 notice. (See PB at 37-38.) Moreover, Sicor has misapplied the quote from TX-5000. The statement is completely unrelated to the vasodilatory effects of ATP, and instead relates to the electrophysiological effects of adenosine on the AV node. (See, e.g., Binkley 1510:18-22.) The effect of adenosine on the AV node is a completely separate activity from the vasodilating activity of ATP interaction with different receptors altogether. The recognition that ATP can work indirectly by breaking down into adenosine to cause AV block is not inconsistent with ATP having a role as a direct vasodilator. (Klabunde 1211:13-19.) If testimony regarding TX-5000 is permitted, the following counterfinding is proposed: PCF78. The effect of adenosine on the AV node is a completely separate

activity from the vasodilating activity of ATP and involves interaction with different receptors altogether. The recognition that ATP can work indirectly by breaking down into adenosine to cause AV block is not inconsistent with ATP having a role as a direct vasodilator. (Klabunde 1211:13-19.) Moreover, the Fukunaga 1984 abstract reported using a dose of 32 mcg/kg/min of ATP following dipyridamole pretreatment to reduce blood pressure by about 40%. (TX-51; Klabunde 549:4-550:24, 1044:5-25.) Dr. Sollevi 15

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 19 of 115

needed approximately 140 mcg/kg/min to get the same effect with adenosine after pretreatment with dipyridamole. (Klabunde 549:4-550:24, 1044:5-25.) This requirement for significantly more adenosine than ATP to obtain the same effect was utterly inconsistent with the idea that ATP was merely acting as a precursor whose effects were being mediated primarily through adenosine. (Klabunde 1044:5-25.) In addition, prior art publications had shown that when ATP worked by being broken down into adenosine (as it did in the treatment of PSVT), ATP was less potent than adenosine, not more potent. (TX36 at 1262; Klabunde 1211:20-1212:18.) For ATP to be more potent than adenosine as a vasodilator was indicative of a direct ATP-mediated vasodilator action in humans. (Klabunde 551:20-552:3, 1044:5-25, 1117:5-1118:21, 1212:19-1213:8.) DFF79. In September 1984, Dr. A.F. Fukunaga wrote:

ATP, a purine nucleotide, when administered parenterally is rapidly hydrolyzed to Ad[enosine] . . . Most of the hemodynamic effects of ATP, however, are attributed to Ad[enosine] because of the speed of this hydrolysis in the blood. (TX 51 at A39; see Klabunde, Tr. 1107:3-12; DTX 3061.) Dr. Fukunaga's 1984 article teaches a person of ordinary skill in the art in 1985 that ATP causes vasodilation through its conversion to adenosine. (Binkley, Tr. 178:14-18; TX 51 at A39.) RESPONSE: The quotation from Fukunaga 1984 (TX-51) is misleading in that it crops the discussion of adenosine's further breakdown into inosine, hypoxanthine, and uric acid. It also omits reference to the concern raised by Dr. Fukunaga about accumulating high levels of the metabolites phosphate and uric acid. It was this concern that led Dr. Fukunaga to recommend dipyridamole pretreatment in connection with ATP infusion. While Sicor focuses on the single statement in the abstract attributing most of the hemodynamic effects of ATP to adenosine, a comparison of the results of Dr. Fukunaga's ATP infusions and Dr. Sollevi's dipyridamole infusions in the presence of dipyridamole demonstrate a significant direct role for ATP in causing vasodilation. (See PFF154, 186-189; PCF79.) Thus, the following counterfinding is proposed: 16

Case 1:05-cv-00336-SLR PCF79.

Document 157

Filed 06/19/2007

Page 20 of 115

The Fukunaga 1984 abstract reported that, on average, 32

mcg/kg/min of ATP lowered blood pressure by about 40% in patients treated with dipyridamole. (TX-51; Binkley 257:12-15; 258:10-13.) If this were a teaching that ATP caused vasodilation solely through its conversion to adenosine, a corresponding equimolar (containing the same number of molecules) dose of 16 micrograms of adenosine should have had a similar effect. (Binkley 258:25-260:1; Klabunde 549:4-550:14.) However, Dr. Sollevi needed 140 micrograms of adenosine, nearly 10 times as much as Dr. Binkley's assumption predicted, to achieve a similar blood pressure reduction after dipyridamole pretreatment. (Binkley 260:2-20; Klabunde 550:15-24; see also PFF154.) Dr. Klabunde noted that, while metabolism of ATP into adenosine may have contributed to the vasodilation observed in Fukunaga 1984, because of the superior potency of ATP itself, even a small percentage of unmetabolized ATP could have a large effect as a direct vasodilator. (Klabunde 1115:5-12; 1116:5-1118:1.) Consequently, significant metabolism of ATP into adenosine does not mean that the majority of the observed vasodilatory effect of ATP is due to adenosine. (Klabunde 1117:22-1118:1.) DFF80. Dr. Sollevi also published several papers in the early 1980s plainly stating that the vascular effects of ATP were due to its conversion to adenosine. (TX 88 at 174-75; TX 236 at 547.) In one paper, Dr. Sollevi expressly recommended the use of adenosine instead of ATP to induce controlled hypotension: We therefore consider it more appropriate to use adenosine instead of ATP to induce controlled hypotension. (TX 236 at 547; see Klabunde, Tr. 1164:5-22.) RESPONSE: Plaintiffs object to this finding because the two dog-study papers relied on in this proposed finding, TX-88 and TX-236, were not disclosed in Dr. Binkley's expert report and the testimony elicited at trial offered previously undisclosed opinions about them. (See, e.g., PB at 37-38.) Thus, the following counterfinding is proposed:

17

Case 1:05-cv-00336-SLR PCF80.

Document 157

Filed 06/19/2007

Page 21 of 115

(See PFF73.) Sicor's expert, Dr. Binkley, also attempted to rely on

two dog studies using ATP that were not disclosed in his expert report and offered previously undisclosed opinions and testimony about them. (TX-88; TX-236; Binkley 1412:1-1421:19.) Yet the record shows very different levels of ATP metabolism and different effects of ATP in various animal species and in animals versus humans. (See, e.g., Binkley 1465:5-1466:15; TX-87 at 277; Klabunde 1215:2-1216:25; TX-126 at 613.) Most importantly, the human data available in the prior art showed ATP to be a more potent vasodilator than adenosine, contradicting the notion that ATP was working solely through metabolic formation of adenosine. (See, e.g., Klabunde 1044:5-25, 1116:5-1118:21.) DFF81. In another paper, Dr. Sollevi stated several times that the effects of ATP were due to adenosine: Hence the vascular effects of parenterally administered ATP are due mainly to adenosine. [T]he present data suggest that adenosine mediates the vasodilatory effects of exogenously administered ATP. In conclusion, the present experiments demonstrate that intravenously administered ATP is eliminated from plasma before reaching the arterial vascular bed where it may cause hypotension. Furthermore, the vasodilatory effect of ATP and adenosine was directly proportional to the arterial adenosine level. (TX 88 at 174-175; see Binkley, Tr. 396:4-23; Klabunde, Tr. 1128:15-17.) RESPONSE: Plaintiffs object because the paper referred to in this finding, TX-88, is one of the same two referred to in Defendants' previous proposed finding and was not disclosed in Dr. Binkley's expert report. The testimony elicited at trial offered previously undisclosed opinions about TX-88. (See, e.g., PB at 37-38.) Thus, the following counterfinding is proposed: PCF81. See PCF80.

DFF82. The view that the vasodilative effects of ATP are due to its breakdown to adenosine was widely-held in the early 1980s, and would have been understood by a person of ordinary skill in the art in 1985. (Binkley, Tr. 112:22-113:16, 115:2-116:3, 166:12-167:1, 178:14-19, 179:13-180:6, 181:17-22, 396:16-397:17, 1410:2-21, 1412:17-1413:11, 1414:2318

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 22 of 115

1416:22, 1420:6-1421:10; Klabunde, Tr. 1043:21-23, 1107:3-12, 1124:18-1126:13, 1127:181128:1, 1164:5-22, 1174:16-20; TX 51 at A39; TX 88 at 174-175; TX 151 at 107-111; TX 228 at 807; TX 236 at 547 n.6.) RESPONSE: Plaintiffs object to this proposed finding because Dr. Binkley's opinions concerning TX-88, TX-151, and TX-236 were not included in his expert reports. (See PB at 37-38; Binkley 1412:2-15, 1417:14-21, 1417:23-1418:6, 1435:6-11.) Dr. Binkley's opinions also failed to address the direct evidence in the prior art that ATP was not acting solely by being broken down to adenosine, but had a substantial vasodilating ability of its own. Thus, the following counterfinding is proposed: PCF82. The recognition that ATP can work indirectly by breaking down into

adenosine to cause AV block is not inconsistent with ATP also having a role as a direct vasodilator in humans. (Klabunde 1211:13-19.) In addition to the evidence of direct action by ATP discussed in PCF79, other references described a direct ATP vasodilating effect. (See TX-151 at 108; Klabunde 1221:11-1222:21.) Notably, Dr. Binkley's opinions concerning TX-88, TX-151, and TX-236 were not included in his expert reports. (See Binkley 1412:2-15, 1417:14-21, 1417:23-1418:6, 1435:6-11.) DFF83. A person of ordinary skill in the art in 1985 would know that this is because the receptors in the blood vessel walls that are responsible for vasodilation were known to bind primarily to adenosine, not ATP. (Binkley, Tr. 1434:4-1435:6, 1435:12-1438:2; Klabunde, Tr. 1169:8-1174:20; TX 151 at 110-111; TX 152 at 195, 196.) RESPONSE: This proposed finding is based on TX-151. Dr. Binkley's opinion concerning the distribution of receptors for ATP and adenosine was not disclosed in his report, nor was there any discussion of TX-151. (Binkley 1435:6-11; PB at 37-38.) Thus, the following counterfinding is proposed: PCF83. A person of ordinary skill in the art in 1985 would not have

understood the vasodilative effects of ATP to be solely due to its breakdown to adenosine based upon the binding preferences of receptors in the blood vessel walls. (Klabunde 1117:5-1118:21, 1221:11-1222:21.) TX-151 merely indicated the predominant distribution 19

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 23 of 115

of receptors, not exclusive sites, and indicated only that "some" of the actions of ATP were inhibited by methylxanthine inhibitors of adenosine. (TX-151 at 110; Klabunde 1171:151173:10.) The article also explicitly described an example in which ATP caused vasodilation that was not inhibited by an inhibitor of adenosine action. (TX-151 at 108; Klabunde 1221:11-1222:21.) Furthermore, Dr. Binkley conceded that the knowledge of the distribution of receptors was still in an imperfect state. (Binkley 1455:9-1456:3.) 7. Counterfindings Regarding Dipyridamole

DFF86. A person of ordinary skill in the art in 1985 would have known that the administration of dipyridamole and the administration of adenosine have the same net result ­ an increase of adenosine in the bloodstream. (Binkley, Tr. 117:16-118:13, 119:15-22, 131:1-14, 181:9-13, 355:16-356:8; Klabunde, Tr. 1092:22-1094:1, 1095:11-21, 1165:2-15; TX 101 at 21; TX 228 at 809.) PCF86. A person of ordinary skill in the art would not have viewed adenosine

and dipyridamole as interchangeable or as having the same "net effect" as indicated by the fact that dipyridamole did not produce hypotension in Dr. Sollevi's studies, whereas adenosine did. (Klabunde 1166:4-20.) Moreover, adenosine had been shown to treat PSVT by interrupting electrical conduction in the heart. (TX-36; TX-45.) DFF87. Dipyridamole functions as a "middle man" by blocking adenosine deaminase, an enzyme responsible for adenosine uptake and metabolism. (Binkley, Tr. 117:16118:13, 119:15-22, 131:1-14, 181:9-13, 355:16-356:8; Klabunde, Tr. 1092:22-1094:1, 1095:1121, 1165:2-15; TX 101 at 21; TX 228 at 809; DTX 3020-A-D.) RESPONSE: None of the cited testimony uses the term "middle man." Given the different effects of dipyridamole and adenosine and the fact that dipyridamole was known to act more effectively to vasodilate the heart than the peripheral vessels, one of ordinary skill would not have viewed dipyridamole merely as a surrogate for exogenously produced adenosine. PCF87. See PCF86.

DFF88. As described supra in paragraphs 61-63, adenosine can either be taken up and metabolized or it can bind to receptor sites in the artery wall to cause vasodilation. 20

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 24 of 115

RESPONSE: See PCF61 and 62. DFF89. When dipyridamole is administered, endogenous adenosine is still able to bind to the receptor sites, but the dipyridamole blocks the uptake of any adenosine and its subsequent metabolism. (Binkley, Tr. 131:16-132:13; DTX 3020-A-B, see purple semicircles.) As a result, endogenous adenosine builds up within the body because it is no longer being rapidly eliminated from the bloodstream. (Binkley, Tr. 117:16-118:13, 119:15-22, 131:1-14, 132:15-16, 136:18-22, 181:9-13, 356:1-8; Klabunde, Tr. 1095:11-21, 1165:2-15; DTX 3020-B.) PCF89. It was known in the prior art that the heart produced relatively larger

amounts of adenosine than other tissues in the body. (Klabunde 1094:3-6.) Therefore, dipyridamole would have a lesser effect in dilating peripheral vessels as opposed to vessels in the coronary circulation. (Klabunde 1102:6-1103:7.) Consequently, dipyridamole is less effective than adenosine at dropping systemic blood pressure because organs besides the heart do not make a large amount of adenosine. (See also Response and Proposed Counterfinding to DFF87.) DFF90. The build-up of endogenous adenosine following the administration of the dipyridamole leads to vasodilation, since the increase in the amount of adenosine that is binding to the receptor sites causes the walls of the arteries to relax. (Binkley, Tr. 132:14-133:1; DTX 3020-B-D.) RESPONSE: The evidence shows that the build-up of endogenous adenosine following dipyridamole administration occurs mainly in the heart, because organs besides the heart do not produce a large amount of adenosine. (See, e.g., Klabunde 1094:3-6, 1095:11-17.) Thus, the vasodilating effect seen would occur mainly in the heart. To the extent the proposed finding implies the effect would be systemic, it is misleading in light of the evidence. Thus, the following counterfinding is proposed: PCF90. The build up of endogenous adenosine following the administration of

dipyridamole leads to vasodilation of the heart's arteries, since the increase in the amount of adenosine that is binding to the receptor sites causes the walls of the arteries of the heart to relax. (Binkley 132:14-133:1; Klabunde 1094:3-6, 1095:11-17.) This is confirmed by the evidence that dipyridamole is less effective than adenosine at dropping systemic blood 21

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 25 of 115

pressure because organs besides the heart do not produce a large amount of adenosine. Thus, dipyridamole has a minimal effect in dilating peripheral vessels as opposed to vessels in the coronary circulation. (Klabunde 1102:6-1103:7.) DFF91. While the net effect of the administration of adenosine and dipyridamole is the same, i.e., the increase of adenosine in the bloodstream, a person of ordinary skill in the art in 1985 would have known that the effects of dipyridamole lasted much longer than the effects of adenosine, due to the much longer "half life" of dipyridamole. (Binkley, Tr. 133:2-16.) RESPONSE: The language in this proposed finding alleging that "the net effect of the administration of adenosine and dipyridamole is the same, i.e., the increase of adenosine in the bloodstream," is not supported by the cited testimony and is contrary to much of the evidence at trial. Thus, the following counterfinding is proposed: PCF91. While it was known that the half-life of dipyridamole was longer than

the half-life of adenosine (See Binkley 133:2-16), it was recognized in the prior art that adenosine and dipyridamole were different compounds and that they had different effects on the body. For example, dipyridamole is less effective than adenosine at dropping systemic blood pressure because organs besides the heart do not make a large amount of adenosine. (Klabunde 1102:6-1103:7.) Consequently, dipyridamole did not induce profound hypotension in Dr. Sollevi's studies, whereas subsequent administration of adenosine did. (Klabunde 1166:4-20.) Also, it was a lack of interest and a lack of recognition by those in the art that adenosine would be a safe or effective alternative to dipyridamole in human patients that prompted researchers to choose dipyridamole rather than adenosine as the first pharmacologic stress agent for use humans in myocardial perfusion imaging studies. (See Binkley 328:22-329:17; 332:3-14.) Indeed, even Dr. Strauss recommended the use of dipyridamole or ethyl-adenosine rather than adenosine for use as a pharmacologic stress agent (See Strauss 774:19-776:4; TX-232 at 248.) (See also PPF 50-53.) In addition, unlike dipyridamole, adenosine had been shown to treat PSVT by interrupting electrical conduction in the heart. (TX-36; TX-45.) 22

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 26 of 115

DFF93. The half life of dipyridamole is 30 to 40 minutes. (Binkley, Tr. 133:2-12, 1381:18-22, 1400:6-1402:14; TX 1173 at 167; TX 1177 at 1080.) RESPONSE: Dr. Binkley gave conflicting testimony on the half-life of dipyridamole, stating it was either 30 to 40 minutes (Binkley 1380:20-1381:7) or 40 to 80 minutes (Binkley 1472:16-1474:23). Moreover, Dr. Binkley attempted at trial to raise a previously undisclosed theory concerning the so-called "functional half-life" of dipyridamole, which Dr. Binkley testified was between 30 and 40 minutes and corresponded to the half-life of the "physiological effect of the drug." (Binkley 1380:20-1381:22.) This new theory was contradicted, however, by Dr. Binkley's deposition testimony that "[t]he half-life of dipyridamole is 40 to 80 minutes and, therefore, you could have greatly prolonged effects of both the dipyridamole and the adenosine." (Binkley 1474:8-23.) (See, e.g., PFF179.) On redirect, Dr. Binkley asserted that his deposition testimony was not referring to the "functional" half-life of dipyridamole, but that assertion is itself inconsistent with the entire thrust of his deposition testimony, which was that the 40 to 80-minute half-life of dipyridamole could lead to "greatly prolonged effects." (Binkley 1507:81-2, 1474:8-23.) Thus, the following counterfinding is proposed: PCF93. The half-life of dipyridamole can be as long as 40 to 80 minutes.

(Binkley 1472:16-1474:23.) DFF94. The half life of adenosine is about 10 to 30 seconds. (Binkley, Tr. 107:1121; Klabunde, Tr. 502:17-22.) RESPONSE: This proposed finding is not supported by either of the citations. Both Dr. Binkley and Dr. Klabunde testified, at the cited portions of the transcript, that the half life of adenosine was ten seconds or less. Thus, the following finding is proposed: PCF94. The half life of adenosine is ten seconds or less. (See TX-101 at 21

(abstract); Binkley 107:11-21; Klabunde 502:17-22.)

23

Case 1:05-cv-00336-SLR C.

Document 157

Filed 06/19/2007

Page 27 of 115

Counterfindings Regarding Obviousness in View of the Prior Art 1. Counterfindings Regarding the Scope and Content of the Prior Art

DFF96. Claims 1, 3, 7, and 9 of the `296 patent are invalid as obvious in view of each of the following three references in combination with the general knowledge of a person of ordinary skill in the art in 1985: (1) A. Sollevi et al., Cardiovascular effects of adenosine during controlled hypotension in cerebral artery aneurysm surgery, Anesthesiology (Circulation II) 59(3): A9 (Sept. 1983) ("Sollevi I"); (2) A. Sollevi et al., Cardiovascular effects of adenosine in man, Acta Physiol. Scan. 120(2): 11A (Feb. 1984) ("Sollevi II"); and (3) A.F. Fukunaga et al., ATP-induced hypotensive anesthesia during surgery, Anesth. & Anesthesiology, 57(3): A65 (1982) ("Fukunaga Abstract"). (Binkley, Tr. 119:23-121:2; TX 275; TX 1170; TX 37; TX 42.) PCF96. Sicor asserts that its three primary references:

(1) A. Sollevi et al., Cardiovascular effects of adenosine during controlled hypotension in cerebral aneurysm surgery, 59(3) Anesthesiology (Circulation II) A9 (1983) ("Sollevi I"); (2) A. Sollevi et al., Cardiovascular effects of adenosine in man, 120(2) Acta Physiol. Scan. 11A (1984) ("Sollevi II"); and (3) A.F. Fukunaga et al., ATP-induced hypotensive anesthesia during surgery, 57(3) Anesth. & Anesthesiology, A65 (1982) ("Fukunaga Abstract") invalidate the asserted claims. None of these references, however, render the asserted claims obvious. (See Klabunde 515:3-10.) Indeed, all of these references were before the Examiner during the examination of the `296 patent and are listed on the face of the `296 patent. (TX-37; TX-42; TX-1170; TX-275.) DFF102. Following administration of adenosine, Sollevi I reported a mean reduction in mean arterial blood pressure ("MABP") of 43%. (Binkley, Tr. 127:10-128:15, 129:17-19; Sollevi, Tr. 483:11-16; TX 1170 at A9; DTX 3027.) Sollevi I teaches a person of ordinary skill in the art in 1985 that the significant decrease in MABP shows that the administration of adenosine resulted in selective arterial vasodilation, since arteries reduce pressure by dilating. (Binkley, Tr. 128:3-12.) RESPONSE: This finding is contrary to the evidence to the extent it implies that the adenosine alone was responsible for the drop in blood pressure reported by Dr. Sollevi, 24

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 28 of 115

whereas the evidence clearly shows that in Sollevi I a dipyridamole pretreatment was used before the adenosine was administered. (See, e.g., Klabunde 527:12-20; Sollevi 438:17-439:6; TX-1170.) In addition, determining whether selective arterial vasodilation has occurred requires measurement of more hemodynamic parameters than MABP alone. Thus, the following counterfinding is proposed: PCF102. Following administration of adenosine after dipyridamole

pretreatment, Sollevi I reported a mean reduction in mean arterial blood pressure ("MABP") of 43%. (Sollevi 442:15-23; TX-1170 at A9.) Vasodilation in response to adenosine is determined by systemic vascular resistance changes calculated from the cardiac output and mean arterial blood pressure. (Klabunde 546:6-16) Determining whether selective arterial vasodilation occurred would require measurement of changes in venous function, such as central venous pressure or right atrial pressure. (Id.) Dr. Sollevi took such measurements in his studies and concluded there was selective arterial vasodilation based on clear-cut reduction in vascular resistance associated with essentially unaffected filling pressures and "without exception" an increase in cardiac output. (Sollevi 433:23-434:11.) DFF103. Following administration of adenosine, Sollevi I reported a relatively large mean decrease in systemic vascular resistance ("SVR") of 61%. (Binkley, Tr. 128:16-129:7, 129:20-22; TX 1170 at A9; DTX 3028.) Sollevi I teaches a person of ordinary skill in the art in 1985 that the significant drop in SVR suggests that the administration of adenosine resulted in selective arterial vasodilation, since arteries reduce resistance by dilating. (Binkley, Tr. 128:24129:7.) RESPONSE: This finding is contrary to the evidence to the extent it implies that the adenosine alone was responsible for the drop in blood pressure reported by Dr. Sollevi, whereas the evidence clearly shows that in Sollevi I a dipyridamole pretreatment was used before the adenosine was administered. (See, e.g., Klabunde 527:12-20; Sollevi 438:17-439:6; TX-1170.) In addition, determining whether selective arterial vasodilation

25

Case 1:05-cv-00336-SLR

Document 157

Filed 06/19/2007

Page 29 of 115

has occurred requires measurement of more hemodynamic parameters than SVR alone. Thus, the following counterfinding is proposed: PCF103. Following administration of adenosine following dipyridamole

pretreatment, Sollevi I reported a mean decrease in systemic vascular resistance ("SVR") of 61%. (TX-1170 at A9.) Vasodilation in response to adenosine is determined by systemic vascular resistance changes calculated from the cardiac output and mean arterial blood pressure. (Klabunde 545:6-16.) Determining whether selective arterial vasodilation occurred would require measurement of changes in venous function, such as central venous pressure or right atrial pressure. (Id.) Dr. Sollevi took such measurements in his studies concluded there was selective arterial vasodilation based on clear-cut reduction in vascular resistance associated with essentially unaffected filling pressures and "without exception" an increase in cardiac output. (Sollevi 433:23-434:11.) (See also PFF85, 90, 92, and 190191.) DFF104. Following administration of adenosine, Sollevi I reported a large increase in cardiac output of 43%. (Binkley, Tr. 129:8-16; TX 1170 at A9; DTX 3029.) Sollevi I teaches a person of ordinary skill in the art in 1985 that the large increase in CO shows that the administration of adenosine resulted in selective arterial vasodilation, since the increase in CO indicates that there was no venodilation. (Binkley, Tr. 130:10-22.) RESPONSE: This finding is contrary to the evidence to the extent it implies that the adenosine alone was responsible for the drop in blood pressure reported by Dr. Sollevi, whereas the evidence clearly shows that in Sollevi I a dipyridamole pretreatment was used before the adenosine was administered. (See, e.g., Klabunde 527:12-20; Sollevi 438:17-439:6; TX-1170.) In addition, while the large increase in cardiac output (CO) was an important factor for demonstrating selective arterial vasodilation. Dr. Sollevi's conclusion was based on additional hemodynamic parameters. Thus, the following counterfinding is proposed:

26

Case 1:05-cv-00336-SLR PCF104.

Document 157

Filed 06/19/2007

Page 30 of 115

Following administration of adenosine following dipyridamole

pretreatment, Sollevi I reported a large increase in cardiac output of 44%. (TX-1170 at A9.) Determining whether selective arterial vasodilation occurred required measurement of changes in venous function, such as central venous pressure or right atrial pressure. (Klabunde 545:6-16.) Dr. Sollevi took such measurements in his studies and concluded there was selective arterial vasodilation based on clear-cut reduction in vascular resistance associated with essentially unaffected filling pressures and "without exception" an increase in cardiac output. (Sollevi 433:23-434:11.) (See also PFF85, 90, 92, and 190-191.) DFF105. Based on the disclosed changes in MABP, SVR, and CO, Sollevi I would teach a person of ordinary skill in the art at the relevant time that the intravenous administration of 140 µg/kg/min of adenosine would selectively dilate the arteries of a human patient without inducing significant venous dilation. (Binkley, Tr. 128:3-10, 130:10-22, 146:10-21; DTX 3030.) As described supra in paragraphs 56-57, a decrease in SVR coupled with a decrease in MABP and an increase in cardiac output a is a strong indication that dilation of arteries occurred. (Binkley, Tr. 94:17-95:7.) An increase in cardiac output would also indicate that little or no venous dilation occurred. (Binkley, Tr. 94:22-95:13.) RESPONSE: This finding is contrary to the evidence to the extent it implies that the adenosine alone was responsible for the drop in blood pressure reported by Dr. Sollevi, whereas the evidence clearly shows that in Sollevi I a dipyridamole pretreatment was used before the adenosine was administered. (See, e.g., Klabunde 527:12-20; Sollevi 438:17-439:6; TX-1170.) In addition, while a decrease in SVR coupled with a decrease in MABP and a large increase in cardiac output (CO) were important factors for demonstrating selective arterial vasodilation, Dr. Sollevi's conclusion was based on additional hemodynamic parameters. Thus, the following counterfinding is proposed: PCF105. Based on the disclosed changes in MABP, SVR, and CO, along with

unaffected filling pressures, Sollevi I would teach a person of ordinary skill in the art at the relevant time that the intravenous administration of 140 µg/kg/min of adenosine following a dipyridamole pretreatment would selectively dilate the arteries of a human patient without inducing significant venous dila