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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

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

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Civil Action No. 05-337 SLR

DEFENDANTS SICOR INC. AND SICOR PHARMACEUTICALS INC.'S POST TRIAL BRIEF Josy W. Ingersoll (No. 1088) John W. Shaw (No. 3362) Karen E. Keller (No. 4489) YOUNG CONAWAY STARGATT & TAYLOR, LLP The Brandywine Building 1000 West Street, 17th Floor Wilmington, DE 19801 (302) 571-6600 [email protected] Of Counsel: David M. Hashmall, P.C. Annemarie Hassett GOODWIN PROCTER LLP 599 Lexington Avenue New York, NY 10022 (212) 813-8800 Attorneys for Defendants SICOR INC. and SICOR PHARMACEUTICALS, INC. Dated: May 9, 2007

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TABLE OF CONTENTS Page I. II. INTRODUCTION .......................................................................................................... 1 THE `877 PATENT ........................................................................................................ 2 A. Priority Dates ...................................................................................................... 2 B. The Asserted Claims............................................................................................ 3 ARGUMENT.................................................................................................................. 4 A. The Asserted Claims Are Invalid As Obvious Under 35 U.S.C. § 103 ................. 4 1. The Law Of Obviousness......................................................................... 4 2. Level Of Ordinary Skill In The Art .......................................................... 7 3. Scope And Content Of The Prior Art ....................................................... 7 a. Pharmacologic Stress MPI Was Known In The Art ...................... 9 b. The Mechanism Of Action Of Dipyridamole Was Known In The Art .................................................................................. 11 c. Rates Of Continuous Intravenous Infusion Of Adenosine, Sufficient To Cause Vasodilation Without Serious Side Effects Were Known In The Art ................................................. 13 d. The Use Of Adenosine For MPI Was Disclosed In The Art ........ 18 4. Reason To Make The Claimed Combination .......................................... 19 5. Expectation Of Success.......................................................................... 22 6. Differences Between The Claimed Invention Of The `877 Patent And The Prior Art .................................................................................. 24 7. The Combination Of Either Gould 1978 Or Albro With Sollevi 1986 Renders The Asserted Claims Obvious.......................................... 25 8. The Combination Of Either Gould 1978 Or Albro With Biaggioni 1986 Renders The Asserted Claims Obvious.......................................... 27 9. Either Gould 1978 Or Albro In Light of The Knowledge In Art Concerning Adenosine Infusion Renders The Asserted Claims Obvious ................................................................................................. 28 10. No Secondary Factors Support Non-Obviousness .................................. 29 B. The Asserted Claims Are Invalid As Anticipated Under 35 U.S.C. § 102 .......... 34 1. The Law Of Anticipation ....................................................................... 34 2. The Asserted Claims Are Invalid In Light Of The `296 Patent ............... 35 a. The Asserted Claims Are Anticipated By The `296 Patent.......... 35 b. The Asserted Claims Are Obvious In Light Of The `296 Patent ......................................................................................... 36 3. Claims 23(17) And 43 Are Anticipated And/Or Rendered Obvious By The Karolinska Request.................................................................... 36 C. Plaintiffs Address The Wrong Questions And/Or Apply The Wrong Standards........................................................................................................... 37 D. Evidentiary Issues ............................................................................................. 40

III.

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IV.

CONCLUSION............................................................................................................. 41

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TABLE OF AUTHORITIES Page CASES Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286 (Fed. Cir. 2006) .................................................................................... 5-6, 19 Amazon.com, Inc. v. Barnesandnoble.com, 239 F.3d 1343 (Fed. Cir. 2001) ........................................................................................... 38 Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313 (Fed. Cir. 2003) ...................................................................................... 34-35 Atofina v. Great Lakes Chemical Corp., 441 F.3d 991 (Fed. Cir. 2006)........................................................................................ 35-36 Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001) ........................................................................................... 34 Brown & Williamson Tobacco Corp. v. Philip Morris Inc., 229 F.3d 1120 (Fed. Cir. 2000) .......................................................................................... 6-7 Dystar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006) .................................................................................... 5-6, 19 Forest Labs., Inc. v Ivax Pharma, Inc., 237 F.R.D. 106 (D. Del. 2006)............................................................................................ 41 Graham v. John Deere Co., 383 U.S. 1 (1966) ................................................................................................................. 5 In re Bigio, 381 F.3d 1320 (Fed. Cir. 2004) ......................................................................................... 7, 9 In re Huang, 100 F.3d 135 (Fed. Cir. 1996)............................................................................................. 38 In re O'Farrell, 853 F.2d 894 (Fed. Cir. 1988)............................................................................................... 6 In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ....................................................................................... 7, 37 Kridl v. McCormick, 105 F.3d 1446 (Fed. Cir. 1997) ........................................................................................... 18

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KSR Int'l Co. v. Teleflex Inc., 550 U.S. --- (2007) ...................................................................................................... Passim Mahurkar v. C.R. Bard Inc., 79 F.3d 1572 (Fed. Cir. 1996)............................................................................................. 18 Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006) .................................................................................... Passim Newell Cos., Inc. v. Kenney Manuf. Co., 864 F.2d 757 (Fed. Cir. 1989)............................................................................................. 34 Novo Nordisk Pharma, Inc. v. Bio-Technology Gen. Corp., 424 F.3d 1347 (Fed. Cir. 2005) ........................................................................................... 34 Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299 (Fed. Cir. 2006) .................................................................................... Passim Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) .................................................................................... Passim Richardson-Vicks Inc. v. UpJohn Co., 122 F.3d 1476 (Fed. Cir. 1997) ............................................................................................. 6 Sibia Neurosciences, Inc., v. Cadmus Pharma. Corp., 225 F.3d 1349 (Fed. Cir. 2000) ........................................................................................... 37 STATUTES 35 U.S.C. § 102 ...............................................................................................................2, 19, 34 35 U.S.C. § 103 .................................................................................................................2, 4, 22

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I.

INTRODUCTION Where "a patent `simply rearranges old elements each performing the same function it

had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." KSR Int'l Co. v. Teleflex Inc., 550 U.S. --- (2007); slip op. at 13 (citation omitted). Here, very little of what was disclosed in the prior art even needed to be "rearranged" to arrive at the subject matter of the asserted claims of United States Patent No. 5,070,877 (the "`877 patent"). The `877 patent claims nothing more than substituting a direct-acting drug for an indirect-acting drug for the same purpose in the same procedure. What could be more obvious than eliminating the middleman ­ accomplishing directly the same result that was already being achieved indirectly? The `877 patent (TX 320) claims a method of diagnosing coronary artery disease using a pharmacologic stress agent rather than exercise stress in connection with myocardial perfusion imaging ("MPI"). Well before even the earliest priority date claimed by Plaintiffs1 in this case, MPI was known and used to diagnose coronary artery disease. The use of pharmacologic stress in place of exercise stress for MPI was also known and used prior to the earliest claimed priority date. The only difference between the asserted claims of the `877 patent and the prior art is the particular pharmacologic stress agent used. The prior art disclosed use of dipyridamole, which was known to act by blocking adenosine uptake, thereby increasing levels of naturally occurring (endogenous) adenosine. The `877 patent merely claims the direct infusion of adenosine for the same purpose. The prior art also disclosed safe, continuous infusion of adenosine to humans at doses sufficient to cause vasodilation. The `877 patent claims nothing more than the use of known,
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"Plaintiffs" as used herein refers to King Pharmaceuticals Research and Development, Inc., Astellas US LLC and Astellas Pharma US, Inc.

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safe doses of adenosine to accomplish directly what was already being done indirectly with dipyridamole infusions. Not only was it obvious to replace dipyridamole with known, safe doses of adenosine for MPI, but the named inventors on the `877 patent were not the only ones to describe doing so. A December 28, 1987 continuation-in-part patent application that led to United States Patent No. 5,731,296 (the "`296 patent") described the use of adenosine in place of dipyridamole for MPI. TX 275, col. 21, ll. 25-61. In short, the asserted claims of the `877 patent are neither novel nor non-obvious. Accordingly, they are not patentable and should be declared invalid under 35 U.S.C. §§ 102 and 103. II. THE `877 PATENT A. Priority Dates

The application that led to issuance of the `877 patent, Application Serial No. 231,117, was filed on August 11, 1988. TX 59; TX 320. A continuation-in-part application, number 330,156, was later filed on March 29, 1989. The `877 patent issued from application number 330,156 on December 10, 1991. TX 320. Although the original application that led to the `877 patent was not filed until August 1988, Plaintiffs assert an earlier priority date in an attempt to avoid certain prior art references. In support of their claim of earlier priority, Plaintiffs rely on a protocol entitled "Clinical Utility of Adenosine in Radionuclide Myocardial Imaging" ("the Protocol," TX 57) which appears to have been authored prior to September 15, 1987 (see TX 1194). Plaintiffs' own expert, Dr. Wackers, conceded that TX 57 does not reveal conception of a specific dose of adenosine for use with MPI. Tr. 1013:13-22; 1015:15-1016:1. Yet the asserted claims set forth a specific dose range. 2

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The Protocol describes three proposed studies under the heading "contemplated method of approach to the problem." TX 57 at 3. The first proposed study is a comparison of adenosine with exercise stress in 20 normal volunteers, aged 19 to 39 years. Id. The proposed dose of adenosine for that study in the normal volunteers involved initiating adenosine infusion at 0.01 mg/kg/min (10 mcg/kg/min) and doubling the dose at 2 minute intervals until one of three things occurred: (1) a maximum dose of .32 mg/kg/min (320 mcg/kg/min) was achieved; (2) the patient developed certain symptoms; or (3) mean arterial blood pressure fell more than 40-50 mmHg. TX 57 at 4. The second proposed study described in the Protocol is a comparison of intravenous adenosine with intravenous dipyridamole for MPI in 20 patients with documented coronary artery disease. TX 57 at 6. The portion of the Protocol concerning this study in patients neither specifies a proposed dosage range nor cross-references section 3.A.d. in which dosing of normal volunteers is described. Compare TX 57 at 6 with TX 57 at 3-5; Tr. 1015:4-7. Thus, Plaintiffs have not demonstrated their right to the earlier priority date, as explained in detail below. B. The Asserted Claims

The `877 patent describes and claims the use of adenosine, as well as various adenosine derivatives and analogues, as pharmacologic stress agents in connection with diagnostic procedures such as MPI. See, e.g., TX 320, col. 3, ll. 6-11. At trial, Plaintiffs asserted dependent claim 23, as read through claims 17 and 18, and independent claim 43 of the `877 patent. Claim 17 claims: A method of detecting the presence and assessing the severity of coronary artery disease in a human comprising the steps of: (a) administering by an intravenous route to said human about 20 mcg/kg/minute to about 200 mcg/kg/minute of an adenosine receptor agonist sufficient to provide coronary artery dilation (b) administering a radiopharmaceutical agent into said human; and

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(c) performing radiopharmaceutical myocardial perfusion imaging on said human in order to detect the presence and assess the severity of coronary artery disease. TX 320, col. 8, ll. 53-65. Dependent claim 18 claims "[t]he method of claim 17 wherein said adenosine receptor agonist is administered by intravenous infusion in a dosage of about 140 mcg/kg/minute." Id. at col. 8, ll. 66-68. Claim 23 claims "[t]he method of claim 17, 19 or 18, wherein said adenosine receptor agonist is adenosine." Id. at col. 9, ll. 34-35. Claim 43 claims: A method of detecting the presence and assessing the severity of coronary artery disease in a human comprising the steps of: (a) administering to said human by intravenous infusion about 20 mcg/kg/min to about 200 mcg/kg/min of adenosine in order to provide coronary artery dilation; (b) administering thallium-201 to said human; and (c) performing the scintigraphy on said human in order to detect the presence and assess the severity of coronary artery disease. TX 320, col. 10, l. 66 - col. 11, l. 9. III. ARGUMENT A. The Asserted Claims Are Invalid As Obvious Under 35 U.S.C. § 103 1. The Law Of Obviousness

A claimed invention is not patentable "if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which the subject matter pertains." 35 U.S.C. § 103(a); see also Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1306 (Fed. Cir. 2006). Obviousness is a legal conclusion, based on underlying factual findings. See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1164 (Fed. Cir. 2006).

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The factual inquiries underlying the legal determination of obviousness include (1) the level of ordinary skill in the art; (2) the scope and content of the prior art; (3) differences between the claimed invention and the prior art; and (4) any relevant secondary considerations. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966); see also Dystar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356, 1360 (Fed. Cir. 2006). The obviousness inquiry should also address question of whether there was "a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." KSR, slip op at 15. The Supreme Court recently clarified the appropriate standard for this inquiry, and expressly rejected a rigid application of the "teaching-suggestion-motivation" ("TSM") test that the Federal Circuit has previously employed. Id. The appropriate, flexible test for considering whether a combination of elements is obvious "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR, slip op at 14. This analysis "cannot be confined by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasis on the importance of published articles and the explicit content of issued patents." Id. at 15. Even before the Supreme Court handed down the decision in KSR, the Federal Circuit also sought to clarify that the "suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself." Dystar, 464 F.3d at 1361; see also Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1291 (Fed. Cir. 2006) ("We do not have a rigid test that requires an actual teaching to combine before

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concluding that one of ordinary skill in the art would know to combine the references."). The "suggestion, teaching or motivation to combine the relevant prior art teachings does not have to be found explicitly in the prior art . . . ." Alza, 464 F.3d at 1290 (emphasis in original). Moreover, the Federal Circuit noted that the suggestion test "not only permits, but requires, consideration of common knowledge and common sense." Dystar, 464 F.3d at 1367 (emphasis in original). A second subsidiary question necessary to the obviousness inquiry is whether a person of ordinary skill in the art would have had a reasonable expectation that the combination of references would succeed for its intended purpose. See Brown & Williamson Tobacco Corp. v. Philip Morris, Inc., 229 F.3d 1120, 1125 (Fed. Cir. 2000). The standard here is not "absolute predictability," but instead is whether a person of ordinary skill in the art would have a "reasonable expectation" of success. In re O'Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988). Indeed, the "case law is clear that obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). In considering obviousness, relevant secondary considerations must also be considered if they are present. Secondary considerations do not, however, control the obviousness determination. Pfizer, 480 F.3d at 1372; Richardson-Vicks Inc. v. UpJohn Co., 122 F.3d 1476, 1483 (Fed. Cir. 1997). Moreover, for secondary considerations to be relevant there must be a nexus between the secondary consideration and the claimed invention. See Ormco, 463 F.3d at 1311-12. Obviousness is determined from the point of view of a hypothetical person of ordinary skill in the art to which the patent pertains, who is presumed to have access to all prior art

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references in the field of the invention. See In re Rouffet, 149 F.3d 1350, 1357 (Fed. Cir. 1998). The person of ordinary skill in the art is also presumed to have ordinary creativity and common sense. KSR, slip op at 17. To establish obviousness, Sicor has the burden of proving any disputed underlying facts by clear and convincing evidence. See Brown & Williamson, 229 F.3d at 1124. The Court must then make the ultimate legal conclusion as to obviousness based on the evidence presented. Id.; see also Pfizer, 480 F.3d at 1359. 2. Level Of Ordinary Skill In The Art

There is no dispute about the relevant field of art of the `877 patent. The `877 patent concerns the use of vasodilators as pharmacological stress agents in connection with MPI. Tr. 644:12-17. The experts agree that the relevant fields of art include cardiology, nuclear cardiology, and nuclear medicine. Tr. 644:12-21; 898:12-14. There is also no real dispute as to the level of training of a person of ordinary skill in the art. Tr. 898:12-:899:1. The person of ordinary skill in the art at the time would have been a practicing physician who either was trained in cardiology, with additional training in nuclear cardiology, or was trained in nuclear medicine, with additional training in cardiology. Tr. 898:15-20; 646:4-14. 3. Scope And Content Of The Prior Art

As noted above, there is no disagreement that the relevant fields of art include cardiology, nuclear cardiology and nuclear medicine. Tr. 644:12-21; 898:12-14. Prior art may be drawn from any of these relevant fields or from other fields so long as the reference in another field is related to the problem that the inventor was trying to solve. See In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004) ("Two separate tests define the scope of analogous prior art: (1) whether the art is from the same field of endeavor, regardless of the problem addressed and, (2) if the reference 7

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is not within the field of the inventor's endeavor, whether the reference still is reasonably pertinent to the particular problem with which the inventor is involved.") In determining what is relevant prior art, it is improper to assume that "a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem." KSR, slip op. at 16. The references on which Sicor's expert Dr. Strauss relied in his analysis all either fall within the field of cardiology, nuclear cardiology and/or nuclear medicine, or are otherwise pertinent to the question of using a pharmacologic stress agent for MPI. In fact, Plaintiffs' expert Dr. Wackers testified that the 1986 article titled Cardiovascular Effects of Adenosine in Man; Possible Clinical Implications, by A. Sollevi ("Sollevi 1986," TX 1171) was "pertinent" (Tr. 927:11-15), and he did not dispute the relevance of any of the other references on which Dr. Strauss relied. There can be no reasonable dispute that the references at issue are either within the relevant art or "pertinent" to the problem at hand. Several of the references on which Dr. Strauss relied, such as the 1984 Sollevi reference, Controlled Hypotension with Adenosine in Cerebral Aneurysm Surgery ("Sollevi 1984," TX 112); the 1987 Owall reference, Clinical Experience with Adenosine for Controlled Hypotension during Cerebral Aneurysm Surgery ("Owall," TX 1169); and the 1987 Fuller reference, Circulatory and respiratory effects of infused adenosine in conscious man ("Fuller," TX 1208), were identified by the inventors in the references section of their own study Protocol (TX 57 at 9-10).2 Named inventor Dr. Hilleman testified that his

2

Notably for purposes of the obviousness analysis, several of the references cited by the inventors in the reference section of their Protocol (TX 57 at 9-10) were not cited during prosecution of the `877 patent. These include Albro et al., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilatation, ("Albro", TX 93); Gould et al., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilatation, ("Gould 1978", TX 38); Sollevi 1984 (TX 112); Fuller (TX 1208); and Owall (TX 1169).

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general practice was to cite articles that are relevant to the research being conducted. Tr. 2128:15-19; 2129:9-23. Accordingly, each of these references is "reasonably pertinent to the particular problem" that the inventors addressed. See In re Bigio, 381 F.3d at 1325. a. Pharmacologic Stress MPI Was Known In The Art

MPI is an imaging technique that provides images of the distribution of blood flow to the heart. Tr. 647:12-17. "Stress" is used with MPI because it creates a disparity in blood flow between healthy vessels, which are able to dilate, and stenosed or blocked vessels, which cannot dilate or expand to accommodate greater demand for blood. Tr. 648:10-649:2. Radioactive tracer is injected into the patient at stress and at rest to "image" the flow. Tr. 649:16-651:6; DTX 3068-70. Comparison of the rest and stress images will reveal disparity in tracer distribution if there is stenosis and therefore enables determination of the location and severity of stenosis. Id. A February 1978 article by K. Lance Gould, M.D., et al., ("Gould 1978") described MPI during pharmacologic coronary vasodilatation. TX 38; Tr. 662:2-663:5. As stated in the article's introduction, Gould 1978 described a "new technique utiliz[ing] myocardial imaging of thallium-201 during coronary vasodilatation induced with intravenously administered dipyridamole (Persantine®)." TX 38 at 279; see also Tr. 662:2-663:6. More specifically, Gould 1978 describes continuous intravenous infusion of dipyridamole to patients for a period of four minutes. TX 38 at 280; see also Tr. 663:10-20. Gould further describes injection of thallium201 after completion of the dipyridamole infusion, and the use of a gamma camera to obtain scintigraphic3 images. Id. at 280-81; see also Tr. 662:17-22. Gould 1978 also describes the expected increase in coronary blood flow caused by dipyridamole infusion. TX 38 at 284. Gould 1978 discusses an earlier study that reported
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Scintigraphy, which applies generally to the technique of obtaining images of radiotracer distribution, encompasses MPI, which applies only to imaging the myocardium. Tr. 652:22-653:5; 647:12-17.

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changes in coronary blood flow from dipyridamole infusion in twenty-eight patients. Id. The average increase in coronary flow was four times baseline control values. Id. However, there was a "wide standard deviation" because three of the twenty-eight patients showed an increase of less than three times baseline blood flow. Id. In short, Gould 1978 described the safe and effective continuous intravenous infusion of dipyridamole to patients, in order to cause vasodilatation and the resultant increased blood flow, for purposes of MPI. TX 38; Tr. 663:10-664:4. In light of Gould 1978, a person of ordinary skill in the art would understand that the technique of vasodilator stress works in human patients. Tr. 665:9-20. That person of ordinary skill in the art would also understand that one could cause a prolonged coronary vasodilation by continuous infusion of the vasodilator agent, and that the prolonged vasodilation was important to allow the tracer to clear while the arteries were dilated. Tr. 665:21-666:7. Gould 1978 also teaches that other vasodilators can be used in place of dipyridamole. Tr. 664:13-18; 686:1-6. Gould 1978 expressly states that "[a]ny other coronary vasodilator that was more potent than dipyridamole would further increase the sensitivity of imaging techniques for identifying coronary disease." TX 38 at 285. Gould 1978 notes that the potential for ischemia4 may also increase with a more potent vasodilator, but the reference also teaches that ischemia is inherent in coronary vasodilation, and that ischemia is less likely to develop with pharmacologic stress than with exercise stress. TX 38 at 285. For example, Gould 1978 states that "because myocardial oxygen demands are not increased as much by dipyridamole as by exercise, an imaging method using a coronary vasodilator will permit greater coronary dilatation and greater
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Ischemia is inadequate blood flow to the heart muscle. Tr. 688:19-21. As described in Gould 1978, because exercise stress increases oxygen demand more than pharmacologic stress does, using a coronary vasodilator is more likely to create the necessary increase in blood flow before ischemia develops than is exercise stress. TX 38 at 285.

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differences in regional myocardial blood flow before ischemia develops as compared with exercise stress." TX 38 at 285. Gould 1978 further teaches that "[f]or imaging purposes the major point is that coronary vasodilators provide greater differences in regional perfusion before ischemia develops as compared with exercise . . . ." TX 38 at 286. A second reference also published in 1978 further elucidates the efficacy of pharmacologic coronary vasodilatation for MPI. Tr. 666:14-667:7; TX 93. That reference, Albro (TX 93), "demonstrates that pharmacologic coronary vasodilatation is as effective as maximal treadmill exercise in creating myocardial perfusion abnormalities detectable with thallium-201 imaging in man." TX 93 at 751. Like Gould 1978, Albro describes continuous intravenous infusion of dipyridamole as pharmacologic stress agent for use with MPI. TX 93 at 752; Tr. 667:15-22. As in Gould 1978, the radio tracer used in Albro is thallium-201. Albro also describes the mechanism by which dipyridamole causes vasodilation ­ through adenosine. See TX 93 at 758-59. b. The Mechanism Of Action Of Dipyridamole Was Known In The Art

Albro expressly sets forth the relationship between dipyridamole infusion and vasodilation caused by adenosine. See TX 93 at 758-59. Under the heading "mechanism, safety and optimal dose of dipyridamole infusion," Albro states: Dipyridamole may induce coronary vasodilatation by several mechanisms. Adenosine, a product of adenine nucleotide utilization in myocardial tissue, has vasodilator activity and has been proposed as a coronary vasoregulator. Dipyridamole prevents inactivation of adenosine by adenosine deaminase in the red blood cells and lung and myocardial tissues, either by inhibiting adenosine deaminase or by preventing the uptake of adenosine into these tissues. Dipyridamole also has a direct effect of sensitizing coronary vascular tissue to the vasodilating effects of a given concentration of adenosine.

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TX 93 at 758-59 (internal citations omitted). As Dr. Strauss testified, a person of ordinary skill in the art would understand from this portion of Albro that "if dipyridamole is selected as the vasodilator, that the effector drug, if you will, is adenosine . . . ." Tr. 670:12-18. Other references in the prior art likewise show that dipyridamole was known to act primarily, if not exclusively, through adenosine. For example, the 1985 edition of Goodman & Gilman included the following statement concerning dipyridamole: The actions of dipyridamole seem to be linked, at least in part, to the metabolism and transport of adenosine and adenine nucleotides; in particular, dipyridamole inhibits the uptake of adenosine by erythrocytes and other cells. Adenosine, which is released from the hypoxic myocardium, is a coronary vasodilator and appears to be an important signal for the autoregulation of coronary blood flow. TX 39 at 822. Goodman & Gilman is a pharmacology textbook that is commonly used by physicians today, and was commonly used by physicians in the mid-1980s. Tr. 678:24-679:12. Based on this portion of Goodman & Gilman, a person of skill in the art would understand that when dipyridamole is infused, it is acting through adenosine to cause vasodilation. Tr. 680:8-22. In addition, a March 1987 article Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole, by Conradson et al. ("Conradson") states that "[d]ipyridamole inhibits the cellular update of adenosine which results in a potentiation of the cardiovascular actions of adenosine." TX 220 at 387 (internal citations omitted). Conradson goes on to state that: Dipyridamole itself caused cardiovascular effects similar to those recorded after adenosine. Our observations therefore support the hypothesis that the cardiovascular effects of dipyridamole are mediated (at least in part) by elevated endogenous plasma adenosine. Id. at 390 (citation omitted). Accordingly, a person of skill in the art would understand from Conradson that dipyridamole acts through adenosine. Tr. 683:8-13.

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The `296 patent sums up the state of knowledge in the art in 1987 concerning dipyridamole's mechanism of action. TX 275; Tr. 684:12-685:6. According to the `296 patent, "[m]ost data concerning the mechanism of action of dipyridamole's vasodilatory effect in fact support the view that it is solely due to adenosine vasodilation." TX 275, col. 21, ll. 49-51 (emphasis added).5 c. Rates Of Continuous Intravenous Infusion Of Adenosine, Sufficient To Cause Vasodilation Without Serious Side Effects Were Known In The Art

By the middle of 1987, a number of investigators had reported continuous infusion of adenosine to human subjects and/or patients at different rates for different purposes. See, e.g., TX 48; 112; 220; 1171 and 1208. These references created a body of knowledge in the art that showed both the safety and the effect of adenosine infusion at the reported rates. Tr. 738:16739:2; 747:18-748:13. Certain specific references, and the body of knowledge as a whole, teach a person of ordinary skill in the art a range of adenosine infusion that (1) is sufficient to cause vasodilation; (2) is not sufficient to cause the undesirable (for purposes of MPI) effect of hypotension; and (3) is unlikely to result in serious side effects such as AV block. 6 Tr. 747:10749:20. One reference, Sollevi 1984, describes continuous intravenous infusion of adenosine for the purpose of inducing controlled hypotension in anesthetized patients undergoing cerebral aneurysm surgery. TX 112; Tr. 692:1-23. The article discusses doses of adenosine infusion necessary to induce controlled hypotension both with and without pretreatment with
5

In addition, in the IND seeking approval to use adenosine for MPI in humans, the Patient's Informed Consent to be used by Dr. Mario Verani's group at Baylor states that "[a]lthough the drug dipyridamole is used to dilate the coronary vessels, the ultimate substance that effectively causes the vasodilation is called adenosine, which is made available in higher amounts by dipyridamole administration." TX 52 at AST0009469. AV block is a slowing or failure of the electrical conductance signal to the heart which can occur in varying degrees. Tr. 696:12-697:4.

6

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dipyridamole.7 TX 112 at 403. According to Sollevi 1984, doses of 200 to 300 mcg/kg/min induced controlled hypotension in those patients who were not pretreated with dipyridamole. TX 112 at 403 n. ++. The person of skill in the art would therefore have understood from Sollevi 1984 that doses of adenosine infusion above 200 mcg/kg/min would likely achieve controlled hypotension. Tr. 695:6-696:1. Accordingly, a person of skill in the art would understand 200 mcg/kg/min to be an upper boundary of any dosage range likely to be useful for MPI. Tr. 699:113.8 Sollevi 1984 also describes several advantages adenosine. TX 112. These desirable properties include "rapidity of onset and termination, stability of action, [and] maintenance of cardiac output . . . ." TX 112 at 404. A person of skill in the art would have understood from Sollevi 1984 that continuous intravenous infusion of adenosine would result in a stable state of coronary vasodilatation. Tr. 693:15-694:7; 695:6-696:1. Notably, even at the doses used to achieve controlled hypotension, Sollevi 1984 does not report any instances of AV block, a known effect of bolus injections of adenosine. Tr. 696:2697:11; 698:13-15; TX 112. Accordingly, based on Sollevi 1984, a person of skill in the art would have understood that continuous intravenous infusion of adenosine is relatively safe, even at doses exceeding 200 mcg/kg/min. Tr. 699:4-17. A 1986 reference also authored by Dr. A. Sollevi, Cardiovascular Effects of Adenosine In Man; Possible Clinical Implications, ("Sollevi 1986") provides a review of the then-known cardiovascular effects of adenosine. TX 1171; Tr. 700:8-18. Like Sollevi 1984, Sollevi 1986
7

Sollevi 1984 notes that pretreatment with the adenosine uptake inhibitor dipyridamole was used in the clinical study to reduce infusion rates of adenosine. TX 112 at 403. The upper boundary of about 200 mcg/kg/min for MPI, based on the doses likely to cause hypotension, is further supported by the Owall reference, TX 1169. Owall describes continuous intravenous infusion of adenosine at rates up to 530 mcg/kg/min, with a mean dose requirement of 210 mcg/kg/min, to induce hypotension in anesthetized patients. TX 1169 at 230, 232; Tr. 721:12-22; 723:3-7; 724:20-725:5.

8

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describes that a dose of 200-300 mcg/kg/min induced controlled hypotension in anesthetized patients. TX 1171 at 333; Tr. 701:4-9. Also like Sollevi 1984, Sollevi 1986 reports no incidence of AV block in connection with the infusion rates used to induce controlled hypotension. Tr. 702:2-6; TX 1171. Sollevi 1986 also describes the effects of continuous infusion of adenosine at lower doses. TX 1171. According to Sollevi 1986, intravenous infusion of adenosine at 80 mcg/kg/min results in a near doubling of coronary blood flow. TX 1171 at 335; Tr. 702:21703:14. In addition, adenosine infused at a rate of 30-50 mcg/kg/min induces a 100% increase in graft flow. TX 1171 at 335, Tr. 704:22-705:5.9 The summary chart at the end of Sollevi 1986 describes a "low dose" of 20-50 mcg/kg/min as inducing "preferential myocardial vasodilation." TX 1171 at 345. A person of ordinary skill in the art would have understood from Sollevi 1986 that there was a range of doses of adenosine from about 20 mcg/kg/min at the low end to about 200 mcg/kg/min at the high end that would cause vasodilation and the related increased blood flow, but would not result in hypotension. Tr. 708:10-709:12; 705:19-707:2; 747:10-748:13; 748:22749:20. Additional prior art references disclose safe, tolerable doses of continuous intravenous infusion of adenosine to conscious humans. Tr. 710:2-11. One such reference is a 1986 publication entitled Cardiovascular effects of adenosine infusion in man and their modulation by dipyridamole, by Biaggioni et al. ("Biaggioni 1986"). TX 48. Biaggioni 1986 describes continuous intravenous infusion of adenosine to seven conscious healthy volunteers at rates of
9

During Dr. Strauss's testimony concerning Sollevi 1986, Plaintiffs objected "to this whole line not being in the report." As discussed in more detail in section E, below, Dr. Strauss cited and relied on Sollevi 1986 in his initial expert report (TX 246), and his testimony at trial was both consistent with and within the scope of his previously expressed opinions.

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10, 20, 40, 60, 80, 100 and 140 mcg/kg/min for 15 minutes each. Tr. 711:1-14; 712:14-16; TX 48 at 2230. Five of the seven conscious subjects described in Biaggioni 1986 tolerated the 140 mcg/kg/min dose of adenosine, while the other two subjects tolerated the 100 mcg/kg/min dose. Tr. 712:14-713:1; TX 48 at 2231. The duration of infusion of each dose is significant because even the 15 minute duration of one of the doses is longer than would be necessary to perform MPI. Tr. 711:20-712:13. Rather than the few minutes that would be necessary to continue infusion of adenosine for MPI, the subjects studied in Biaggioni 1986 were infused with adenosine for a total of either 1-1/2 or 1-3/4 hours. Tr. 711:20-712:13; Tr. 717:2-15. Biaggioni 1986 also describes the side effects experienced by the conscious subjects at the highest tolerated infusion rates. According to Biaggioni 1986, those side effects, which included headache, subjective flushing in the head and neck, nervousness and an urge to breathe deeply, "disappeared immediately after discontinuation of the infusion." TX 48 at 2233; Tr. 715:4-8.10 According to Biaggioni 1986, the study shows "that adenosine administered by infusion over the range of 60 to 140 µg/kg/min to healthy conscious human subjects, lowers diastolic blood pressure but raises heart rate, systolic blood pressure and levels of plasma norepinephrine." TX 48 at 2234. The increase in systolic blood pressure coupled with the decrease in diastolic blood pressure reported in Biaggioni 1986 indicates that the subjects had a "very significant vasodilation response to the adenosine infusion." Tr. 718:4-719:2; TX 48. A person of ordinary skill in the art would understand from Biaggioni 1986 that adenosine could be

10

Biaggioni 1986 notes in the results section of the article that one of the seven subjects experienced a prolonged PR interval of 0.16 to 0.22 seconds, or first degree AV block. Tr. 715:12-18; TX 48 at 2231. First degree AV block is the first of three possible levels of AV block which, by itself, is not necessarily dangerous. Tr. 715:23-716:21.

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safely, continuously infused to conscious humans for extended periods of time at rates up to 140 mcg/kg/min and that the adenosine infusion would cause vasodilation. Tr. 718:4-719:18. Additional prior art references likewise describe the safe, continuous infusion of adenosine to conscious humans. Conradson, published in March 1987, describes stepwise increases of the dose of adenosine infusion from 20 mcg/kg/min to a maximum of 100 mcg/kg/min in eight normal volunteers. Tr. 726:7-727:5; TX 220 at 388. Each dose was administered for six minutes. Tr. 727:6-15. As reported in Conradson, all eight subjects tolerated 70 mcg/kg/min; six of eight tolerated 90 mcg/kg/min; and three of the eight tolerated 100 mcg/kg/min. TX 220 at 388. Similar to Biaggioni 1986, various side effects were reported, and such side effects "completely vanished within 2 min after stopping the adenosine infusion." TX 220 at 389; Tr. 728:15-729:3. Fuller, published in September 1987, also describes continuous intravenous infusion of adenosine to conscious humans. TX 1208; Tr. 729:13-18. The infusion rates in Fuller begin at 12 mcg/kg/min and increase to 25, 50, and 100 at 6 to 7 minute intervals for each dose. TX 1208 at 310; Tr. 729:19-730:4. Two of the six subjects described in Fuller tolerated 200 mcg/kg/min for 1 and 2 minutes, respectively. TX 1208 at 311; Tr. 730:16-22. Yet another reference from 1987, Cardiovascular and respiratory effects of adenosine in conscious man ("Biaggioni 1987") also describes continuous intravenous infusion of adenosine to conscious humans. TX 226; Tr. 731:17-732:2. Biaggioni 1987 describes, inter alia, increasing doses of adenosine from 80 to 180 mcg/kg/min with each dose administered for 15 minutes. TX 226 at 780; Tr. 732:20-733:6. All eight subjects in Biaggioni 1987 tolerated a dose of 140 mcg/kg/min. TX 226 at 781-82; Tr. 733:17-22. Biaggioni 1987 shows that adenosine can be safely, continuously infused for extended periods of time, that doses up to 140 mcg/kg/min

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are tolerable in conscious humans, and that adenosine has a predictable vasodilatory action. Tr. 735:4-12. As Dr. Strauss summarized in his testimony and in demonstrative exhibits 3091 and 3112, the prior art references showed a range of adenosine infusions rates that had been safely used in humans. Tr. 738:16-739:22; DTX 3091; DTX 3112. That range substantially overlapped with and provided the outer limits for the range of 20 to 200 mcg/kg/min that is claimed in claims 23(17) and 43 of the `877 patent. Tr. 739:2-740:18; 748:22-750:22. The prior art also expressly describes the continuous intravenous infusion of 140 mcg/kg/min of adenosine to conscious humans. Tr. 748:2-13; TX 48; TX 226. d. The Use Of Adenosine For MPI Was Disclosed In The Art

Plaintiffs argue that they are entitled to a priority date of no later than September 1987 based on "conception" by at least that date. Plaintiffs have the burden offering evidence showing conception of the claimed invention prior to the August 11, 1988 filing date of the `877 patent. See Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1576-77 (Fed. Cir. 1996). Plaintiffs have not established "conception" of the subject matter of the asserted claims until at least March of 1988. "Conception is the formation `in the mind of the inventor of a definite and permanent idea of the complete and operative invention, as it is therefore to be applied in practice.'" Kridl v. McCormick, 105 F.3d 1446, 1449 (Fed. Cir. 1997) (citation omitted). "Conception must include every feature or limitation of the claimed invention." Id. Dr. Wackers conceded that the evidence of "conception" on which Plaintiffs rely, the Protocol (TX 57), does not show conception of a specific dose of adenosine for use with MPI. Tr. 1013:13-22; 1015:15-1016:1. Accordingly, Plaintiffs cannot establish an earlier conception date based on the Protocol. Example XIII of the `296 patent was added in a continuation-in-part patent application filed on December 27, 1987. Statement of Admitted Facts, ¶ 17. December 27, 1987 is prior to 18

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the filing date of the `877 patent, and prior to any date by which Plaintiffs' can establish conception of the claimed subject matter. Example XIII is therefore prior art to the `877 patent pursuant to 35 U.S.C. § 102(e). See 35 U.S.C. § 102(e). Example XIII of the `296 patent discloses "adenosine in the diagnosis of coronary heart disease by radionucleide (sic) scintigraphy." TX 275, col. 21, ll. 25-61. More specifically, Example XIII begins by describing the use of dipyridamole in connection with MPI using thallium 201. Id. Example XIII further explains the relationship of dipyridamole's action with adenosine's vasodilatory properties, and teaches that adenosine can be used in place of dipyridamole as a pharmacologic stress agent for MPI. Id. Example XIII also teaches a dosage range of 10 to 150 mcg/kg/min of adenosine for MPI. Tr. 750:12-22; TX 275, col. 21, ll. 59-61. The use of adenosine as a pharmacologic stress agent with MPI is also taught in a proposal that was submitted to the Karolinska Institute in Sweden in or around February of 1988 (the "Karolinska Request"). TX 1193 at SIC010940. Like example XIII of the `296 patent, the Karolinska Request discloses that adenosine could be used to replace dipyridamole as the pharmacologic stress agent for MPI. TX 1193 at SIC010943-44; Tr. 754:9-13. The dose described in the Karolinska Request is 60 mcg/kg/min. TX 1193 at SIC010944; Tr. 755:6-14. 4. Reason To Make The Claimed Combination

Even before the Supreme Court's recent decision in KSR, the case law was clear that a reason to combine could be found in any of the art as a whole, the knowledge of persons skilled in the art, or with the application of common sense. See Alza, 464 F.3d at 1290; Dystar, 464 F.3d at 1367. Now, after KSR, there can be no question that is the applicable standard. "[T]he analysis need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR, slip op. at 14. In other words, far from 19

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requiring that the art explicitly state "use adenosine for MPI," the obviousness inquiry must take into account not only the teachings in the art, but also the ordinary creativity and common sense of the person of skill in the art. Common sense alone provides a reason to use a direct acting agent in place of an indirect acting agent that causes the same effect. A person of ordinary skill in the art in 1987 would have known that dipyridamole acts indirectly, and that adenosine is the direct acting agent. See, e.g., TX 93; TX 275. In fact, the Albro reference, which describes the use of dipyridamole for MPI, spells out the relationship between infusion of dipyridamole and vasodilation by adenosine. TX 93 at 758; Tr. 668:18670:11. A person of ordinary skill in the art would have reason to substitute adenosine for dipyridamole in connection with MPI because that person would have known that the actual agent causing the vasodilation was adenosine. Tr. 670:12-671:12. Even if there were no such suggestion in the art, common sense alone would spark a person of ordinary skill to eliminate the middleman and directly infuse the drug that is actually having the desired effect in a known procedure. Here, however, much more than simple common sense provided a reason for a person of ordinary skill in the art to use adenosine in place of dipyridamole for MPI. The very first published account of pharmacologic stress for MPI in humans, Gould 1978, teaches that "[a]ny other coronary vasodilator that was more potent than dipyridamole would further increase the sensitivity of imaging techniques for identifying coronary disease." TX 38 at 285; Tr. 664:1518. Moreover, Gould 1978 discusses imaging methods using "a coronary vasodilator" generally, further suggesting that other vasodilators could be used instead of dipyridamole. TX 38 at 285. A person of skill in the art would also have had reason to replace dipyridamole with adenosine based on the knowledge of adenosine's shorter duration of action. Dipyridamole was

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known to have a relatively long duration of action. Tr. 673:17-674:11. Because of the long duration of dipyridamole, it is not possible to turn off negative side effect by simply turning off the infusion. Id.; see also Tr. 674:18-675:12. Instead, use of a reversal agent may be necessary. Tr. 673:17-674:11; 674:12-17; see also TX 38 at 283 (describing use of reversal agent aminophylline in two patients ­ five percent of the study population). Adenosine, in contrast, has a very short duration of action. Tr. 673:17-674:11. A person of ordinary skill in the art at the time would have known of adenosine's short duration, and would have expected the effects of adenosine to be far more easily controlled than dipyridamole. Tr. 672:17-673:2; 673:17-674:11; 675:13-21; 742:2-18; see also TX 1171 at 345 (adenosine's "effect is easy to control due to the extremely short plasma half life."). A person of ordinary skill in the art would have understood that adenosine could be continuously infused to maintain a stable effect for the duration of time needed to perform the MPI, but that the effects could then be turned off almost immediately upon termination of the infusion. Tr. 676:9-678:2; 692:12694:7. Indeed, it was generally known that a drug with a shorter duration of action would be preferable in terms of side effects. Tr. 2137:22-2139:7. A person of ordinary skill in the art would therefore have recognized at least two advantages of adenosine over dipyridamole: (1) it would allow almost immediate termination of negative side effects, and (2) it would eliminate the extended effect of the drug past its usefulness for the procedure. Tr. 673:17-674:11; 674:18-675:12; 676:9-677:8; 687:11-688:2. Knowledge in the art of these advantages provided more than adequate incentive to substitute adenosine for dipyridamole as a pharmacologic stress agent for MPI. Tr. 673:17-674:11; 687:11-688:2; 688:22-690:9.

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Whether one looks to the extensive knowledge in the art concerning adenosine or merely applies common sense to the teachings of Gould 1978 and Albro, it is clear that the single change from using adenosine indirectly, through dipyridamole infusion, to using adenosine directly was "the product not of innovation but of ordinary skill and common sense," and is obvious under § 103. See KSR, slip op. at 17. 5. Expectation Of Success

A person of ordinary would have reasonably expected adenosine to work as a coronary vasodilator for pharmacologic stress for MPI. As noted above, Gould 1978 expressly suggests the use of other, more potent coronary vasodilators. TX 38 at 285; Tr. 664:15-18. Such a strong suggestion that any other more potent coronary vasodilator is likely to work is more than adequate to suggest that the known coronary vasodilator adenosine will work as a pharmacologic stress agent for MPI. See Pfizer, 480 F.3d at 1365 (finding that a prior art patent "contained a strong suggestion that any and all pharmaceutically-acceptable anions would form non-toxic acid addition salts and would work for their intended purpose . . . ."). Moreover, a person of skill in the art at the time would have known that adenosine was already working as a pharmacologic stress agent for MPI through the mechanism of action of dipyridamole infusion in the method described in Gould 1978 and Albro. See TX 93 at 285; Tr. 670:12-671:21; 687:11-688:2. Certainly, then, a person of skill in the art employing common sense would have reasonably expected that the direct infusion of adenosine would work for the same purpose. Indeed, the named inventors expected adenosine to work for MPI precisely for this reason. See Tr., 1864:12-1865:6; Tr. 2125:15-1216:15. Accordingly, as was the case in Pfizer, the reasonable expectation of success is "amply reflected" in the inventors' testimony. See Pfizer, 480 F.3d at 1364. While these facts alone would make the expectation of success

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reasonable, there were even more teachings in the art to provide further guidance as to a range of adenosine doses that would likely succeed. It was widely known in the art that adenosine was a potent vasodilator. Tr. 705:19-706:4; see also Tr., 1858:5-12; Tr. 2131:4-8. Moreover, the prior art disclosed a range of doses of adenosine that would cause vasodilation without causing hypotension or other severe side effects. For example, based on Sollevi 1986, a person of skill in the art would have known that a dose of about 20-30 mcg/kg/min would cause vasodilation. Tr. 704:22-705:15; TX 1171 at 335, 345. Sollevi 1986 further teaches that a dose of 30-50 mcg/kg/min caused a doubling of graft flow, and a dose of 80 mcg/kg/min caused a near doubling of myocardial blood flow. Tr. 702:21-703:14; 704:22-705:16; TX 1171 at 335. A person of skill in the art would have expected, based on Sollevi 1986 alone, that doses beginning as low as 30 mcg/kg/min would likely be effective to cause vasodilation. Tr. 704:22-705:15; see also 739:2-22. The person of ordinary skill in the art would have also expected the upper range of useful doses for MPI to be around 200 mcg/kg/min because each of Sollevi 1984, Sollevi 1986 and Owall teach that continuous infusion of adenosine at levels greater than 200 mcg/kg/min result in hypotension. Tr. 695:6-16; 700:19-701:9; 723:3-7; TX 112, TX 1169, TX 1171. Moreover, a person of skill in the art would be aware that an effective dose would also have to be tolerable in most conscious humans. In light of the teachings of Biaggioni 1986, Conradson, Fuller and/or Biaggioni 1987, a person of skill in the art would have expected that most conscious patients would be able to tolerate doses somewhere between 90 and 140 mcg/kg/min. Tr. 719:3-18; 728:15-729:3; 731:1-12: 735:4-12; TX 220; TX 226; TX 1169; TX 1208. Accordingly, a person of ordinary skill in the art would have expected that doses in the range of 20-200 mcg/kg/min, and more likely doses above 50 mcg/kg/min but less than 200 mcg/kg/min would be very likely

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to work for MPI. Tr. 738:16-740:18. At a minimum, a person of ordinary skill would have had good reason to pursue the finite number of doses in the range between 20 mcg/kg/min and 200 mcg/kg/min and would have anticipated that a dose or doses of adenosine within this range would be effective to cause sufficient vasodilation for MPI. Under these circumstances, arriving at any particular dose or range of doses is nothing more than routine and does not render any claim patentable. See KSR, slip op. at 17 ("When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.") Even if the dose(s) were claimed to be optimal, which is not the case in the `877 patent, arriving at the dose would still have been obvious under the circumstances. Pfizer, 480 F.3d at 1368 ("discovery of an optimum value of a variable in a known process is usually obvious.") 6. Differences Between The Claimed Invention Of The `877 Patent And The Prior Art

There is a single difference between the Gould 1978 and Albro references and the claims of the `877 patent ­ substituting adenosine within the specified dosage ranges for dipyridamole. Everything else in the asserted claims of the `877 patent is disclosed in each of Gould 1978 and Albro. In particular, Gould 1978 and Albro disclose a method for detecting and assessing coronary artery disease. Tr. 663:10-20; 665:9-20; 667:15-22; TX 38, TX 93. Both disclose administering a pharmacologic stress agent by intravenous route, and administering enough of the stress agent to cause vasodilation. Tr. 663:10-20; 667:15-22; 668:18-669:1; TX 38; TX 93. Both disclose administering a radiopharmaceutical agent, specifically thallium-201, into the human. Tr. 667:15-22; TX 38; TX 93. Both references disclose performing MPI (scintigraphy)

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to detect and assess the severity of coronary artery disease. Tr. 664:23-665:2; 667:15-22; TX 38; TX 93. Finally, Gould 1978 suggests use of other coronary vasodilators, while Albro expressly sets forth the relationship between dipyridamole coronary vasodilation and adenosine. Tr. 664:13-18; 669:2-670:11; TX 38 at 285; TX 93 at 758-59. The only remaining question is whether it would have been obvious to a person of ordinary skill in the art at the time to use adenosine directly, at the doses stated in the asserted claims of the `877 patent, in place of indirect use of adenosine through dipyridamole. The clear and convincing answer is that it would have been obvious. 7. The Combination Of Either Gould 1978 Or Albro With Sollevi 1986 Renders The Asserted Claims Obvious

Each of Gould 1978 and Albro discloses every element of the claims of the asserted claims of the `877 patent except the specific use of adenosine at the claimed dosages ranges. Moreover, both Gould 1978 and Albro disclose the use of dipyridamole as a pharmacologic stress agent with MPI. A person of ordinary skill in the art at the time would have known that dipyridamole actually worked through increasing endogenous adenosine. Tr. 680:17-22; 682:17683:13; 684:12-685:6. The person of skill in the art would have known that dipyridamole had a much longer duration than adenosine, and that the effects of adenosine infusion could be more readily controlled than could the effects of dipyridamole infusion. Tr. 672:17-25; 673:17674:11. In particular, the person of ordinary skill in the art would have known that, because of its short duration, any side effects from adenosine infusion could be terminated almost immediately upon termination of the infusion. Tr. 715:4-8; 742:2-18; TX 48 at 2233; TX 220 at 389; see also TX 52 at AST0009482 ("Because adenosine's effects last only seconds, if side effects should occur, they would be very transient.") Accordingly, the person of skill in the art

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would have had ample reason to substitute the direct acting agent, adenosine, for the indirect acting agent, dipyridamole. Sollevi 1986 teaches a range of doses of adenosine that can be safely, continuously infused to humans. Even at the low end of the range disclosed in Sollevi 1986, 20-50 mcg/kg/min, Sollevi 1986 states that "preferential myocardial vasodilation" is achieved. TX 1171 at 345; see also TX 1171 at 335 (describing 100% graft flow increase at doses of 30-50 mcg/kg/min). Sollevi 1986 further teaches that a dose of 80 mcg/kg/min caused a near doubling of myocardial blood flow in one patient. Tr. 702:21-704:11; TX 1171 at 335. Sollevi also provides a high end of the likely effective range of doses for MPI by disclosing that doses of 200-300 mcg/kg/min resulted in controlled hypotension, an undesirable effect when performing MPI. Tr. 702:7-20; TX 1171 at 333. In light of the teachings of Sollevi 1986, a person of ordinary skill in the art would have expected continuous infusion of adenosine within the range of doses disclosed in Sollevi 1986 as sufficient to cause coronary vasodilation, but not sufficient to cause hypotension, to be "very likely to work for myocardial perfusion imaging as a vasodilator." Tr. 708:10-709:20. Specifically, in light of Sollevi 1986, a person of skill in the art would have expected a dose in the range of 20 to 200 mcg/kg/min to work for MPI. See id.; see also TX 1171. Moreover, in light of the teachings of Sollevi 1986, the specific dose of 140 mcg/kg/min as claimed in dependent claim 18 is one of the doses that would have been "very likely to work." Tr. 748:2-13. In short, adenosine was known to be the active agent causing vasodilation in dipyridamole stress MPI. In addition, a range of doses of direct infusion of adenosine sufficient to cause coronary vasodilation ­ a range that overlaps and includes the range claimed in the `877 patent ­ was also known in the art. Accordingly, the asserted claims are obvious in light of

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either Gould 1978 or Albro in combination with Sollevi 1986. See Ormco, 463 F.3d at 1311 ("Where a claimed range overlaps with a range disclosed in the prior art, there is a presumption of obviousness."); Medichem, 437 F.3d at 1167 (selecting a narrow range from within a somewhat broader range disclosed in a prior art reference is no less obvious than identifying a range that simply overlaps a disclosed range). Moreover, even if the claimed range of adenosine doses sufficient to cause vasodilation without causing hypotension were not disclosed in the art, the process of arriving at a useful value of a single variable is nothing more than routine and the claims are obvious on that basis as well. See KSR, slip op. at 17; Pfizer, 480 F.3d at 1368. 8. The Combination Of Either Gould 1978 Or Albro With Biaggioni 1986 Renders The Asserted Claims Obvious

For the same reasons described above, a person of ordinary skill in the art would have had reason to combine Biaggioni 1986 with either Gould 1978 or Albro to arrive at the subject matter of the asserted claims. Biaggioni 1986 discloses continuous intravenous infusion of adenosine to seven conscious subjects at increasing rates at successive 15 minutes intervals. TX 48 at 2230. Two of the seven subjects tolerated a dose of 100 mcg/kg/min, and the other five subjects tolerated a dose of 140 mcg/kg/min for 15 minutes. Tr. 711:1-713:1; TX 48 at 2231. Biaggioni 1986 states that the results show "that adenosine administered by infusion over a range of 60 to 140 µg/kg/min to healthy conscious human subjects, lowers diastolic blood pressure but raises heart rate, [and] systolic blood pressure . . . ." TX 48 at 2234. These results are indicative of significant vasodilation. Tr. 718:4-719:2. Moreover, the duration of infusion of adenosine in Biaggioni 1986 lasted much longer than is necessary to carry out an MPI procedure, indicating that the effect could