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

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE KING PHARMACEUTICALS RESEARCH AND DEVELOPMENT, INC., ASTELLAS US LLC, and ASTELLAS PHARMA US, INC. Plaintiffs, v. SICOR INC. and SICOR PHARMACEUTICALS, INC. Defendants. ) ) ) ) ) ) ) ) ) ) ) ) )

Civil Action No. 05-337 SLR

PLAINTIFFS' 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 E. Crawford #493 Patricia Smink Rogowski #2632 CONNOLLY BOVE LODGE & HUTZ LLP 1007 North Orange Street Wilmington, DE 19801 (302) 658-9141 [email protected] F. Dominic Cerrito Brian Poissant JONES DAY 222 E. 41st Street New York, NY 10017 (212) 326-3939 Attorneys for Plaintiff King Pharmaceuticals Research and Development, Inc.

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TABLE OF CONTENTS I. Page PLAINTIFF'S PROPOSED COUNTERFINDINGS TO DEFENDANTS' PROPOSED FINDINGS OF FACT ....................................................................................1 A. B. Counterfindings Regarding the `877 Patent.............................................................2 Counterfindings Regarding Obviousness ................................................................3 1. 2. 3. 4. 5. 6. C. 1. 2. 3. II. A. Counterfindings Regarding Level of Ordinary Skill In the Art...................3 Counterfindings Regarding Scope and Content of the Prior Art .................3 Counterfindings Regarding Use of Adenosine In Place of Dipyridamole .............................................................................................31 Counterfindings Regarding Expectations That Adenosine Would Work For MPI............................................................................................35 Counterfindings Regarding Differences Between the Asserted Claims and the Prior Art ............................................................................41 Counterfindings Regarding Secondary Indicia..........................................43 Counterfindings Regarding Whether the `296 Patent and the Karolinska Request Are Prior Art..............................................................66 Additional Counterfindings Regarding the `296 Patent.............................70 Additional Counterfindings Regarding the Karolinska Request ...............72

Counterfindings Regarding the `296 Patent and the Karolinska Request..............66

PLAINTIFFS' PROPOSED COUNTERCONCLUSIONS OF LAW ..............................72 Counterconclusions Regarding Obviousness.........................................................72 1. 2. 3. 4. 5. B. Counterconclusions Regarding the Law Of Obviousness .........................72 Counterconclusions Regarding the Scope of the Prior Art........................82 Counterconclusions Regarding the Combination of Either Gould 1978 Or Albro and Sollevi 1986................................................................83 Counterconclusions Regarding the Combination of Either Gould 1978 Or Albro and Biaggioni 1986 ...........................................................87 Counterconclusions Regarding Either Gould 1978 Or Albro In Light of "Knowledge In Art" ....................................................................88 Counterconclusions Regarding Legal Standard.........................................91 Counterconclusions Regarding the `296 Patent.........................................92 Counterconclusions Regarding the Karolinska Request............................95

Counterconclusions Regarding Anticipation .........................................................91 1. 2. 3.

III.

CONCLUSION..................................................................................................................97

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I.

PLAINTIFFS' PROPOSED 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. As an aid to the Court, 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. 145); "DB" refers to Defendants Sicor's Post-Trial Brief, as filed on May 9, 2007, (D.I. 143); "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. 146); "DFF" refers to Defendants' Proposed Findings of Fact, as filed on May 16, 2007, (D.I. 148); "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. 146); "DCL" refers to Defendants' Proposed Conclusions of Law, as filed on May 16, 2007, (D.I. 148); and "PCC" refers to Plaintiffs' Counterconclusions of Law corresponding to the DCL of the same number, as filed on June 19, 2007.

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A.

Counterfindings Regarding the `877 Patent

DFF16. The `877 patent relates to use of the adenosine, and adenosine derivatives and analogues, as pharmacologic stress agents in connection with MPI. (Strauss, Tr.642:17643:2; TX 320.) PCF16. The asserted claims of the `877 patent relate to methods for using

adenosine in connection with diagnostic coronary imaging. (TX-320.) DFF18. The `877 patent includes 47 claims. (TX 320.) At trial, Plaintiffs asserted three claims: claim 23 as read through claim 17 ("claim 23(17)"); claim 23 as read through claim 18 ("claim 23(18)"); and claim 43. (Tr. 600:7-13.) PCF18. The `877 patent includes 47 claims, some of which are multiply

dependent claims. (TX-320.) At trial, Plaintiffs asserted three claims: claim 23 as read through claim 17 ("claim 23(17)"); claim 23 as read through claim 18 ("claim 23(18)"); and claim 43. (Tr. 600:7-13.) DFF25. On its face, the priority date of the `877 patent is August 11, 1988. The priority date of the `877 patent is no earlier than March 14, 1988. (Wackers, Tr. 1010:12-23, 1012:2-5, 1013:1-12, 1015:23-1016:1.) RESPONSE: Reference to the term "priority date" in the proposed finding is inaccurate. The August 11, 1988 date is the effective filing date of the `877 patent under 35 U.S.C. § 120. Plaintiffs contend that Example XIII of the `296 patent is removed as prior art, as demonstrated by a prior possession of as much of the claimed invention as Example XIII happens to show. Plaintiffs have demonstrated prior possession as of a date no later than December 9, 1987, when the Creighton Protocols were filed with the FDA. (See TX-57; PFF83-84, 136-146; PB at 37-39.). Accordingly, the following counterfinding is proposed: PCF25. The effective filing date of the `877 patent under 35 U.S.C. § 120 is

August 11, 1988. (D.I. 133, Ex. 1, ¶ 8; TX-320.) Plaintiffs also proved that the inventors of the `877 patent were in possession of as much of the claimed invention as was disclosed by

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Example XIII of the `296 patent by at least December 9, 1987, and proceeded diligently thereafter to actually and constructively reduce that subject matter to practice. (See PFF137-146; PCL54-55.) DFF26. The named inventors had not conceived of using a dose of adenosine in the range of 20-200 mcg/kg/minute prior until at least March 14, 1988. (Wackers, Tr. 1010:12-15, 1013:1-12, 1015:23-1016:1; see also TX 57.) RESPONSE: The requested finding is irrelevant because Example XIII of the `296 patent does not describe a specific adenosine dose for conducting myocardial perfusion imaging in heart patients, describing only the case-by-case determination of such doses by titration. (See PCF25; PCL53-56; see also PCF230.) DFF27. The named inventors had not conceived of using a dose of 140 mcg/kg/minute until at least March 14, 1988. (Wackers, Tr. 1010:16-18, 1012:2-5, 1015:231016:1; see also TX 57.) PCF27. B. See Response to DFF26 and PCF25; see also PCF230.

Counterfindings Regarding Obviousness 1. Counterfindings Regarding Level of Ordinary Skill In the Art

DFF29. A person of ordinary skill in the art at the relevant 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. (Strauss, Tr. 646:4-14; Wackers, Tr. 898:15-20.) PCF29. Both parties' experts essentially agreed on the educational

qualifications of the person of ordinary skill in the art: a physician trained in cardiology with an additional 1-2 years training in nuclear cardiology, or a physician trained in nuclear medicine with at least 1 year of additional training in nuclear cardiology. (Strauss 646:4-14; Wackers 898:15-899:1, 899:7-11.) 2. Counterfindings Regarding Scope and Content of the Prior Art

DFF32. Dr. Wackers did not dispute the relevance of any of the other references on which Dr. Strauss relied in his obviousness analysis. (Wackers, Tr. 900:21-24.)

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RESPONSE: The cited testimony of Dr. Wackers does not indicate that he considered each of the references considered by Dr. Strauss "relevant." The cited testimony merely indicates that Dr. Wackers considered each reference raised by Dr. Strauss and included it in his report. (Wackers 900:21-24.) DFF33. Several of the references on which Dr. Strauss relied in his analysis, such as 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.) RESPONSE: DFF33 is irrelevant given that there is no allegation of inequitable conduct in this case. If proffered on the issue of obviousness, the finding improperly suggests that the inventors' thought processes can be used to establish obviousness. Thus, the following counterfinding is proposed: PCF33. The inventor's subjective consideration of the prior art is irrelevant to

an obviousness analysis, as "[p]atentability shall not be negatived by the manner in which the invention was made." 35 U.S.C. § 103(a). DFF34. Named inventor Dr. Hilleman testified that his general practice was to cite articles that are relevant to the research being conducted, and he assumed that he followed his general practice in connection with the Protocol. (Hilleman, Tr. 2128:15-19, 2129:9-23.) PCF34. See Response to DFF33 and PCF33.

DFF35. 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 (TX 320). 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) (compare TX 57 at 9-10 with TX 320).

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RESPONSE: See Response to DFF33. Regardless of whether or not all of the references cited in the Creighton Protocols (TX-57) were cited during the prosecution of the `877 patent, the references actually relied upon by Sicor were either submitted to the Patent and Trademark Office (PTO), cumulative with references submitted to the PTO, or generally addressed in the `877 patent application. Thus, the following counterfinding is proposed: PCF35. The references actually relied upon by Sicor were either submitted to

the PTO, cumulative with references submitted to the PTO, or generally addressed in the specification of the `877 patent. For instance, Biaggioni 1986 was cited to the PTO and is listed on the face of the `877 patent. (See TX-320.) Biaggioni 1986 is a normal volunteer study, like many of the references relied on here by Sicor, and was singled out by Sicor in its obviousness contentions. Moreover, WO87/01593, a PCT publication authored by Dr. Sollevi, is also listed on the face of the `877 patent. (See TX-320; TX-311.) This PCT publication (1) discloses the use of adenosine for surgical hypotension; (2) discloses the information from Dr. Sollevi's hypotension studies upon which Sicor here relies; and (3) corresponds to the `296 patent without Example XIII. (See TX-311; Strauss 837:7-16.) Moreover, dipyridamole imaging, the subject of the Gould 1978 (TX-38) and Albro (TX-93) references, was discussed in the specification of the `877 patent itself. (See TX-320 at col. 1, ll. 34-40, cols. 4-5 (Example I), col. 7, ll. 19-32.) The Examiner nonetheless found the claims allowable. If a patent challenger alleges invalidity based on prior art the PTO considered during prosecution of the patent, that challenger has the "added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job." Ultra-Tex Surfaces, Inc. v. Hill Bros. Chem. Co., 204 F.3d 1360, 1367 (Fed. Cir. 2000).

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DFF41. Gould 1978 describes the clinical feasability and methodology of performing MPI by continuous infusion of a pharmacological stress agent. (Strauss, Tr. 663:10664:4; TX 38 at 279.) PCF41. Gould 1978 does not describe the feasibility of human pharmacologic

MPI using anything other than intravenous dipyridamole as a pharmacologic stress agent. Gould 1978 stated that the use of more potent vasodilators could risk inducing ischemia or myocardial steal, depriving the heart of needed oxygen. (TX-38 at 285; Wackers 905:6-19; PFF46, 47.) In the preceding article in the same journal, Dr. Gould and his colleagues explained that an appropriate pharmacologic stress agent must be "selective for the coronary arteries," have "insignificant systemic effects," and have "an effect for at least 3 minutes until thallium-201 is removed from the systemic circulation." (TX-391 at 275.) Adenosine did not fit this profile, as it was associated with systemic hypotension, was known to cause AV block, was associated with ischemia, and had an extremely short duration of effect. (See, e.g., TX-36 at 1254; TX-217 at 430; Strauss 790:3-791:3; Wackers 909:9-910:17.) DFF44. Gould 1978 further describes injection of thallium-201 after completion of the dipyridamole infusion, and the use of a gamma camera to obtain scintigraphic images. (Strauss 662:17-22, 664:23-665:2; TX 38 at 280-81.) RESPONSE: The proposed finding incorrectly suggests that the tracer in the technique of Gould 1978 is infused immediately upon completion of the dipyridamole infusion. In fact, the tracer in that protocol is introduced no earlier than 4 minutes after completion of the dipyridamole infusion. (TX-38 at 280.) Because the effect of adenosine would be gone 4 minutes after completion of the infusion due to adenosine's exceptionally short half-life, it would not be possible to substitute adenosine for dipyridamole in the pharmacologic MPI protocol described in Gould 1978. (TX-45 at 418; Strauss 837:20-839:7.) Accordingly, the following counterfinding is proposed: 6

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PCF44.

Gould 1978 (TX-38) described injection of a thallium-201 tracer no

earlier than 4 minutes after completion of the dipyridamole infusion, and the use of a gamma camera to obtain scintigraphic images. (Strauss 662:17-22, 664:23-665:2; TX-38 at 280-81.) Because of adenosine's extremely short half-life, whereby its effects would no longer be present 4 or more minutes after infusion, adenosine could not be substituted for dipyridamole in the Gould 1978 protocol. (TX-45 at 418; Strauss 837:20-839:7.) DFF46. Gould 1978 discusses an earlier study that reported changes in coronary blood flow from dipyridamole infusion in 28 patients. According to Gould 1978, the average increase in coronary flow shown in the study was four times baseline control values. However, there was a "wide standard deviation" because three of the 28 patients showed an increase of less than three times baseline blood flow. (TX 38 at 284: see also Strauss, Tr. 663:10-20.) PCF46. Gould 1978 reported that dipyridamole had a "potent, selective" effect

on the coronary arteries, increasing coronary flow four hundred percent (400%) over baseline levels. (TX-38 at 279, 284; Wackers 924:3-6.) The diagnostic reliability of MPI images obtained with a 400% increase in blood flow was reported to compare favorably with the results of exercise stress tests. (See TX-38 at 279, 284.) It is irrelevant that three of the 28 patients showed an increase of less than three times baseline blood flow, except to suggest that coronary blood flow measurements should not be based on very small sample sizes, such as the single patient measured in Sollevi 1986. (See TX-1171 at 335; Wackers 923:20-23.) DFF47. Gould 1978 describes the safe and effective continuous intravenous infusion of a pharmacologic stress agent to patients, in order to cause vasodilatation and the resultant increased blood flow, for purposes of using MPI as a diagnostic tool. (Strauss, Tr. 663:10-20, 664:5-12, 665:21-666:7; TX 38 at 279.) PCF47. See PCF41, 46.

DFF50. Albro demonstrated that pharmacologic coronary vasodilatation is as effective as treadmill exercise in creating myocardial perfusion abnormalities detectable with thallium-201 imaging in humans. (Strauss, Tr. 667:15-22; TX 93 at 751.) Albro states:

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However, sensitivity and specificity in identifying significant coronary stenoses were identical for dipyridamole and exercise images. (TX 93 at 759.) PCF50. Albro taught that diagnostically-reliable MPI images could be

obtained after pharmacologic inducement of a 400% increase in coronary flow but does not describe the feasibility of human pharmacologic MPI using anything other than intravenous dipyridamole as a pharmacologic stress agent. (TX-93.) Albro nowhere taught, suggested, or even mentioned the possibility of direct administration of adenosine instead of dipyridamole. (TX-93; Wackers 907:18-908:18.) DFF51. Prior to 1987, the mechanism of dipyridamole was known in the art. (Wackers, Tr. 908:19-24.) PCF51. As reflected in the quotations reproduced in DFF53 and DFF56, it had

been reported in the literature that dipyridamole "may" induce coronary vasodilation by several different mechanisms. One proposed mechanism was prevention of inactivation of endogenous adenosine. DFF52. Albro describes the mechanism of dipyridamole as preventing the inactivation of adenosine by adenosine deaminase in the red blood cells and the lung and myocardial tissues, leading to an increase in endogenous adenosine. (Strauss, Tr. 669:10-670:1; TX 93 at 758-59.) PCF52. DFF53. See PCF51. Specifically, Albro states that:

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. (TX 93 at 758.)

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PCF53.

See PCF51.

DFF54. A person of ordinary skill in the art at the time would understand from this portion of Albro that "if dipyridamole is selected as the vasodilator, that the effector drug, if you will, is adenosine . . . ." (Strauss, Tr. 670:12-18.) PCF54. The "drug" used for human pharmacologic MPI in the prior art was

exogenously-administered dipyridamole, not exogenously-administered adenosine. No one considered adenosine as a realistic substitute for dipyridamole because adenosine was viewed as too dangerous. (See, e.g., TX-46; TX-47; Strauss 803:11-804:8, 805:23-806:8.) For example, Dr. Melvin Marcus, acknowledged by Sicor as an expert in the field, wrote in a well-regarded treatise in 1983 that intravenous administration of adenosine into animals caused "marked systemic hypotension and reflex tachycardia [abnormally rapid heart beat]." (TX-217 at 430; Strauss 799:19-800:2; Wackers 909:9-910:25.) Dr. Marcus stressed that "[b]ecause of the hypotensive effects of adenosine, it is not utilized clinically to produce maximal coronary dilation." (TX-217 at 430; Wackers 909:19-910:7.) Even Sicor's technical expert acknowledged that hypotension was "undesirable" during MPI. (Strauss 799:9-13.) Indeed, the art as a whole taught away from the use of adenosine as a pharmacologic stress agent. (PFF50-53.) DFF55. The 1985 edition the textbook of pharmacology commonly used by students and physicians in 1985, Goodman and Gilman, states that dipyridamole acts, at least in part, through the metabolism and transport of adenosine and adenosine nucleotides. In particular, dipyridamole inhibits the uptake of adenosine by erythrocytes and other cells. (Strauss, Tr. 679:16-680:7; TX 39 at 822.) PCF55. DFF56. See PCF51. Goodman and Gilman states of 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

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myocardium, is a coronary vasodilator and appears to be an important signal for the autoregulation of coronary blood flow. (TX 39 at 822.) PCF56. See PCF51.

DFF57. Based on this portion of Goodman & Gilman, a person of skill in the art at the time would understand that when dipyridamole is infused, it is acting through adenosine to cause vasodilation. (Strauss, Tr. 680:8-22.) PCF57. See PCF51, 54.

DFF58. A March 1987 article entitled, Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole, by Conradson et al. ("Conradson"), describes how the cardiovascular effects of dipyridamole in man, at least in part, are mediated by the (sic) potentiation of the cardiovascular actions of the increased endogenous adenosine. (Strauss, Tr. 682:17-24, 683:8-13; TX 220 at 387.) PCF58. DFF59. See PCF51. Conradson states that:

Dipyridamole inhibits the cellular update of adenosine which results in a potentiation of the cardiovascular actions of adenosine ... [t]here is also evidence that the cardiovascular effects of dipyridamole in man, at least in part, are mediated by endogenous adenosine. (TX 220 at 387 (internal citations omitted).) PCF59. See PCF51.

DFF60. A person of skill in the art would understand from Conradson that dipyridamole acts through adenosine. (Strauss, Tr. 683:8-13.) PCF60. See PCF51, 54.

DFF61. United States Patent No. 5,731,296 (the "`296 patent") states that, "[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, co1.21, ll.49-51; see Strauss, Tr. 684:12-685:2.) PCF61. The cited text of the `296 patent, which is based on material added on

December 28, 1987, is not prior art to the `877 patent. (See, e.g., PFF131; see also PCF25, 51, 54.)

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DFF62. The statement concerning dipyridamole's mechanism of action, as set forth in the `296 patent, reflects the state of knowledge in the art in 1987. (Strauss, Tr. 684:12685:6.) PCF62. See PCF51, 54, 61.

DFF63. A 1987 "Patient's Informed Consent" form to be used by Dr. Mario Verani and his group at Baylor College of Medicine in connection with use of adenosine of MPI 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.) RESPONSE: DFF63 is misleading. It does not acknowledge that Dr. Mario Verani was working in connection with Medco's IND, based on the work of Drs. Hilleman and Mohiuddin. Thus, the following counterfinding is proposed: PCF63. Dr. Mario Verani and his group at Baylor College of Medicine

developed a "Patient's Informed Consent" form in connection with Medco's IND after being told of the invention of Drs. Hilleman and Mohiuddin. (TX-52; Wackers 1022:211024:11; Salzberg 1843:5-1844:3.) Thus, Dr. Verani's protocol is based on the inventors' own work and has not been shown to be prior art. DFF64. By mid-1987, safe doses of adenosine that could be administered by continuous infusion and that would result in vasodilation were known in the art. RESPONSE: The studies relied upon by Sicor produced conflicting results regarding tolerable dosing in healthy volunteers, and provided no information about the safety of adenosine infusions in patients with coronary artery disease. Therefore, the following counterfinding is proposed: PCF64. While adenosine had been continuously infused previously, it was

unknown if there was an effective dose that could be administered safely in MPI. In fact, rather than addressing the use of adenosine in MPI, the prior art relied upon by Sicor relates to studies in which: (1) heart patients, the relevant patient population for MPI,

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were systemically excluded; (2) the number of subjects studied was small; (3) measurements of coronary blood flow (necessary for determining potency) are largely lacking; (4) no mention was made of MPI; (5) dose-limiting negative side effects were reported; and (6) the dose at which those side effects were reported to be intolerable to healthy subjects was as low as 70 mcg/kg/min and varied widely. (See generally DTX-2017; Strauss 826:24-831:6; TX-48; TX-220; TX-226; TX-1208; TX-1211; PFF 69-76.) These studies produced conflicting results regarding tolerable dosing, and provided no information about the safety of adenosine infusions in patients with coronary artery disease. (Strauss 826:24-831:6; Wackers 934:21-935:5, 938:19-939:1.) Further, none of these studies characterized adenosine as a more potent coronary vasodilator than dipyridamole. (See TX-48; TX-220; TX-226; TX-1208; TX-1211.) DFF65. In 1987, pharmaceutical grade adenosine for intravenous administration to humans had only recently become available. TX52 at AST009465; Tr. 1023:22-1024:4.) Medco, the original assignee of the `877 patent, was the only source of pharmaceutical grade adenosine at the time. Tr. 1854:22-1855:16; see also Tr., 2119:13-2120:10.) RESPONSE: Contrary to DFF65, adenosine availability was not an impediment to its use or suggestion for use in other applications, as evidenced by the at least 6 separate publications describing work administering adenosine to humans. (See DTX-2016.) Thus, the following, more accurate, counterfinding is proposed: PCF65. Adenosine was readily available from several major U.S. and British

chemical manufacturers. For example, DiMarco and coworkers at the University of Virginia and Biaggioni and coworkers at Vanderbilt reported that they purchased their adenosine from Sigma, a U.S. chemical manufacturer, while Fuller and coworkers and Conradson and coworkers reported that they purchased their adenosine from Fluorochem, a British manufacturer. (See TX-36 at 1256; TX-48 at 2233; TX-1208 at 310; TX-1211 at

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526; Strauss 822:7-823:22.) Adenosine had been formulated by researchers into forms suitable for administration to humans as far back as 1933. (TX-187; Strauss 822:2-6; see also PFF105-108.) DFF66. The ability to obtain adenosine in pharmaceutical grade from Medco was sufficiently valuable that it was the only consideration either named inventor received for assigning all rights to the `877 patent to Medco. (Tr. 1896:9-18; 1897:9-14; Hilleman, Tr. 2148:5-23.) RESPONSE: The proposed finding is unsupported by the evidence. As Dr. Hillman, explained, no additional consideration was requested by the inventors, and the inventors assigned their rights to Medco following the advice of Creighton University's counsel. (Hilleman 2148:24-2150:13.) Thus, the following counterfinding is proposed: PCF66. The inventors assigned their rights to Medco following the advice of

Creighton University's counsel, without requesting any additional consideration from Medco. (Hilleman 2148:24-2150:13.) They did so because neither they nor the University were in the business of developing pharmaceutical products. (Hilleman 2149:18-2150:8.) DFF67. Absent a source of pharmaceutical grade adenosine, anyone wishing to use intravenous adenosine in humans would have to purify chemical grade adenosine and qualify it as suitable for intravenous infusion to humans. (See Strauss, Tr. 671:6-672:16.) PCF67. Sicor's expert, Dr. Strauss, acknowledged that virtually any academic

institution was equipped to take chemical grade adenosine and turn it into a pharmaceutical grade drug. (See Strauss 823:23-824:14; see also PCF65.) Research groups interested in doing so had done so since 1933. (DTX-2016; see also PFF105-109.) DFF68. A November1986 (sic) publication entitled, Cardioavascular Effects of Adenosine in Man; Possible Clinical Implications, by Dr. A. Sollevi ("Sollevi 1986") describes infusing adenosine at a rate of 80 mcg/kg/minute. (TX 1171 at 335.) Sollevi 1986 further states that this infusion rate was associated with a "doubling of the myocardial blood flow." (Strauss, Tr. 702:21-703:14, 704:3-9; TX 1171 at 335, Fig.11.) Sollevi 1986 also states that "[t]his study is additional evidence for adenosine being an extremely effective coronary vasodilator in man." (TX 1171 at 335).

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RESPONSE: The assertions attributed to Dr. Strauss in DFF68 regarding a doubling in coronary blood flow were not in his expert reports and should, therefore, be excluded. (Objection at 707:9-11; TX-70; TX-246.) The contention is also without merit, and thus, the following counterfinding is proposed: PCF68. Data from Sollevi 1986 cited by Dr. Strauss represented

measurements taken from only a single patient. (TX-1171 at 335; Wackers 923:20-23.) Moreover, the figure illustrating the data from this patient (Fig. 11), showed that the alleged "doubling" of coronary blood flow was in actuality an increase of only 70% and that this increase was associated with a reduction of blood pressure (hypotension) of about 20%. (TX-1171 at 335; Wackers 923:24-924:2.) In contrast, Gould 1978 had previously reported that the dipyridamole dose used for diagnostically-reliable myocardial imaging produced a 400% increase in blood flow with little to no decrease in blood pressure. (TX-38 at 284, Fig. 8; Wackers 924:3-17.) Systemic effects like the hypotension described in Sollevi 1986 are antithetical to the requirements for MPI. (TX-391 at 275; Wackers 910:8-17, 922:7-9; Strauss 805:23-809:14.) Thus, the results from this single patient would have confirmed what had already been described by Dr. Sollevi, that adenosine was a potent vasodilator that caused significant systemic effects at doses below what would be required for diagnostically-reliable myocardial perfusion imaging. (TX-1171 at 335; Wackers 923:24-924:17.) DFF69. Sollevi 1986 states that a dose of 30-50 mcg/kg/minute caused a 100 percent increase in graft flow. (Strauss, Tr. 704:22-705:5; TX 1171 at 335.) Sollevi 1986 further states that the "data demonstrate that intravenously administered adenosine can produce preferential coronary vasodilation in man." (TX 1171 at 335; see also Strauss, Tr. 704:22-705:5.) RESPONSE: The assertions of Dr. Strauss on which DFF69 is premised were not in his expert reports and should, therefore, be excluded. (Objection at 707:9-11; TX-70;

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TX-246.) In addition to being untimely, they are unmeritorious. Therefore, the following counterfinding is proposed: PCF69. The 30-50 mcg/kg/min adenosine infusion in Sollevi 1986 described

testing surgical grafts in anesthetized, open-chest heart patients prior to closure of the thorax. This testing represented a form of surgical "quality control"--a context that is "totally different" from MPI. (See TX-1171 at 335; Wackers 926:5-24.) The degree of increased coronary blood flow attained in this experiment was well below the 400% increase reported in Gould 1978 (TX-38 at 284) to yield diagnostically-reliable MPI images with dipyridamole. (TX-1171 at 355; Wackers 925:7-926:4; PCF68.) Thus, the statement plainly does not suggest the appropriateness of higher doses of adenosine for MPI where systemic effects, such as hypotension, would have been expected. DFF70. Sollevi 1986 describes adenosine infusion doses greater than 200 mcg/kg/minute as inducing controlled hypotension in anesthetized patients. (Strauss, Tr. 701:4-9; TX 1171 at 333.) PCF70. Sollevi 1986 states that adenosine induced an "extremely rapid" fall in

blood pressure, mediated by "a profound decrease in the systemic vascular resistance." (TX-1171 at 332.) Plaintiffs' and Defendants' experts agree that producing profound systemic hypotension was undesirable for MPI. (Strauss 768:22-769:2; Wackers 910:8-17, 922:7-9.) Systemic blood pressure reduction is said elsewhere in Sollevi 1986 to result from doses as low as 150 mcg/kg/min and is explicitly reported at a dose of 80 mcg/kg/min. (See PCF68, 69, 73.) DFF71. Sollevi 1986 did not report any instances of AV block in connection to the doses required to produce controlled hypotension. (Strauss, Tr. 702:2-6; TX 1171.) PCF71. Sollevi 1986 (TX 1171) is a review article based on references that not

only lacked any systematic study of patients with coronary artery disease but generally

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excluded or expressly cautioned against the administration of adenosine infusions to such patients. (Wackers 921:5-931:6.) In fact, a later publication co-authored by Dr. Sollevi, Owall 1987, reported that heart block began in such patients at adenosine doses as low as 140 mcg/kg/min. (TX-1169 at 231.) Moreover, Owall 1987 reported that two patients with a past history of myocardial infarction 9 and 13 years before the surgery both experienced side effects from the adenosine infusion requiring medical intervention. (TX-1169 at 229; Wackers 927:16-928:3.) DFF72. The summary chart at the conclusion of Sollevi 1986 states that a property of the "low dose" of 20-50 mcg/kg/minute of adenosine is "preferential myocardial vasodilation." (TX 1171 at 345, Table 6.) PCF72. The summary chart, entitled, "Some Tentative Therapeutic

Properties of Adenosine Administration" (TX-1171 at 345), is completely silent on the magnitude of the alleged preferential myocardial vasodilation, and does not teach or suggest that sufficient coronary vasodilation for diagnostically-reliable human MPI, reported as being a 400% increase (TX-38 at 279, 284; Wackers 924:3-6), was obtained at the 20-50 mcg/kg/min level. Indeed, it is reported elsewhere in Sollevi 1986 that an even higher dose of 80 mcg/kg/min produced only a 70% increase in coronary blood flow. (TX-1171 at 335; see PCF68.) DFF73. The summary chart at the conclusion of Sollevi 1986 also describes a "mean dose" of 50-150 mcg/kg/minute and a "high dose" of 150-350 mcg/kg/min. (TX 1171 at 345, Table 6.) PCF73. Sollevi 1986, Table 6, indicates that the high dose of 150-350

mcg/kg/min was used during the administration of anesthesia. Table 6 also indicates that hypotension is associated with these doses. (TX-1171 at 345, Table 6.) However, systemic hypotension should be avoided during MPI. (Strauss 768:22-769:2; Wackers 910:8-17, 922:7-9.) Further, the "mean doses" of 50-150 mcg/kg/min are described as useful for 16

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controlling excessively high blood pressure during surgery--the very type of systemic blood pressure reduction cautioned against in the contemporaneous MPI literature. (See TX-1171 at 345; TX-229 at 432; Strauss 813:3-24.) DFF74. Sollevi 1986 states that "adenosine may be used in many clinical situations as a vasodilator, antiaggregatory compound as well as an antiarrythmic agent. Its effect is easy to control due to the extremely short plasma half-life." (TX 1171 at 345.) RESPONSE: Notably missing from Sicor's proposed finding is any reference to effects of adenosine cited in Sollevi 1986 that teach away from the use of adenosine in human MPI. Thus, the following counterfinding is proposed: PCF74. Sollevi 1986 described the dramatic decreases in blood pressure that

can result from intravenous infusions of adenosine, stating that adenosine induced an "extremely rapid" fall in blood pressure, mediated by "a profound decrease in the systemic vascular resistance." (TX-1171 at 332.) As agreed by both parties' experts, systemic hypotension should be avoided during MPI. (See Strauss 768:22-769:2; Wackers 910:8-17, 922:7-9.) The "antiarrythmic" uses referred to involve disruption of electrical signals in the heart and are contraindicated for patients with coronary artery disease. (PFF52, 55, 56.) Further, despite the recognition of the enormous scientific experience with adenosine and the expressly stated purpose of the article to set forth "possible clinical implications" of adenosine administration, adenosine is nowhere suggested as a candidate pharmacologic stress agent for myocardial perfusion imaging. (See TX-1171; Strauss 774:13-18.) DFF75. 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. (Strauss, Tr. 708:10-709:12; 705:19-707:2; 747:10-748:13; 748:22-749:20.

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RESPONSE: DFF75 mischaracterizes Sollevi 1986 ignoring the internally contradictory evidence teaching away from the use of adenosine infusions for MPI. Therefore, the following counterfinding is proposed: PCF75. Table 6 of Sollevi 1986 expressly states that the "high dose" range,

which includes the range of 150-200 mcg/kg/min, is associated with hypotension, thereby teaching away from the use of this range for myocardial perfusion imaging. (TX-1171 at 345, Table 6; see also PCF73.) Furthermore, and again contrary to Sicor's characterization, Sollevi 1986 indicates that only doses of 30-50 mcg/kg/min would be both non-hypotensive and provide the "preferential" coronary vasodilation believed needed for human MPI. The increase in coronary blood flow attainable with such low doses was well below the 400% increase reported to result in diagnostically-reliable human MPI. (TX1171 at 335-336; TX-38 at 279, 284; see PCF46.) DFF78. Sollevi 1984 describes several advantagous features of adenosine. Specifically, Sollevi 1984 states that "[t]he rapidity of onset and termination, stability of action, maintenance of cardiac output, and decrease in oxygen demand differentiate adenosine from other antihypotensive agents. These excellent properties justify further clinical investigation." (TX 112 at 404.) PCF78. The discussion in Sollevi 1984b (TX-112) of any advantageous features

is in the context of producing profound hypotension in surgical patients. Hypotension would have been perceived as disadvantageous for a heart patient undergoing a pharmacologic stress test. (See TX-112 at 400; Strauss 797:7-21, 768:22-769:2.) Indeed, heart patients were excluded from the Sollevi 1984b study. (TX-112 at 400.) The reference does not explicitly or impliedly suggest the use of adenosine as a pharmacologic stress agent for human MPI, particularly at a dose of 140 mcg/kg/min, and does not include any data regarding a safe and efficacious dose for producing maximal coronary vasodilation in

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patients with suspected coronary artery disease. (See, e.g., TX-112; Wackers 921:5-931:6; see DTX-2027.) DFF79. Sollevi 1984 did not report any instances of AV block. (Strauss, Tr. 696:2-697:11, 698:13-15.) PCF79. Unlike patients in need of MPI (see PFF18, 19), the patients in Sollevi

1984b were described as having no known history of cardiopulmonary disease. (TX-112 at 400; Wackers 922:10-15.) The report of the results in patients not receiving dipyridamole pretreatment was in a five-line footnote that did not purport to be a complete report of all the study data. (TX-112 at 403.) The complete report of the study, Owall 1987 (TX-1169), described adverse side effects in two patients with a history of heart problems and some AV block beginning at a dose of 140 mcg/kg/min. (Id. at 229, 231.) DFF80. 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. (Strauss, Tr. 699:4-17.) RESPONSE: The cited testimony of Dr. Strauss does not support Sicor's proposed finding. Indeed, the testimony does not make any reference to a stable state (or any other state) of coronary vasodilation. Further, although omitted in the citation in DFF80, the final sentence of Dr. Strauss's answer states that the patients being infused with adenosine "could not describe all the symptoms because they were anesthetized," thereby recognizing that the adenosine infusions used in Sollevi 1984b would not necessarily be tolerable in MPI patients. (Strauss 699:4-20.) Therefore, the following counterfinding is proposed: PCF80. A person of ordinary skill would understand that, according to Sollevi

1984b, continuous intravenous infusion of adenosine could be used to decrease blood pressure by forty percent (40%) in patients with no history of cardiopulmonary disease, a drop which Sicor's expert characterized as "quite significant," and which would have been

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highly undesirable in a patient undergoing a pharmacologic stress test. (See TX-112 at 400; Strauss 797:7-21, 768:22-769:2.) DFF81. A person of skill in the art would have understood from Sollevi 1984 that continuous intravenous infusion of adenosine is relatively safe, even at doses exceeding 200 mcg/kg/min. (Strauss Tr. 699:4-17.) PCF81. See PCF80.

DFF82. An article by Dr. Owall et al. ("Owall") published in March 1987 entitled, Clinical Experience with Adenosine for Controlled Hypotension during Cerebral Aneurysm Surgery, describes results from adenosine infusion in a series of 47 anesthetized patients without pretreatment with dipyridamole. (Strauss, Tr. 721:8-22; TX 1169.) PCF82. Owall 1987 described continuous intravenous infusions of adenosine

into patients to induce controlled hypotension (TX-1169), a result Plaintiffs' and Defendants' experts agree is undersirable for MPI. (Strauss 768:22-769:2; Wackers 910:8-17, 922:7-9.) DFF84. Owall concludes that "adenosine induces a stable and easily controlled hypotension without negative effects on cardiac output or acid-base balance in patients undergoing cerebral aneurysm surgery during neurolept anesthesia." (TX 1169 at 233; see also Strauss, Tr. 724:20-725:11.) RESPONSE: Absent from Sicor's proposed findings regarding Owall 1987 is any mention that the only two subjects participating in the study who had a history of heart disease experienced significant adverse events that required medical intervention. (TX-1169 at 229, 231; Wackers 927:16-929:17.) Also missing is any mention that Owall 1987 reported heart block beginning at a dose of 140 mcg/kg/min. (TX-1169 at 231.) Therefore, the following counterfinding is proposed: PCF84. In Owall 1987, the only two subjects participating in the study who

had a history of heart disease experienced significant adverse events that required medical intervention. (TX-1169 at 229, 231; Wackers 927:16-929:17.) Based on these results, the authors explicitly cautioned against infusing adenosine into patients with a history of heart 20

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disease. (TX-1169 at 233; Wackers 929:18-930:2.) In addition, Owall 1987 reported some heart block beginning at doses as low as 140 mcg/kg/min. (TX-1169 at 231.) DFF85. A person of skill in the art would have understood from Owall that one would need an infusion dose of adenosine of about 200 mcg/kg/minute or more to achieve hypotension and, once the desired result was achieved, one could maintain it for a prolonged period of time. (Strauss, Tr. 724:20-725:11; TX 1169.) PCF85. See Response to DFF84 and PCF84.

DFF86. A 1986 publication entitled, Cardiovascular effects of adenosine infusion in man and their modulation by dipyridamole, by Biaggioni et al. ("Biaggioni 1986"), describes continuous intravenous infusion of adenosine to seven conscious healthy volunteers at rates of 10, 20, 40, 60, 80, 100 and 140 mcg/kg/min. (Strauss, Tr. 711:1-14, 712:14-16; TX 48 at 2230.) Each infusion rate was maintained for 15 minutes. (Strauss, Tr. 711:9-14; TX 48 at 2230.) RESPONSE: Several key distinctions between Biaggioni 1986 (TX-48) and the use of adenosine for MPI are not reflected in DFF86. (See, e.g., DTX-2017.) Thus, the following, more comprehensive counterfinding is proposed: PCF86. Two of the seven healthy subjects in Biaggioni 1986 could not tolerate

doses above about 100 mcg/kg/min. (TX-48; Strauss 826:24-829:5, 831:7-11; DTX-2017.) Biaggioni 1986 also did not teach a safe dose for administration to patients with coronary artery disease, as the study specifically excluded such patients. (Wackers 938:19-939:1.) The patient population requiring pharmacologic stress imaging, however, was known to suffer from numerous adverse circulatory and coronary conditions. (TX-168 at 1344; see also PFF18, 19.) In fact, a subsequent publication reported that 50% of over 9,000 patients receiving pharmacologic stress testing had a history of coronary artery disease and nearly 25% of those patients had suffered a heart attack. (TX-103 at 386; Strauss 835:1-836:1.) As a result, one cannot determine from Biaggioni 1986 how cardiac patients would respond to the doses studied. (Wackers 934:9-20.) Nor can it be determined from Biaggioni 1986 whether sufficient coronary vasodilation had been achieved for diagnostically-reliable MPI.

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While Sicor's expert contends that the patients in Biaggioni 1986 experienced a significant vasodilatory response, such systemic vasodilation would have been contraindicated in a human MPI procedure. (See PCF90.) DFF87. The duration of infusion of each dose is significant. Only a few minutes are needed for MPI, so even the 15 minute duration of one of the doses is longer than would be necessary to perform MPI. (Strauss, Tr. 711:20-712: 13) RESPONSE: Sicor's proposed finding DFF87 is irrelevant to the ultimate issues of whether cardiac patients could tolerate adenosine infusions without experiencing severe side effects and whether diagnostically-reliable MPI images could be attained at the doses they could tolerate. Indeed, there is no linkage in the prior art between Biaggioni 1986 and human pharmacologic MPI. (See TX-48.) Thus, the following counterfinding is proposed: PCF87. The duration of adenosine infusions into young, healthy, normal

volunteers is irrelevant to addressing the questions of whether cardiac patients could tolerate adenosine infusions without experiencing severe side effects and whether diagnostically-reliable MPI images could be attained at doses such patients could tolerate. (See PFF74, 75; Strauss 826:24-831:11; Wackers 934:21-935:5, 938:3-939:1.) Patients that are in need of pharmacological stress imaging are typically more infirm. (See PCF86.) They are also older, with a mean age of 65. (TX-103 at 386; Strauss 835:1-11.) It is well known that age can influence the response to a given pharmaceutical. (Wackers 934:9-20.) The doses in Biaggioni 1986, for which there is no disclosed medical use (TX-48), are also irrelevant to an effective dose for use in MPI. (See PCF86.) DFF88. Biaggioni 1986 described total adenosine infusions of either 1-1/2 or 1-3/4 hours. (Strauss, Tr. 711:21-712:13, 717:10-15; see TX 48 at 2230.) PCF88. See PCF86, 87.

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DFF89. Of the seven patients described in Biaggioni 1986, five tolerated a dose of 140 mcg/kg/minute and all patients tolerated a dose of 100 mcg/kg/minute. (Strauss, Tr. 712:14713:1; TX 48 at 2231.) PCF89. See PCF86, 87.

DFF90. 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; see Strauss, Tr. 718:6-16.) PCF90. Sicor's expert alleged that Biaggioni 1986 indicates that the subjects

had a "very significant vasodilation response to the adenosine infusion." (Strauss 718:6-719:2.) However, systemic vasodilation, as opposed to vasodilation limited to the coronary circulation, was considered undesirable in the context of diagnostic cardiac imaging and could potentially lead to ischemia and other ill effects. (Wackers 910:8-17, 922:7-9, see also PCF86, 87.) DFF91. 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." (Strauss, Tr. 718:4-719:2.) PCF91. See PCF86, 87, 90.

DFF93. A person of ordinary skill in the art would understand from Biaggioni 1986 that adenosine could be 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. (Strauss, Tr. 719:3-18.) PCF93. See PCF86, 87, 90. There is no demonstration in Biaggioni 1986 of a

degree of attainment of a degree of coronary vasodilation sufficient for diagnosticallyreliable MPI. DFF94. Conradson, published in March 1987, describes stepwise infusion rates in conscious human subjects of 20 mcg/kg/min to a maximum of 100 mcg/kg/min in eight normal volunteers. Each dose was administered for six minutes. (Strauss, Tr. 726:23-727:15; TX 220 at 388.)

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RESPONSE: Several key distinctions between Conradson (TX-220) and the use of adenosine for MPI are not reflected in DFF94. (See, e.g., DTX-2017.) Therefore, the following counterfinding is proposed: PCF94. Conradson did not teach a safe adenosine dose for administration to

patients with coronary artery disease. The study was specifically limited to healthy subjects, thereby excluding such heart patients. (TX-220 at 388; Wackers 938:19-939:1.) The patient population requiring pharmacologic stress imaging was known to be older and to suffer from numerous adverse circulatory and coronary conditions. (TX-168 at 1344; see also PFF18, 19.) In fact, a subsequent publication reported that 50% of over 9,000 patients receiving pharmacologic stress testing had a history of coronary artery disease and nearly 25% of those patients had suffered a heart attack. (TX-103 at 386; Strauss 835:1-836:1.) As a result, one cannot determine from Conradson how cardiac patients will respond to the doses studied. (Wackers 934:9-20.) It is also impossible to determine from Conradson whether sufficient coronary vasodilation had occurred to yield diagnostically-reliable MPI images. (See, e.g., Wackers 938:3-18; DTX-2017; TX-220.) Conradson did not include any measures of coronary blood flow or any mention of MPI, or any other medical use for adenosine. (TX-220.) Moreover, Conradson reported doselimiting negative side effects associated with adenosine infusions, and two of the eight healthy subjects could not tolerate doses over 70 mcg/kg/min. (TX-220; Strauss 829:6-831:11.) DFF95. All eight subjects described Conradson tolerated 70 mcg/kg/min; six of eight tolerated 90 mcg/kg/min; and three of the eight tolerated 100 mcg/kg/min. (Strauss, Tr. 726:19-727:5; TX 220 at 388.) PCF95. See PCF94.

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DFF96. The duration of the adenosine infusions in Conradson exceeds the time necessary for MPI. (Strauss, Tr. 727:13-15.) PCF96. See PCF94.

DFF98. A person of ordinary skill in the art would understand from Conradson that adenosine could be safely, continuously infused to conscious humans at rates up to 100 mcg/kg/min. (Strauss, Tr. 728:19-729:3.) PCF98. See PCF94.

DFF99. An article by Dr. Fuller, et al., ("Fuller") published in September 1987 and entitled, Circulatory and Respiratory Effects of Infused Adenosine in Conscious Man, describes adenosine infusion beginning at 12 mcg/kg/min and increasing to 25, 50, and 100. (Strauss, Tr. 729:13-730:9; TX 1208 at 310.) RESPONSE: Several key distinctions between Fuller (TX-1208) and the use of adenosine for MPI are not reflected in DFF99. (See, e.g., DTX-2017.) Thus, the following, more comprehensive counterfinding is proposed: PCF99. There are several key distinctions between Fuller and the use of

adenosine for MPI. Fuller dealt with normal, healthy subjects ranging from 28 to 40 years old, not elderly heart patients. No measures of coronary blood flow were reported. No mention was made of MPI. No medical use for adenosine in humans was proposed. Doselimiting negative side effects were reported, with the maximum dose being 100 mcg/kg/min or less depending upon the subject. (TX-1208; Strauss 828:14-16, 830:15-831:11.) Fuller, therefore, did not teach a safe dose for administration to patients with coronary artery disease. (Wackers 938:19-939:1.) The patient population requiring pharmacologic stress imaging was known to suffer from numerous adverse circulatory and coronary conditions. (TX-168 at 1344; see also PFF18, 19.) In fact, a subsequent publication reported that 50% of over 9,000 patients receiving pharmacologic stress testing had a history of coronary artery disease and nearly 25% of those patients had suffered a heart attack. (TX-103 at 386; Strauss 835:1-836:1.) As a result, one cannot determine from Fuller whether cardiac 25

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patients could tolerate adenosine infusions without experiencing severe side effects and whether diagnostically-reliable MPI images could be obtained at the doses such patients could tolerate. (Strauss 826:24-831:6; Wackers 934:21-935:5, 938:3-939:1; DTX2017; see also PFF74, 75.) DFF100. Each dose of adenosine was infused for 6 to 7 minutes. (Strauss, Tr. 729:19-730:4; TX 1208 at 310.) PCF100. See PCF99.

DFF101. Two of the six subjects described in Fuller tolerated 200 mcg/kg/min for 1 and 2 minutes, respectively. (Strauss, Tr. 730:16-22; TX 1208 at 311.) PCF101. See PCF99.

DFF102. A person of skill in the art would understand from Fuller that adenosine could be safely, continuously infused to conscious human at a rate of at least 100 mcg/kg/min and up to 200 mcg/kg/min. (Strauss, Tr. 731:1-12.) PCF102. See PCF86, 99.

DFF103. An article published in December 1987 by Biaggioni et al. ("Biaggioni 1987") entitled. Cardiovascular and Respiratory Effects of Adenosine in Conscious Man, describes adenosine infusion at rates of 80-180 mcg/kg/minute to healthy male volunteers. (Strauss, Tr. 732:6-733:6; TX 226.) PCF103. The key distinctions between the use of adenosine for MPI and

Biaggioni 1987 (TX-226) are essentially the same as those for Biaggioni 1986 (TX-48). (See PCF86, 87, 90.) Indeed, Sicor asserts Biaggioni 1986 and Biaggioni 1987 for the same purpose. (See DB15-17.) DFF104. Eight subjects are discussed in connection with the continuous intravenous infusion of adenosine described in Biaggioni 1987. Each of the eight subjects tolerated an infusion rate of 140 mcg/kg/minute. (Strauss, Tr. 732:17-22; TX 226 at 781-82, Fig. 3, 784-86.) PCF104. See PCF103.

DFF105. Biaggioni 1987 states that the adenosine infusions produced dosedependent increases in heart rate and systolic blood pressure and decreases in diastolic blood pressure. (TX 226 at 781, Fig. 3, see also Strauss, Tr. 736:8-13.)

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PCF105.

See PCF103 and PCF90 regarding the undesirability of systemic

vasodilation in human MPI. DFF106. A person of ordinary skill in the art would understand from Biaggioni 1987 that adenosine can be safely, continuously infused for extended periods of time, that doses up to 140 mcg/kg/min are tolerable in conscious humans, and that adenosine has a predictable vasodilatory action. (Strauss, Tr. 735:4-19.) PCF106. See PCF103, 105.

DFF107. The `296 patent describes use of adenosine as a pharmacologic stress agent for MPI. (TX 275 at col. 21.) PCF107. Example XIII of the `296 patent consists of a half-column prophetic

suggestion on the use of adenosine in connection with MPI. (TX-275 at cols. 21-22.) Example XIII did not identify adenosine doses that were both tolerable and effective for reliable MPI diagnosis. (Id.) Nor did it describe a dose of about 140 mcg/kg/min. (Wackers 959:14-22.) It stated instead that "[t]he exact dose will normally have to be titrated individually" and went on to speculate that the dose "should lie in the range of 10 to 150 [mcg/kg/min]." (TX-275 at col. 21, ll. 59-61.) While titration was proposed, the endpoint of the titration was not defined. (TX-275; Wackers 957:14-958:13.) Additionally, the cited portion of the `296 patent is not prior art to the `877 patent, because the inventors conceived of as much of the invention as is disclosed in Example XIII prior to its effective date, and then diligently reduced that subject matter to practice. (Compare TX-57 at 4 with TX-275 at cols. 21-22; Wackers 971:11-973:11; see also PFF138-146.) Specifically, Example XIII was not added to the patent application for the `296 patent until December 28, 1987--after the December 9, 1987 submission to the FDA by Drs. Hilleman and Mohiuddin of protocols for their own experiments with adenosine for use in MPI. (See TX-52 at AST0009417; TX-275; Wackers 973:24-974:14; DTX-2028; PFF139-142.) While Example XIII of the `296 patent merely provided instructions to titrate and a speculative 27

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dose range, without defining any titration endpoints, the inventors had previously conceived a titration protocol with defined starting and ending points. (See TX-57; Wackers 971:11-973:11; PFF138-140.) DFF108. The `296 patent states that "a safer and more reliable test can be expected if adenosine is used" instead of dipyridamole. (TX 275 at col.21, ll.57-58.) PCF108. See PCF107.

DFF109. The `296 patent further states that "[t]he exact dose will normally have to be titrated individually but should lie in the range of 10 to 150 micrograms per kilogram per minute." (TX 275 at col. 21, ll. 59-61). PCF109. See PCF107.

DFF110. A person of ordinary skill in the art would understand from the `296 patent that doses within the range of 10-150 mcg/kg/min would likely be both safe and effective for MPI. (Strauss, Tr. 752:7-19.) PCF110. The `296 patent cannot be read as disclosing safe and effective doses

between 10 and 150 mcg/kg/min, and particularly cannot be read as disclosing a dose of 140 mcg/kg/min. The `296 patent states that heart block can surely be avoided in conscious patients only at doses below 100 mcg/kg/min. (TX-275 at col. 3, lines 23-26; Strauss 864:23-865:12.) Moreover, nothing in the `296 patent would lead one of ordinary skill to the dose of 140 mcg/kg/min. (Wackers 959:17-22.) The point to which the titration in Example XIII should be conducted is unstated. (TX-275; Wackers 957:14-958:13.) Dr. Strauss acknowledged that: (1) the `296 patent taught that infusing adenosine above 100 mcg/kg/min caused risk of heart block in conscious patients (TX-275 at col. 3, lines 23-26; Strauss 864:23-865:12) and (2) Wilson 1990 reported that adenosine doses below 100 mcg/kg/min. can result in cyclical variations in coronary blood flow leading to the possibility of falsely negative results (see TX-46 at 1600, 1603; Wackers 963:20-964:7). (See also PCF109.) Moreover, the testimony of Dr. Strauss established that the dose

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titration set forth in Example XIII would not lead to a dose of 140 mcg/kg/min. (See, e.g., PFF149-150.) Dr. Strauss admitted that titrating to a point where side effects were mild or just beginning could well result in a dose too low for useful myocardial imaging, and that, in his experience, while many people can tolerate 100 mcg/kg/min, some patients who receive 140 mcg/kg/min will sit up on the table and yell, STOP! (Strauss 849:21-851:5; see also PFF149-150.) Mere titration would not have led to the claimed 140 mcg/kg/min dose, but to a lower one with fewer side effects. (Strauss 850:11-851:5.) Consequently, a person of ordinary skill in the art would not understand from Example XIII that the dose of 140 mcg/kg/min would likely be considered both safe and effective. DFF111. The `296 patent describes, inter alia, the use of adenosine as a pharmacologic stress agent for MPI. (TX 275 at col. 21). PCF111. See PCF107, 110.

DFF114. Example XIII discloses "adenosine in the diagnosis of coronary heart disease by radionucleide (sic) scintigraphy." (TX 275 at col.21, ll.25-61.) PCF114. See PCF107, 110.

DFF115. Example XIII describes the use of dipyridamole in connection with MPI using thallium 201. (TX 275 at col.21, ll.25-61.) Example XIII then 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. (TX 275 at col.21, ll.2561.) PCF115. See PCF107, 110.

DFF116. Example XIII of the `296 patent teaches a dose range of 10 to 150 mcg/kg/min of adenosine for MPI. (TX 275 at col.21, ll.59-61; see also Strauss, Tr. 750:2-22.) PCF116. See PCF107, 110.

DFF117. The use of adenosine as a pharmacologic stress agent for 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.)

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PCF117.

The Karolinska Request is not prior art. It reflects activity outside

the United States and is, therefore, neither prior knowledge nor prior use in this country under 35 U.S.C. § 102(a). It is prior art only if it qualifies as a "printed publication" under U.S. law. (See PCL57-61.) The record is devoid of foundational testimony authenticating the document or indicating how, if it all, the Karolinska Request was disseminated or stored. (See PFF159-160.) The sole support cited by Sicor for DFF243, TX-1193 at SIC010940, is inadmissible hearsay, and consists of a letter written by a European patent attorney submitting a request to the European Patent Office. This letter to the European Patent