Free Proposed Pretrial Order - District Court of Delaware - Delaware

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

) ) ) ) Plaintiffs, ) ) v. ) ) SICOR, INC. and SICOR PHARMACEUTICALS, INC. ) ) Defendants. ) ________________________________________________)

KING PHARMACEUTICALS RESEARCH AND DEVELOPMENT, INC., ASTELLAS US LLC, and ASTELLAS PHARMA US, INC.

Civil Action No. 05-337-SLR

PROPOSED PRETRIAL ORDER On January 31, 2007, counsel for Plaintiffs Astellas US LLC and Astellas Pharma US, Inc. (collectively "Astellas") and King Pharmaceuticals Research and Development Inc. ("King"), and Defendants Sicor, Inc. and Sicor Pharmaceuticals, Inc. (collectively "Sicor") attended a pre-trial conference before this Court. The Court hereby orders the following matters as to the trial scheduled to begin on February 12, 2007. I. NATURE OF THE ACTION AND PLEADINGS (DEL. L.R. 16.4(D)(1)). 1. This is an action by King and Astellas against Sicor for infringement of U.S.

Patent No. 5,070,877 ("the `877 patent") under 35 U.S.C. § 271(e)(2), also known as the HatchWaxman Act. 2. On December 6, 2004, Sicor, Inc. and Sicor Pharmaceuticals, Inc. filed an

Abbreviated New Drug Application ("ANDA") seeking permission from the FDA to market an

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injectable adenosine product for use as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately. The ANDA was amended on April 16, 2005, to include a Paragraph IV certification. 3. On May 26, 2005, Astellas and King filed a Complaint for infringement of the

`877 patent against Sicor, Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries Ltd. (Civil Action No. 05-337-SLR) (D.I. 1). 4. On August 8, 2005, Sicor filed an Answer and Affirmative Defense and a Motion

to Dismiss Count III of the Complaint (D.I. 6; D.I. 8). On the same day, the parties filed a Stipulation of Dismissal of Complaint as to Teva Pharmaceuticals, USA, Inc. and Teva Pharmaceutical Industries Ltd. in which the Teva entities agreed to be bound by the judgment in this matter (D.I. 10). On August 9, 2005, the Court entered the order approving this stipulation. 5. The Court granted in part and denied in part Sicor's Motion to Dismiss Count III

on March 31, 2006 (D.I. 79). 6. On May 16, 2006, Astellas and Sicor stipulated and agreed, subject to the Court's

approval, that Defendants' making, using, offering to sell, importing, or selling Sicor's Adenosine Injection USP in the United States would infringe claims 1, 3-12, 17, 18, 20-26 and 43 of the `877 patent. (D.I. 104). On May 17, 2006, the Court entered the order approving this stipulation. 7. (D.I. 107). 8. (D.I. 111). II. BASIS FOR FEDERAL JURISDICTION (D. DEL. L.R. 16.4(D)(2)) 9. This is an action by Plaintiffs King and Astellas against Sicor for infringement of 2 On August 11, 2006, the parties filed their Joint Claim Construction Statement. On June 29, 2006, the Court denied Sicor's Motion to amend the pleadings.

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the `877 patent under 35 U.S.C. § 271(e)(2). 10. This action arises under the patent laws of the United States, Title 35,

United States Code. The Court has subject matter jurisdiction under 28 U.S.C. §§ 1331, 1338(a), 2201, and 2202. 11. Venue is proper in this judicial district under one or more of 28 U.S.C. §§

1391(b), (c), and (d), and 1400(b). III. STATEMENT OF FACTS WHICH ARE ADMITTED AND REQUIRE NO PROOF (D. DEL. L.R. 16.4(D)(3)) 12. IV. The parties admit the facts stated in attached Exhibit 1.

ISSUES OF FACT THAT REMAIN TO BE LITIGATED AND EXPECTED PROOFS (D. DEL. L.R. 16.4(D)(4)) 13. Plaintiffs' Statement of Issues of Fact That Remain to be Litigated is attached as

Exhibit 2. 14. as Exhibit 3. V. ISSUES OF LAW THAT REMAIN TO BE LITIGATED (D. DEL. L.R. 16.4(D)(5)) 15. Exhibit 4. 16. Exhibit 5. VI. EXHIBIT LISTS (D. DEL. L.R. 16.4(D)(6)) 17. The exhibits that Plaintiffs may introduce into evidence in C.A. 05-337-SLR are Defendants' Statement of Issues of Law that remain to be litigated is attached as Plaintiffs' Statement of Issues of Law that remain to be litigated is attached as Defendants' Statement of Issues of Fact That Remain to be Litigated is attached

included on the list attached hereto as Exhibit 6. 18. The exhibits that Defendants may introduce into evidence in C.A. 05-337-SLR

are included on the list attached hereto as Exhibit 7.

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19.

The parties' respective exhibit lists identify all the exhibits they may introduce

into evidence in C.A. 05-337-SLR and the companion case C.A. 05-336-SLR. 20. Plaintiffs' objections to Defendants' trial exhibits and Defendants' identification

of FRE in support of admission are listed on Exhibit 7. Defendants' objections to Plaintiffs' trial exhibits and Plaintiffs' identification of FRE in support of admission are listed on Exhibit 6. Plaintiffs provided additional bases of objections to Defendants' exhibits on January 25, 2006, to which Defendants agree to respond by January 29, 2006. 21. The parties reserve the right to supplement these exhibit lists during the period

prior to the commencement of trial. Except for exhibits which are to be used solely for impeachment, only the exhibits that have been identified on the parties' exhibit lists and provided to the opposing party by 7 p.m. on February 7, 2007, may be introduced at trial. Summaries under Rule 1006 must be provided by January 29, 2007. 22. The parties will offer at trial one or more of the exhibits set forth in their

respective lists. These lists include the exhibit numbers to be used at trial and a description sufficient to identify the exhibits. These exhibit lists may include exhibits that may not necessarily be offered or introduced into evidence. 23. Each party may use an exhibit that is listed on the other side's exhibit list, to the

same effect as though it were listed on its own exhibit list, subject to evidentiary objections, and provided that the party has complied with the notice provisions of paragraph 26. Any exhibit, once admitted, may be used equally by each party for any proper purpose and subject to the rules of evidence. 24. The parties shall produce a copy of any and all exhibits to be used at trial, labeled

with the exhibit number.

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25.

Each party reserves the right to object to the relevancy of any exhibit offered by

the other party, at the time such exhibit is offered, in view of the specific context in which such exhibit is offered. 26. Plaintiffs and Defendants disagree on the notice to be provided of exhibits that

may be offered on redirect. 27. 28. Defendant's Proposed Language: [The parties will exchange all demonstratives and exhibits to be used on

examination of a witness to be called by that party and the identity of the witness with whom they will be used, by 7 p.m. two calendar days before the anticipated use. The party calling the witness may not use any other exhibits in the examination of that witness, except by agreement of the parties or leave of Court with respect to exhibits the need for which was not reasonably foreseeable to the party calling the witness.] 29. 30. Plaintiffs' Proposed Language: [The parties will exchange all demonstratives and exhibits to be used on

direct examination of a witness and the identity of the witness with whom they will be used by 7:00 p.m. two calendar days before the anticipated use.] 31. For demonstratives, the parties will exchange on 8.5 x 11 paper black and white

representations of these demonstrative exhibits, or color representations if color is necessary to interpret the exhibit. The notice provisions of this paragraph shall not apply to demonstrative exhibits created in the courtroom during testimony at trial or the enlargement, simple highlighting, ballooning, or excerption of trial exhibits or testimony. The opposing party shall, by 7 p.m. one (1) calendar day before the expected use, notify the other side of any objections it intends to maintain to the exhibits or pose to the demonstratives. These objections will be taken

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up with the Court prior to the witness's testimony, as directed by the Court. Exhibits to which no objection has been made shall be admitted if offered. 32. The parties have agreed that a copyright page will not be necessary to authenticate

a journal article that is used as a trial exhibit, as long as the article sets forth the date of its publication elsewhere on its face. 33. The parties have agreed that the Defendants will treat color versions of Plaintiffs'

documents as equivalent to the originally marked black and white exhibits. In addition, the parties have agreed to replace any truly illegible exhibits with better versions that will be treated as equivalent to the originally marked exhibits. 34. The parties have agreed that the Defendants will not object to Plaintiffs' reliance

on the certified translations accompanying exhibits TX085, TX274, TX293, and TX412. Defendants reserve and expressly do not waive all other objections to exhibits TX085, TX274, TX293 and TX412. VII. WITNESS LISTS (D. DEL. L.R. 16.4(D)(7)) 35. Exhibit 8A. 36. Exhibit 9A. 37. Exhibit 8B. 38. as Exhibit 9B. 39. 40. Plaintiffs' description of its experts' qualifications is attached as Exhibit 8C. Defendants' description of its experts' qualifications is attached as Exhibit 9C. 6 Defendants' rebuttal list of witnesses to be called live or by deposition is attached Plaintiffs' rebuttal list of witnesses to be called live or by deposition is attached as Defendants' list of witnesses to be called live or by deposition is attached as Plaintiffs' list of witnesses to be called live or by deposition is attached as

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41.

The parties have agreed that the party going first at trial shall identify the

witnesses it intends to call to testify, whether live or by deposition, for the first day of trial or its first (3) witnesses, whichever number is greater, by 7 p.m. on Friday, February 9, 2007 or by 7 p.m. three (3) calendar days prior to the commencement of trial in the event that the start of trial is moved. A party intending to call as a witness an employee of an opposing party shall provide notice of its intent to do so four (4) calendar days before the witness is called. Other than for the first day of testimony in each party's case, a party will identify the witnesses it intends to call by 7 p.m. two (2) calendar days prior to the expected testimony. 42. Each party will give 48 hours notice of when it intends to complete the

presentation of its evidence. Not more than twelve (12) hours after receiving such notice, the opposing party shall identify the witnesses it intends to call on the first day of its case in chief or rebuttal or its first three (3) witnesses, whichever number is greater. 43. The parties shall exchange designation of the deposition testimony that they

intend to offer at trial on Friday, February 2, 2007. The opposing side shall provide objections and counter-designations on Monday, February 5, 2007. Any objections to the counterdesignations and further designations in response to counter-designations shall be exchanged on Thursday, February 8, 2007. Except by agreement of the parties or by leave of Court, no other deposition designations may be introduced at trial. 44. With respect to deposition designations and counter-designations, each side shall

be charged only with the time needed to read, or play by videotape, its own designations or counter-designations, and will not be charged with the time necessary to read, or play by videotape, the other side's designations or counter-designations. 45. The listing of a witness on a party's witness list does not require that party to call

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that witness to testify, either in person or by deposition. 46. Each party must identify by 7 p.m. on January 29, 2007 the witnesses that it

intends to call live at trial. VIII. BRIEF STATEMENT OF INTENDED PROOF (D. DEL. L.R. 16.4(D)(8)-(10)) 47. 48. IX. Plaintiffs' list of intended proofs is attached as Exhibit 10. Defendants' list of intended proofs is attached as Exhibit 11.

GOOD FAITH SETTLEMENT EFFORTS (D. DEL. L.R. 16.4(D)(12)) 49. Two-way communications have occurred between persons having authority in a

good faith effort to explore the resolution of the controversy by settlement. The parties have not reached any agreement that would resolve this matter. X. OTHER MATTERS WHICH THE PARTIES DEEM APPROPRIATE (D. DEL. L.R. 16.4(D)(13)) 50. 51. The parties agree that each side will be allowed a one hour opening statement. A list and brief discussion of miscellaneous issues that Plaintiffs deem appropriate

to discuss at the pretrial conference is set forth in Exhibit 12. 52. A list and brief discussion of miscellaneous issues that Defendants deem

appropriate to discuss at the pretrial conference is set forth in Exhibit 13. 53. The parties request that the Court grant access to the Courtroom on the day before

trial for the purposes of setting up electronic and computer devices. 54. Once the parties have arrived in Delaware for the trial, service of documents and

exhibits shall occur by hand delivery and email on lead trial counsel and copies by email to local counsel and each party's designee for email service. This agreement ends when trial is concluded.

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XI.

PRETRIAL ORDER TO CONTROL FUTURE PROCEEDINGS (D. DEL. L.R. 16.4(D)(14)) 55. This Order shall control the subsequent course of trial, unless modified by the

Court to prevent manifest injustice.

SO ORDERED: Dated: ________________, 2007 ____________________________________ UNITED STATES DISTRICT JUDGE

/s/ Richard K. Herrmann Richard K. Herrmann #405 Mary B. Matterer # 2696 MORRIS JAMES LLP 500 Delaware Avenue, Suite 1500 Wilmington, DE 19801-1494 (302) 888-6800 [email protected] [email protected] Attorneys for Plaintiffs Astellas US LLC and Astellas Pharma US, Inc.

/s/ Karen E. Keller Josy W. Ingersoll #1088 Karen E. Keller #4489 YOUNG CONAWAY STARGATT & TAYLOR, LLP The Brandywine Building 1000 West Street Wilmington, DE 19801 (302) 571-6672 [email protected] [email protected] Attorneys for Defendants Sicor Inc. and Sicor Pharmaceuticals, Inc.

/s/ Paul E. Crawford Paul E. Crawford #493 Patricia Smink Rogowski # 2632 CONNOLLY BOVE LODGE & HUTZ LLP 1007 N. Orange Street Wilmington, DE 19801 (302) 658-9141 [email protected] [email protected] Attorneys for Plaintiff King Pharmaceuticals Research and Development, Inc.

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EXHIBIT 1

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EXHIBIT 1 STATEMENT OF ADMITTED FACTS I. 1. THE PARTIES Plaintiffs Astellas US LLC and Astellas Pharma US, Inc. (collectively,

"Astellas") are both corporations organized and existing under the laws of the State of Delaware, with their principal places of business at Three Parkway North, Deerfield, Illinois 60015-2548. 2. Plaintiff King Pharmaceuticals Research and Development, Inc. ("King"), is a

corporation organized and existing under the laws of the State of Delaware having a principal place of business at 7001 Weston Parkway, Suite 300, Cary, North Carolina 27513. 3. Defendant Sicor Pharmaceuticals Inc. (Sicor Pharma) is a corporation organized

and existing under the laws of the State of Delaware having a principal place of business at 19 Hughes, Irvine, California 92618. 4. Defendant Sicor Inc. is a corporation organized and existing under the laws of the

State of Delaware having a principal place of business at 19 Hughes, Irvine, California 92618. 5. "Sicor"). II. 6. THE `877 PATENT The United States Patent and Trademark Office ("PTO") issued U.S. Patent No. Sicor Pharmaceuticals is a wholly owned subsidiary of Sicor Inc. (collectively,

5,070,877 ("the `877 patent") on December 10, 1991 from Application No. 07/330,156 ("the `156 application") filed on March 29,1989. The patent is entitled "Novel Method of Myocardial Imaging." The face of the patent lists Syed Mohiuddin and Daniel Hilleman as the inventors. 7. III. 8. The face of the `877 patent lists Medco Research, Inc. as the assignee. THE PROSECUTION OF THE PATENT The `156 application was filed as a continuation-in-part of Application No.

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07/231,217, filed August 11, 1988 (the original Mohiuddin application). 9. IV. 10. 11. 12. The `877 patent is assigned to King. ADENOSCAN® Astellas is the exclusive licensee of certain rights under the `877 patent. Astellas manufactures Adenoscan pursuant to NDA No. 20-059. Astellas sells Adenoscan® (Adenosine Injection , USP), an adenosine-based

product for use as an adjunct to the thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately. 13. Pursuant to 21 U.S.C. § 355(b)(1) and the FDA regulations promulgated pursuant

thereto, the `877 patent is listed with respect to Adenoscan® in "Approved Drug Products with Therapeutic Equivalence Evaluations" ("the Orange Book"), 24th Edition, published by the United States Food and Drug Administration ("the FDA"). V. SICOR'S ANDA 14. On December 6, 2004, Sicor filed Abbreviated New Drug Application No. 77-425

("ANDA No. 77-425") with the FDA, addressed to a proposed product identified as adenosine (Adenosine Injection, USP). 15. The proposed labeling and/or proposed package insert submitted with ANDA No.

77-425 states that it is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately. VI. 17. OTHER Example 13 of the `296 patent was added on December 28, 1987, as part of the

continuation in part application 07/138,306 and is titled "Adenosine in the Diagnosis of Coronary Heart Disease by Radionucleide Scintigraphy."

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EXHIBIT 2

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EXHIBIT 2 PLAINTIFFS' STATEMENT OF ISSUES OF FACT THAT REMAIN TO BE LITIGATED To the extent that Plaintiffs' Statement of Issues of Law That Remain to be Litigated contain issues of fact, those issues are incorporated herein by reference. Should the Court determine that any issue identified in this list as an issue of fact is more properly considered an issue of law, Plaintiffs incorporate such issues by reference into its Statement of Issues of Law That Remain to be Litigated. Plaintiffs have stated the issues of fact more generally than defendants, but intend to litigate, as required, the numerous sub-issues set forth by Defendants. I. ANTICIPATION For purposes of determining infringement of the `877 patent, the Plaintiffs will assert only claim 23 as read through claim 17 (hereinafter "claim 23(17)"), claim 23 as read through claim 18 (hereinafter "claim 23(18)"), and claim 43.1 The parties will litigate whether Sicor has proven by clear and convincing evidence that: 1. Claims 23(17), 23(18) and 43 of U.S. Patent No. 5, 070,877 ("the asserted claims

of the `877 patent") are anticipated under 35 U.S.C. § 102(e) by United States Patent No. 5,731,296 ("the `296 patent"); and/or 2. The asserted claims of the `877 patent are anticipated under 35 U.S.C. § 102(a) by

the Karolinska Institute Request to the Ethics Committee of the Karolinska Institute, Sweden (1988)(the "Karolinska Request").

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Plaintiffs reserve the right to further narrow the asserted claims.

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II.

OBVIOUSNESS The parties will litigate whether Sicor has proven by clear and convincing evidence that: 3. The subject matter of the asserted claims of the `877 patent would have been

obvious under 35 U.S.C. § 103 to one of ordinary skill in the relevant art at the time the invention was made over the `296 patent and/or the Karolinska Request; 4. The subject matter of the asserted claims of the `877 patent would have been

obvious under 35 U.S.C. § 103 to one of ordinary skill in the relevant art at the time the invention was made over the `296 patent and/or the Karolinska Request in view of one or more of the following publications; a. Sollevi et al., Cardiovascular Effects of Adenosine During Controlled Hypotension in Cerebral Aneurysm Surgery, 59 Anesthesiology (Circulation II) A9 (1983) ("Sollevi I"); b. Sollevi et al., Controlled Hypotension with Adenosine in Cerebral Aneurysm Surgery, 61 Anesthesiology 400 (1984) ("Sollevi III"); c. Sollevi, Cardiovascular Effects of Adenosine in Man: Possible Clinical Implications, 27 Progress in Neurobiology 319 (1986) ("Sollevi 1986"); d. Biaggioni et al., Cardiovascular Effects of Adenosine Infusion in Man and Their Modulation by Dipyridamole, 39 Life Sciences 2229 (1986) ("Biaggioni 1986"); e. Biaggioni et al., Cardiovascular and Respiratory Effects of Adenosine in Conscious Man, 61 Circulation Research 779 (1987) ("Biaggioni 1987") f. Conradson et al., Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole, 129 Acta Physiologica Scandinavica 387 (1987) ("Conradson"); 2

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g.

Fuller et al., Circulatory and respiratory effects of infused adenosine in conscious man, 24 British J. Clinical Pharmacology 309 (1987) ("Fuller"); or

h.

Owall et al., Clinical experience with adenosine for controlled hypotension during cerebral aneurysm surgery, 66 Anesthesia Analgesia 229 (1987) ("Owall");

5.

The subject matter of the asserted claims of the `877 patent would have been

obvious under 35 U.S.C. § 103 to one of ordinary skill in the relevant art at the time the invention was made over Gould et al., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilatation. II. Clinical Methodology and Feasibility, 41 Am. J. Cardiology 279 (1978) ("Gould 1978") in combination with any of Sollevi I, Sollevi III, Sollevi 1986, the `296 patent, Biaggioni 1986, Biaggioni 1987, Conradson, Fuller, or Owall; 6. The subject matter of the asserted claims of the `877 patent would have been

obvious under 35 U.S.C. § 103 to one of ordinary skill in the relevant art at the time the invention was made over Albro et al., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilatation. III. Clinical Trial, 42 Am. J. Cardiology 751 (1978) ("Albro") in combination with any of Sollevi I, Sollevi III, Sollevi 1986, the `296 patent, Biaggioni 1986, Biaggioni 1987, Conradson, Fuller, or Owall; 7. The subject matter of the asserted claims of the `877 patent would have been

obvious under 35 U.S.C. § 103 to one of ordinary skill in the relevant art at the time the invention was made over Iskandrian, Dipyridamole cardiac imaging, 115 Curriculum in Cardiology, Am. Heart J. 432 (1988) ("Iskandrian") and Lagerkranser et al., Central and

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Splanchinic Hemodynamics in the Dog during Controlled Hypotension with Adenosine, 60 Anesthesiology 547 (1984) ("Lagerkranser") in combination with any of Sollevi I, Sollevi III, Sollevi 1986, the `296 patent, Biaggioni 1986, Biaggioni 1987, Conradson, Fuller, or Owall; 8. The subject matter of the asserted claims of the `877 patent would have been

obvious under 35 U.S.C. § 103 to one of ordinary skill in the relevant art at the time the invention was made over Strauss et al., Noninvasive Detection of Subcritical Coronary Arterial Narrowings With a Coronary Vasodilator and Myocardial Perfusion Imaging, 39 Am. J. Cardiology 403 (1977) and any of Gould 1978, Albro, or Iskandrian in combination with any of Sollevi I, Sollevi III, Sollevi 1986, the `296 patent, Biaggioni 1986, Biaggioni 1987, Conradson, Fuller, or Owall; 9. The subject matter of the asserted claims of the `877 patent would have been

obvious under 35 U.S.C. § 103 to one of ordinary skill in the relevant art at the time the invention was made over Leppo et al. Quantiative Thallium-201 Redistribution with a Fixed Coronary Stenosis in Dogs, 63 Circulation 632 (1981) and any of Gould 1978, Albro or Iskandrian in combination with any of Sollevi I, Sollevi III, Sollevi 1986, the `296 patent, Biaggioni 1986, Biaggioni 1987, Conradson, or Owall; and whether 10. Sicor should be precluded from offering proof in support of its contentions that

Gould 1978 and Albro 1978 anticipate the asserted claims where neither reference was identified as anticipatory prior art in Sicor's contentions and expert reports. III. PRIOR ART The parties will litigate whether Sicor has proven by clear and convincing evidence that: 11. Example XIII of the `296 patent, the Karolinska Request, and Iskandrian are prior

art in accordance with 35 U.S.C. §§ 102, 103, with respect to the `877 patent.

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IV.

EXCEPTIONAL CASE Unless severed for separate trial, the parties will litigate whether the present case is an

exceptional case and Plaintiffs are entitled to reasonable attorneys fees under 35 U.S.C. § 285.

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EXHIBIT 3

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EXHIBIT 3 DEFENDANTS' STATEMENT OF ISSUES OF FACT THAT REMAIN TO BE LITIGATED To the extent that any issue identified by Defendants as an issue of law should properly be considered an issue of fact, Defendants incorporate it herein by reference. Similarly, to the extent that any issue identified herein as an issue of fact should properly be considered an issue of law, it should be so considered. The parties will litigate at trial whether the following are true statements of fact: I. Myocardial Perfusion Imaging 1. Myocardial perfusion imaging is a diagnostic technique used to identify and

assess conditions such as coronary artery disease and stenosed arteries. Myocardial perfusion imaging utilizes a radiation-sensitive camera to depict the distribution of radiotracers to identify the regional distribution of blood flow in the myocardium under normal conditions and under circumstances of increased myocardial blood flow. 2. Myocardial perfusion imaging was identified as potentially useful in the 1960s,

but the test procedure remained sub-optimal through at least the early 1970s. 3. The usefulness of the technique improved through the 1970s with the

identification of better radiotracers, such as thallium-201. 4. By the mid to late 1970s, it had been determined that detection of coronary artery

disease with myocardial perfusion imaging was improved by injecting the radiotracer near the end of a period of maximal exercise, instead of when the patient was at rest. Also by the mid to late 1970s, it was recognized that coronary vasodilators could be used as a possible alternative to maximal exercise as a means of increasing blood flow, to increase the radiotracer extraction, in connection with myocardial perfusion imaging. -1-

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5.

By 1978, dipyridamole had been used as a pharmacological stress agent in

connection with myocardial perfusion imaging in humans. By the mid 1980s, research showed that dipyridamole was at least as effective as exercise for improving imaging. 6. At the relevant time, it was known in the art that dipyridamole was an adenosine

uptake inhibitor and that the vasodilation action of dipyridamole was linked to metabolism and transport of adenosine. 7. humans. 8. At the time of the application for the `877 patent, the only United States source of Adenosine has long been known to be a vasodilator in mammals, including in

pharmaceutical grade adenosine for intravenous administration was Medco Research, Inc., the original assignee of the `877 patent. 9. Pharmaceutical grade adenosine is required for intravenous administration of

adenosine in humans. II. The `877 Patent 10. Several of the asserted claims, including claims 1 and 17, are generally directed to

continuous intravenous infusion of an adenosine receptor agonist, infused at a rate within the range of 20 to 200 µg/kg/min, to cause coronary artery dilation, and then performing a technique, such as myocardial perfusion imaging, to detect and assess dysfunction. Other claims, including claims 7-9, 23-24, and 43, specify that the adenosine receptor agonist is adenosine. Claims 4 and 20 identify a group, which includes adenosine, from which the adenosine receptor agonist is chosen. 11. Claims 6 and 18 require that the adenosine receptor agonist be administered by

intravenous infusion at a dosage of about 140 µg/kg/min.

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12.

Claim 3 requires that the myocardial dysfunction be selected from the group

consisting of coronary artery disease, ventricular dysfunction and differences in blood flow through the disease free coronary vessels and stenotic coronary vessels. 13. Claim 5 specifies certain techniques for detecting the presence and assessing the

severity of the myocardial dysfunction, including by radiopharmaceutical myocardial perfusion imaging. Claims 10 and 22 identify a group -- including scintigraphy, SPECT and PET, among others -- from which the method of radiopharmaceutical myocardial perfusion imaging may be selected. Claims 12 and 26 require that the method of radiopharmaceutical myocardial perfusion imaging is scintigraphy. 14. Claims 11, 12, 21 and 25 identify radiopharmaceutical agents for use with the

radiopharmaceutical myocardial perfusion imaging, including thallium-201. 15. The alleged inventions in asserted claims 1, 3-12, 17, 18, 20-26 and 43 of the `877

patent were conceived on or after December 28, 1987. III. Anticipation 16. The asserted claims of the `877 patent are invalid as anticipated by one or more of

United States Patent No. 5,731,296 ("the `296 patent") and Request to the Ethics Committee at Karolinska Institute dated December 28, 1987, and identified as having arrived on February 3, 1988 (the "Karolinska Request"). 17. Plaintiffs cannot establish conception of the alleged inventions in asserted claims

1, 3-12, 17, 18, 20-26 and 43 of the `877 patent prior to December 28, 1987. 18. 19. The `296 patent, including Example XIII thereof, is prior art to the `877 patent. The `296 patent discloses every element of the asserted claims of the `877 patent.

Example XIII of the `296 patent describes the use of adenosine in the diagnosis of coronary heart

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disease in humans by radionuclide scintigraphy. Example XIII states that the dose of adenosine for this purpose should lie in the range of 10 to 150 µg/kg/minute. Example XIII also identifies the use of radio-isotopes such as thallium-201 and gamma radiation detection to visualize myocardial irrigation. The `296 patent further discloses continuous infusion of adenosine to humans at varying rates under varying conditions. 20. 21. The Karolinska Request is prior art to the `877 patent. The Karolinska Request discloses every element of asserted claims 1, 3-5, 7-12,

17, 20-26 and 43 of the `877 patent. The Karolinska Request proposes replacing the coronary dilating substance of dipyridamole with adenosine. The Karolinska Request notes that dipyridamole has the same effect as adenosine and is used as a diagnostic tool in myocardial scintigraphy with thallium. The Karolinska Request identifies a dose of 60 µg/kg/minute of adenosine, which, according to the Karolinska Request, is sufficient for dilation of coronary arteries. The Karolinska Request also identifies use of thallium-201 as the radiopharmaceutical agent for scintigraphy. IV. Obviousness 22. The asserted claims of the `877 patent are invalid as obvious in light of various

combinations of the following references and/or the knowledge and skill in the art at the time: The `296 patent; Albro, P.C., et al., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Coronary Vasodilatation: III. Clinical Trial, Am. J. Cardiol., 42:751-760 (1978) ("Albro"); I. Biaggioni et al., Cardiovascular effects of adenosine infusion in man and their modulation by dipyridamole, Life Sciences 39:2229-2236 (1986) (Biaggioni 1986);

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I. Biaggioni et al., Cardiovascular and respiratory effects of adenosine in conscious man: evidence for chemoreceptor activation, Circulation Research 61(6):779-786 (Dec. 1987) ("Biaggioni 1987"); T.B.G. Conradson et al., Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole, Acta Physiol Scand. 129:387-391 (1987) ("Conradson"); R.W. Fuller, Circulatory and respiratory effects of infused adenosine in conscious man," Br. J. Clin. Pharma., 24:309-317 (1987) ("Fuller"); Gould, K.L., Noninvasive Assessment of Coronary Stenoses by Myocardial Imaging During Pharmacologic Vasodilatation: II. Clinical Methodology and Feasibility, Am. J. Cardiol., 41:279-287 (1978) ("Gould 1978"); A.S. Iskandrian et al., Dipyridamole cardiac imaging, Am. Heart J. 115(2):432443 (Feb. 1988) ("Iskandrian"); M. Lagerkranser et al., Central and splanchinic hemodynamics in the dog during controlled hypotension with adenosine, Anesth. 60:547-552 (June 1984) ("Lagerkranser"); J. Leppo et al., Quantitative thallium-201 redistribution with a fixed coronary stenosis in dogs, Circulation 63(3):632-639 (March 1981) ("Leppo"); A. Öwall et al., Clinical experience with adenosine for controlled hypotension during cerebral aneurysm surgery, Anesth Analg. 66:229-34 (1987) ("Owall"); A. Sollevi et al., Cardiovascular effects of adenosine during controlled hypotension in cerebral artery aneurysm surgery, Anesthesiology 59(3): A9 (Sept. 1983) ("Sollevi 1983"); A. Sollevi, et al., Controlled hypotension with adenosine in cerebral aneurysm surgery, Anesthesiology, 61:400-405 (Oct. 1984) ("Sollevi 1984b"); A. Sollevi, Cardiovascular effects of adenosine in man: possible clinical implications, Progress in Neurobiology 27:319-349 (1986) ("Sollevi 1986"); H. W. Strauss and Bertram Pitt, Noninvasive detection of subcritical coronary arterial narrowings with a coronary vasodilator and myocardial perfusion imaging; The American Journal of Cardiology, 30:403-406 (1977) ("Strauss 1977"); and The Karolinska Request. 23. Gould 1978 discloses a method of detecting the presence and assessing the

severity of myocardial dysfunction in a human by (1) administering dipyridamole intravenously

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in an amount sufficient to cause coronary artery dilation (142 µg/kg/min) and (2) performing a technique on the human ­ administration of thallium-201 followed by myocardial imaging ­ to detect the presence and assess the severity of the dysfunction. Gould 1978 also expressly suggests substituting another, more potent, vasodilator for dipyridamole in the diagnostic procedure. 24. Albro discloses a method of detecting the presence and assessing the severity of

myocardial dysfunction in a human by (1) intravenously administering dipyridamole in an amount sufficient to cause coronary artery dilation (142 µg/kg/min) and (2) performing a technique on the human ­ administration of thallium-201 followed by myocardial perfusion imaging ­ to detect the presence and assess the severity of the dysfunction. Albro also provides motivation to substitute adenosine for dipyridamole in the method described in Albro. 25. It was known prior to 1987 that the particular vasodilator used to increase blood

flow for myocardial perfusion imaging was not critical, provided that adequate vasodilation was achieved. 26. It was known in the art at the relevant time that dipyridamole was an adenosine

uptake inhibitor and that the vasodilation action of dipyridamole was linked to metabolism and transport of adenosine. 27. By mid 1987, it was known in the art that adenosine could be safely administered

to humans as a continuous, intravenous infusion at various infusion levels. 28. Sollevi 1983 discusses continuous intravenous infusion of adenosine at a mean

dose of 140 µg/kg/min to anesthetized patients undergoing surgery who had been pretreated with dipyridamole. Sollevi 1984b discloses continuous intravenous infusion of adenosine at rates of 10 to 320 µg/kg/min to anesthetized patients who had been pretreated with dipyridamole.

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Sollevi 1986 discusses continuous intravenous infusion of adenosine to humans for various purposes at various rates, including ranges of 20-50 µg/kg/min, 50-150 µg/kg/min, and 150-350 µg/kg/min. 29. Biaggioni 1986 discloses continuous intravenous infusion of adenosine to

conscious humans at rates of 10, 20, 40, 60, 80, 100 and 140 µg/kg/min for periods of 15 minutes each. Biaggioni 1987 discloses continuous intravenous infusion of adenosine to humans at doses of 80 to 180 µg/kg/min. 30. Conradson discloses continuous, intravenous infusion of adenosine to conscious

humans at rates of 70 to 100 µg/kg/min. Fuller discloses continuous intravenous infusion of adenosine to conscious healthy humans at rates up to 200 µg/kg/min. Owall discloses continuous infusion of adenosine to anesthetized patients at rates of 88 to 530 µg/kg/min. 31. Iskandrian, a February 1988 article, discusses the then-established method of

detecting the presence and assessing the severity of myocardial dysfunction in a human by (1) administering dipyridamole in an amount sufficient to cause coronary artery dilation, including intravenous administration at a rate of 142 µg/kg/min, and (2) administering thallium-201 followed by myocardial perfusion imaging to detect the presence and assess the severity of the dysfunction. Iskandrian also provides motivation for substituting another vasodilator, such as adenosine, for dipyridamole in the described method. 32. Iskandrian identifies adenosine triphosphate as a coronary vasodilator.

Lagerkranser teaches that adenosine triphosphate is degraded entirely to adenosine and its breakdown products. 33. A person of ordinary skill in the art at the relevant time would have reasonably

expected that continuous infusion of adenosine, at rates within the ranges disclosed in the art,

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would likely succeed as a pharmacologic stress agent in connection with myocardial perfusion imaging. 34. A person of ordinary skill in the art at the time would have reasonably expected

that adenosine, administered at a rate within the ranges disclosed in the art, would succeed as a substitute for dipyridamole as a pharmacologic stress agent in connection with myocardial perfusion imaging. 35. The asserted claims of the `877 patent are also obvious in light of studies

involving the use of pharmacological stressors for myocardial perfusion imaging in dogs, in combination with the knowledge in the art and/or specific references in the art, as discussed below. 36. Strauss 1977 describes intravenous bolus injection of the coronary vasodilator

ethyl-adenosine-5'-carboxylic acid in connection with myocardial perfusion imaging in dogs. Ethyl adenosine was known as an intense coronary vasodilator. Strauss 1977 also expressly suggests that other vasodilators could be used. 37. Leppo describes a study of thallium distribution in dogs where the pharmacologic

stress agent used was adenosine. Leppo describes continuous intravenous infusion of adenosine to dogs in combination with a mixture of thallium-201 and microspheres. Leppo further describes recording myocardial scintigraphic images with a standard gamma camera. 38. A person of ordinary skill in the art would have had a reasonable expectation,

based on Strauss or Leppo in light of the knowledge in the art and/or in combination with the other references in that art, that use of adenosine for myocardial perfusion images in humans would succeed.

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V.

Secondary Considerations 39. Throughout this case, Plaintiffs have consistently relied upon three secondary

considerations in an attempt to rebut Defendants' prima facie obviousness case: commercial success, skepticism of experts, and unexpected results. 40. In their Statement of Issues of Law that Remain to Be Litigated, Plaintiffs refer to

at least four additional secondary considerations: long-felt need, teaching away, failure of others, and acclaim in the field. 41. As set forth in Defendants' Statement of Issues of Law that Remain to be

Litigated, determining whether or not certain secondary considerations exist in a case is a factual inquiry. Plaintiffs have not yet offered any factual proof with respect to the secondary considerations of long-felt need, teaching away, failure of others, and acclaim in the field, and none of them were addressed in Plaintiffs' expert reports. 42. Plaintiffs cannot be permitted to rely upon the secondary considerations of

long-felt need, teaching away, failure of others, and acclaim in the field at trial. A. 43. Commercial Success Plaintiffs have failed to demonstrate nexus between the asserted claims of the

`877 patent and the alleged commercial success of their Adenoscan® product. 44. The sales levels achieved by Adenoscan® provide no evidence of any superiority

of Adenoscan®, as these sales levels have no demonstrated nexus to the subject matter of the asserted claims of the `877 patent. 45. The commercial sales of Adenoscan® are a result of extensive marketing and

promotional campaigns; an increase in demand for myocardial perfusion imaging employing pharmacological stress agents that occurred for reasons unrelated to the asserted inventions; and

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the absence of marketing and promotion by the manufacturers of drugs that are competitive alternatives to Adenoscan®. B. 46. Skepticism There is no evidence of skepticism that demonstrates the non-obviousness of the

asserted claims of the `877 patent. 47. Numerous prior art publications describe the continuous intravenous infusion of

adenosine to humans. 48. The state of the art and knowledge in the art suggested substituting adenosine, the

direct acting agent, for dipyridamole, which acted indirectly either by inhibiting adenosine deaminase or by preventing the uptake of adenosine into these tissues. C. 49. Unexpected Results Plaintiffs have not demonstrated any unexpected results for the methods of the

asserted claims. 50. Any difference in results between adenosine and dipyridamole were expected

based on the knowledge in the art at the time of the properties, mechanism and half-life of both agents. VI. Exceptional Case 51. Plaintiffs have identified exceptional case under 35 U.S.C. § 285 as an issue to be

litigated. Defendants maintain that it is improper, and a waste of the parties' and Court's time and resources, to address issues of exceptional case at this time, and that all such issues should be bifurcated until the Court has rendered a decision on the merits and determined that there is a "prevailing party" as required by 35 U.S.C. § 285.

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EXHIBIT 4

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EXHIBIT 4 PLAINTIFFS' STATEMENT OF ISSUES OF LAW THAT REMAIN TO BE LITIGATED Plaintiffs reserve the right to modify, supplement, or change this Statement of Issues of Law That Remain to be Litigated (the "Statement") to the extent necessary to fairly respond to any issues that Defendants raise or drop in its Statement of Issues of Law That Remain to be Litigated. If any statement included herein as an issue of law should properly be considered an issue of fact, then it should be so considered. Similarly, if any statement included as an issue of fact should properly be considered an issue of law, then it is incorporated herein by reference. I. 1. PATENT VALIDITY The parties will litigate whether the Defendants have proven invalidity of the `877

patents by a showing of clear and convincing evidence. A patent is presumed valid. 35 U.S.C. § 282. In order to overcome the presumption of validity, the challenger bears the burden of proving invalidity by clear and convincing evidence. TP Labs., Inc. v. Prof'l Positioners, Inc., 724 F.2d 965, 971 (Fed. Cir. 1984). That burden is "constant and remains throughout the suit on the challenger" and "does not shift at any time to the patent owner." Id. 2. The challenger's "burden is especially difficult when the prior art was before the

PTO examiner during prosecution of the application." Al-Site Corp. v. VSI Int'l, Inc., 174 F.3d 1308, 1323 (Fed. Cir. 1999) (quoting Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1467 (Fed. Cir. 1990)). In other words, the 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

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(Fed. Cir. 2000) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, Inc., 725 F.2d 1350, 1359 (Fed. Cir. 1984)). A. 3. Anticipation

The Federal Circuit "requires that a party seeking to invalidate a patent under

§ 102 show that the allegedly invalidating prior art contains each and every element of [the] claimed invention." Union Oil Co. of California v. Atlantic Richfield Co., 208 F.3d 989, 994-95 (Fed. Cir. 2000) (internal citations omitted); In re Dillon, 919 F.2d 688, 715 (Fed. Cir. 1990) ("Section 102 describes prior art as what is published or otherwise known, including subject matter in public use or on sale. Not included is what is unknown, or knowledge that became known to the inventor through the inventor's own research."). 4. Thus, the parties will litigate whether Sicor, as the patent challenger, has proven

by clear and convincing evidence that every limitation of the asserted claims of the `877 patent are contained, in a single prior art reference. See Union Carbide Chemicals & Plastics Technology Corp. v. Shell Oil Co., 308 F.3d 1167, 1188 (Fed. Cir. 2002). A. 5. Obviousness

The parties will litigate whether Sicor, as the patent challenger, has proven by

clear and convincing evidence that the asserted claims of the `877 patent would have been obvious to one of ordinary skill in the art at the time of the invention. Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17 (1966); National Steel Car, Ltd. v. Canadian Pacific Railway, Ltd., 357 F.3d 1319, 1334 (Fed. Cir. 2004) ("It is elementary in patent law that, in determining whether a patent is valid . . . the first step is to determine the meaning and scope of each claim in suit. After construing the claims, a court must compare the prior art to claims as one of ordinary skill of art at the time of the invention would have done.") (internal citations omitted).

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6.

Obviousness is a conclusion of law based on the factual inquiries, as set forth in

Graham, which include consideration of (1) the scope and content of the prior art, (2) the differences between the prior art and the claimed subject matter as a whole, (3) the level of skill in the art, and (4) objective evidence of nonobviousness. Yamanouchi Pharm. Co., Ltd. v. Danbury Pharmacal, Inc., 231 F.3d 1339, 1343 (Fed. Cir. 2000). 7. The scope and content of the prior art must be considered as a whole. In re

Wesslau, 353 F.2d 238, 241 (C.C.P.A. 1965) ("It is impermissible . . . to pick and choose from any one reference only so much of it as will support a given position, to the exclusion of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art."). 8. The Federal Circuit has instructed that the prior art, not hindsight knowledge of a

patentee's success, must motivate a person of ordinary skill in the art to do what the patentee has done. Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., 2006 WL 3792689, *7 (Fed. Cir. 2006) (instructing that "mere identification in the prior art of each component of a composition does not show that the combination as a whole lacks the necessary attributes for patentability"); Yamanouchi, 231 F.3d at 1343; Grain Processing Corp. v. Am. Maize-Prods. Co., 840 F.2d 902, 907 (Fed. Cir. 1988) ("Care must be taken to avoid hindsight reconstruction by using `the patent in suit as a guide through the maze of prior art references, combining the right references in the right way so as to achieve the result of the claims in suit.'") (citing Orthopedic Equip. Co. v. United States, 702 F.2d 1005, 1012 (Fed. Cir. 1983)); C. & A. Potts & Co. v. Creager, 155 U.S. 597, 608 (1895) ("The apparent simplicity of a new device often leads an inexperienced person to think that it would have occurred to any one familiar with the subject; but the decisive answer

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is that, with dozens and perhaps hundreds of others laboring in the same field, it had never occurred to any one before."). 9. Proceeding contrary to the accepted wisdom is strong evidence of

nonobviousness. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 1542 (Fed. Cir. 1983). The Federal Circuit has recognized that a reference may "teach away" when "a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant." Tec Air, Inc. v. Denso Mfg. Michigan Inc., 192 F.3d 1353, 1360 (Fed. Cir. 1999). 10. Further, the prior art must provide a reasonable expectation of success. In re Dow

Chem. Co., 837 F.2d 469, 473 (Fed. Cir. 1988). Arguments that the claimed invention would have been "obvious to try" are not sufficient. Gillette Co. v. S.C. Johnson & Son, Inc., 919 F.2d 720 (Fed. Cir. 1990) (commenting that "we have consistently held that `obvious-to-try' is not to be equated with obviousness"). B. 11. Issues of Law Specific to the `877 Patent

With respect to claim 23, as read through claim 18 from which it depends

(hereinafter "claim 23(18)"), the parties will litigate whether a multiple dependent claim like claim 23 of the `877 patent, should be read as a plurality of dependent claims (Plaintiffs' position), or in the alternative, as simultaneously claiming all embodiments of all the claims from which it depends (Defendants' position). A multiple dependent claim shall be construed to incorporate by reference the limitations of the particular claim in relation to which it is being considered. 35 U.S.C. § 112, ¶ 5 (2000); M.P.E.P. § 608.01(n) 600-86 (explaining that multiple dependent claims "must be considered in the same manner as a plurality of single dependent claims"); H.R. Rep. No. 94-592, at 1241 (1975) ("[A] multiple dependent claim, as such, does

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not contain all the limitations of all the claims to which it refers, but rather, contains at any one time only those limitations of the particular claim under consideration."). 12. The parties will litigate whether the disclosure of a broad numerical range is

sufficient to anticipate the dose of claim 23(18) of the `877 patent. Atofina v. Great Lakes Chem. Corp., 441 F.3d 991, 1000 (Fed. Cir. 2006) ("The disclosure is only that of a range, not a specific temperature in that range, and the disclosure of a range is no more a disclosure of the end points of the range than it is of each of the intermediate points."). 13. The parties will litigate whether Example XIII of the `296 patent qualifies as prior

art under 35 U.S.C. § 102(e) to each of the claims of the `877 patent. See, e.g., Waldemar Link, GmbH & Co. v. Osteonics Corp., 32 F.3d 556, 558 (Fed. Cir. 1994). In order to antedate a reference, "all the applicant can be required to show is priority with respect to so much of the claimed invention as the reference happens to show. When he has done that he has disposed of the reference." In re Stempel, 241 F.2d 755 (C.C.P.A. 1957) ("In the case of a reference, it is fundamental that it is valid only for what it discloses and if the applicant establishes priority with respect to that disclosure, and there is no statutory bar, it is of no effect at all."). 14. The parties will litigate whether the Karolinska Request qualifies as a "printed

publication" under 35 U.S.C. § 102(a) to anticipate the `877 patent. The Federal Circuit instructs that dissemination and public accessibility are key factors when determining whether a reference qualifies as a "publication." According to Bruckelmyer v. Ground Heaters, a reference is "publicly accessible" if it has "been disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art exercising reasonable diligence, can locate it . . . ." 453 F.3d 1374, 1378 (Fed. Cir. 2006). The ability to locate a printed publication is critical. Id. at 1379 (upholding In re Cronyn, 890 F.2d 1158 (Fed. Cir.

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1989)); see also Cronyn, 890 F.2d at 1160-61 (holding that theses kept in a university library along with an index of cards containing the students' names and the theses' titles but no indication of the subject matter were not meaningfully indexed or catalogued and therefore insufficient to qualify as prior art). C. 15. Objective Evidence of Nonobviousness

The parties will litigate whether objective indicia of nonobviousness demonstrate

the patentability of the methods claimed in the `877 patent. Graham, 383 U.S. at 17-18; ProMold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1573 (Fed. Cir. 1996) ("It is the secondary considerations that are often the most probative and determinative of the ultimate conclusion of obviousness or nonobviousness."); Ruiz v. A.B. Chance, Co., 234 F.3d 654, 667 (Fed. Cir. 2000) (stating that "secondary considerations, when present, must be considered in determining obviousness"). 16. The Federal Circuit has emphasized the need for evaluating objective evidence of

nonobviousness. Id. This evaluation must be made during a court's consideration of whether the claimed invention is obvious, not after such a determination is complete. Lindemann Maschinfabrik GMBH v. American Hoist and Derrick Co., 730 F.2d 1452, 1461 (Fed. Cir. 1984). (1) 17. Long-Felt Need

Evidence of a long-felt and unresolved need until the solution offered by the

patented invention supports a finding of nonobviousness. Goodyear Tire & Rubber Co. v. RayO-Vac Co., 321 U.S. 275, 279 (1944); Georgia Pacific Corp. v. United States Gypsum Co., 195 F.3d 1322, 1330 (Fed. Cir. 1999, as amended 2000). (2) 18. Unexpected Results

Evidence of unexpected results, in the eyes of a person of ordinary skill in the art,

can rebut a prima facie case of obviousness. See In re Papesch, 315 F.2d 381 (C.C.P.A. 1963)

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(reversing a finding of obviousness where the claimed chemical compound contained minor structural changes at three locations that transformed the un-modified compound from an inactive anti-inflammatory agent to an active anti-inflammatory compound). This is particularly true in fields such as chemistry or medicine, where even slight changes in a product may "yield substantially different results." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). (3) 19. Commercial Success

The commercial success of an invention, generally demonstrated by a showing of

significant sales in the relevant market, is evidence of nonobviousness. Goodyear Tire & Rubber Co., 321 U.S. at 279; Pro-Mold, 75 F.3d at 1573-74; Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851 F.2d 1387 (Fed. Cir. 1988); Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1382 (Fed. Cir. 1986) ("[The] record shows that advertising makes those in the industry-- hospitals, doctors, and clinical laboratories-- aware of the diagnostic kits but does not make these potential users buy them; the products have to work, and there is no evidence that that is not the case here or that the success was not due to the merits of the claimed [invention]-clearly contrary to the district court's finding.") (emphasis added). (4) 20. Teaching Away and Skepticism in the Field

Where the prior art "teaches away" from the claimed invention rather than

motivating a person of ordinary skill in the art to do what the patentee has done, the claimed invention is nonobvious. In re Hedges, 783 F.2d 1038, 1041 (Fed. Cir. 1986). 21. Evidence of initial skepticism, surprise, or incomprehension upon learning of the

invention and thereafter praising its value is strong evidence of nonobviousness. United States v. Adams, 383 U.S. 39, 52 (1966); Evtl. Designs, Ltd. v. Union Oil Co. of Cal., 713 F.2d 693, 69798 (Fed. Cir. 1983); Ruiz, 234 F.3d at 668 ("Proceeding contrary to the accepted wisdom . . . is strong evidence of unobviousness.") (internal citations omitted). This is particularly true where 7

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"the skepticism is expressed at the time of the invention, in a nonadversarial setting." Burlington Industries, Inc. v. Quigg, 229 U.S.P.Q. 916, 919 (D.D.C. 1986), aff'd, 822 F.2d 1581 (Fed. Cir. 1987). D. 22. Exceptional Case

The parties will litigate whether this is an exceptional case and whether Plaintiffs

are entitled to reasonable attorney fees. In ANDA-induced infringement actions, attorney fees for an "exceptional case" are specifically authorized under 35 U.S.C. § 271(e)(4) (in accordance with 35 U.S.C. § 285). For example, a baseless Paragraph IV certification, when combined with litigation misconduct, is sufficient to support a claim for an "exceptional case." See Yamanouchi, 231 F.3d at 1347.

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EXHIBIT 5

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EXHIBIT 5 DEFENDANTS' STATEMENT OF ISSUES OF LAW Anticipation: 1. Whether the alleged inventions in asserted claims 1, 3-12, 17, 18, 20-26 and 43 of

the `877 patent are invalid under 35 U.S.C. § 102. Obviousness: 2. Whether the alleged inventions in asserted claims 1, 3-12, 17, 18, 20-26 and 43 of

the `877 patent are invalid under 35 U.S.C. § 103. 3. Whether there is a nexus between any alleged commercial success of Adenoscan®

and the alleged invention of asserted claims 1, 3-12, 17, 18, 20-26 and 43 of the `877 patent. Conception: 4. Whether the alleged inventions of claims 1, 3-12, 17, 18, 20-26 and 43 of the `877

patent were conceived by the named inventors of the `877 patent prior to December 28, 1987. Exceptional Case: 5. Plaintiffs have identified exceptional case under 35 U.S.C. § 285 as an issue to be

litigated. Defendants maintain that it is improper, and a waste of the parties' and the Court's time and resources, to address issues of exceptional case at this time and that all such issues should be bifurcated until the Court has rendered a decision on the merits and determined that there is a "prevailing party" as required by 35 U.S.C. § 285. Additional Issues: 6. Plaintiffs' Statement of Issues of Law That Remain to be Litigated (Exhibit 4)

includes under the heading "objective evidence of nonobviousness" topics relating to alleged secondary factors, which Defendants believe raise issues of fact, not law. See Para-Ordnance

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Mfg., Inc. v. SGS Importers Int'l, Inc., 73 F.3d 1085, 1091 (Fed. Cir. 1995). Defendants address these topics concerning alleged secondary factors in their Statement of Issues of Fact That Remain to be Litigated (Exhibit 3). To the extent that any issue identified by Defendants as an issue of fact should properly be considered as an issue of law, Defendants incorporate it herein by reference. Similarly, to the extent that any issue identified herein as an issue of law should properly be considered an issue of fact, it should be so considered. 7. Plaintiffs' Statement of Issues of Law That Remain To Be Litigated includes

argument and characterizations of legal authority which Defendants dispute. Defendants will respond where necessary and appropriate, as the issues arise at trial and/or in post-trial briefing, or as otherwise directed by the Court.

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EXHIBIT 6

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Plaintiffs' Response to Sicor's Objections

Trial Summary Exhibit # TX001 U.S. Patent No. 5,731,296 (filed on Mar. 15, 1993, issued on Mar. 29,1998).

Depo Exhibit #

Bates Begin

Bates End

FRE Bases of Objection

FRE Bases of Admission

Admit

Case

TX002

TX003

PDX001 PDX043 PDX125 PDX148 PDX167 Klabunde03 DDX047 U.S. Patent No. 5,070,877 PDX002 (filed Mar. 29, 1989, issued DDX003 on Dec. 10, 1991). PDX044 PDX124 PDX146 Adenoscan product PDX003 description. PDX046

No objection

Item/King

No objection

King

SIC005325

SIC005331

Item: 402 403 (cumulative) King: 402 403 (cumulative) Item: 402 403 (cumulative) King: 402 403 (cumulative) 402 403 (cumulative) 801(c) and 802 Lack of foundation Item: 402 King: 402

Item: 402 403, no basis for exclusion King: 402 403, no basis for exclusion Item: 402 403, no basis for exclusion King: 402 403, no basis for exclusion 402 403, no basis for exclusion 803(6) 901(a), 902(11) Item: 402 King: 402

Item/King

TX004

Excerpt from Sicor's ANDA PDX004 for Adenosine Injection, PDX045 USP, dated 12/06/2004.

SIC004124

SIC004184

Item/King

TX005

TX006

Letter from R. Blevins to D. DDX039 Hilleman, copying S. Mohiuddin, dated 08/02/1989. Teva Press Release PDX048 announcing approval of adenosine injection, dated 06/16/2004.

K06996

K06997

King

Item/King

Page 1 of 86

Case 1:05-cv-00337-SLR

Document 133

Filed 01/26/2007

Page 44 of 181

Plaintiffs' Response to Sicor's Objections

Trial Summary Depo Exhibit Bates Begin Exhibit # # TX007 Amendment to application PDX050 SIC005356 to market adenosine injection for thallium myocardial imaging submitted by Sicor to FDA, dated 4/16/2005. TX008 Sicor's ANDA for Adenosine Injection, USP, dated 12/06/2004. PDX054 PDX053 SIC004124

Bates End

FRE Bases of Objection

FRE Bases of Admission

Admit

Case

SIC005362

Item: 402 King: 402

Item: 402

Item/King

SIC005324

Item: 402 403 (cumulative) 1006 (voluminous document)

King: 402 Item: 402 403, no basis for exclusion 1006, no basis for exclusion King: 402 403, no basis for exclusion 1006, no basis for exclusion Item: 402 King: 402 Item: 402 King: 402 Item: 402 403, no basis for exclusion non-hearsay use (801); 803(6); 801(d)(2)(D) King: 402 403, no basis for exclusion non-hearsay use (801); 803(6); 801(d)(2)(D)

Item/King

TX009

Fujisawa Product Development Report for Adenoscan IV, dated 11/30/1993.

PDX057

AST0075387

King: 402 403 (cumulative) 1006 (voluminous document) AST0075467 Item: 402 King: 402 Item: 402 King: 402 Item: 402 403 (waste of time) 801(c) and 802 King: 402 403 (waste of time) 801(c) and 802

Item/King

TX010

TX011

Teva Press Release PDX058 announcing tentative approval of adenosine injection, dated 02/13/2006. Email from R. Lowe to J. PDX059 Pastore, W. Bondinell, and K. Feldtmose, copying S. Hernandez, dated 11/16/2004.

Item/King

SIC011505

SIC011505

Item/King

Page 2 of 86

Case 1:05-cv-00337-SLR

Document 133

Filed 01/26/2007

Page 45 of 181

Plaintiffs' Response to Sicor's Objections

Trial Summary Exhibit # TX012 Letter from Sicor to Item, Fujisawa, and Astellas, dated 04/16/2005.

Depo Exhibit # PDX060A

Bates Begin

Bates End

FRE Bases of Objection

FRE Bases of Admission

Admit

Case

AST0086511

AST0086524 Item: 402 403 (waste of time) King: 402 403 (waste of time) AST0086545 Item: 402 403 (waste of time) King: 402 403 (waste of time) AST0213253 Item: 402 403 (waste of time) King: 402 403 (waste of time) Item: 403 (cumulative) 801(c) and 802 King: 403 (cumulative) 801(c) and 802 Further objections reserved pending Court's consolidation of issue for trial

Item: 402 403, no basis for exclusion King: 402 403, no basis for exclusion Item: 402 403, no basis for exclusion King: 402 403, no basis for exclusion Item: 402 403, no basis for exclusion King: 402 403, no basis for exclusion Item: 403, no basis for exclusion non-hearsay use (801); 801(d)(2) King: 403, no basis for exclusion