I. Modified Agreements

Biotech Company**

Pharma Company(Symbol)

Type/Product Area

Amount

Terms/Details (Month)

Abgenix Inc.

Pfizer Inc. (NYSE:PFE)

Expansion of 12/97 collaboration and license agreement on use of Abgenix¿s XenoMouse technology to make fully human antibodies to 3 of Pfizer¿s antigen targets

$10M

Pfizer exercised option for 2nd antigen target (undisclosed; 1st target is for oncology applications); with exercise of option, Abgenix gets $10M in cash plus royalties (10/98)

Advanced Tissue Sciences Inc.

Smith & Nephew plc (U.K.)

Expansion of 4/96 joint venture to commercialize Dermagraft for treating diabetic foot ulcers to include indications of venous and pressure ulcers as well as commercialization of Dermagraft-TC for treating burns

$111M (equity; % ND)

Companies signed binding letter of intent to expand joint venture; Advanced Tissue gets $35M over next 12 months for additional indications, including immediate $20M in equity purchase, $16M in milestones and 1-time payment of $10M for demonstrating ability of Dermagraft-TC for treating pressure sores (1/98)

Advanced Tissue Sciences Inc.

Smith & Nephew plc (U.K.)

Expansion of 4/96 joint venture to commercialize Dermagraft (for diabetic foot ulcers and venous and pressure ulcers) and Dermagraft-TC (for full and partial-thickness burns) to include new territory

ND

This joint venture was expanded once in 1/98 to include Dermagraft-TC for all wound-care applications outside the U.S. and all non-burn wound care applications in U.S.; now, Smith & Nephew will market Dermagraft-TC (to be renamed TransCyte) for burns in the U.S. (8/98)

Affymetrix Inc.

American Home Products Corp. (NYSE:AHP)

Exercise of option to subscribe to Affymetrix¿s Easy Access program for GeneChip expression probe arrays

ND

American Home exercised option under 1/98 agreement between its Genetics Institute subsidiary and Affymetrix; American Home and its affiliates get broad access to custom and standard GeneChips plus instrumentation and software; Affymetrix gets subscription fees and fixed per-chip fees (9/98)

Alliance Pharmaceutical Corp.

Ortho Biotech Inc./ The R.W. Johnson Pharmaceutical Research Institute (both are affiliates of Johnson & Johnson; NYSE:JNJ)

Restructuring of R&D and licensing agreement on Oxygent (intravascular perfluoro-chemical emulsion to be used as temporary oxygen carrier during surgery)

ND

Parties disagreed as to scope and timing of further clinical development, including whether to proceed with Phase III trials and for what indication; Alliance assumes full control of and responsibility at its own cost for remaining product development; Johnson & Johnson subsidiaries retain certain marketing rights (5/98)

Allelix Biopharmaceuticals Inc. (Canada)

Eli Lilly Canada Inc. (unit of Eli Lilly & Co.; NYSE: LLY)

Expansion of 1989 basic research collaboration to apply new technologies to 2 drug discovery programs (excitatory amino acid receptors as targets for drugs to treat central nervous system disorders; neuropeptide Y receptor as target for drugs to treat eating disorders)

ND

Expansion will increase Lilly¿s total investment in Allelix to more than US$21M since partnership began; collaboration already extended once in 1/95 (1/98)

Allelix Biopharmaceuticals Inc. (Canada)

Eli Lilly Canada Inc. (unit of Eli Lilly & Co.; NYSE: LLY)

Extension and expansion of partnership dating from 1989 on products for treating psychiatric, neurological and eating disorders

ND

Glutamate receptor program (for psychiatric and neurological disorders) has been extended for 2 years; genetic target program (for eating disorders) has been extended for 1 year (12/98)

Alza Corp.

Janssen Pharmaceutica Inc. (Belgium; unit of Johnson & Johnson; NYSE:JNJ)

Expansion of agreement to develop an E-Trans fentanyl product for treating acute pain (currently in Phase III trials; uses electric current to control drug administration through skin)

$21.5M

Alza will make 1-time payment of $21.5M to Janssen and will share operating profits from U.S. sales and get royalties on sales elsewhere; Janssen has right to market product and Alza has right to copromote in U.S. (1/98)

ArQule Inc.

Amersham Pharmacia Biotech

Extension of joint collaboration to develop advanced separations products, especially affinity ligands, via ArQule¿s combinatorial chemistry; agreement dates from 3/95

ND

This is the 4th extension; further details ND (8/98)

ArQule Inc.

Roche Bioscience (division of Roche Holding Ltd.; Switzerland)

Amendment to 9/96 collaboration on new therapeutics via ArQule¿s directed arrays (custom libraries of compounds closely analogous to leads provided by Roche Bioscience)

ND

Companies will continue collaboration in a different form (not defined) through 3/99; ArQule will provide Roche with screening libraries while continuing to optimize a number of Roche compounds (10/98)

Aurora Biosciences Corp.

Parke-Davis (division of Warner-Lambert Co.; NYSE: WLA)

Expansion of 9/97 agreement on Aurora¿s ultra-high-throughput screening system (UHTSS) to include development of automated master compound storage system for long-term housing of chemical and biological compounds

$9M

Wyeth-Ayerst will pay $9M over 15 months for the new system (8/98)

Aurora Biosciences Corp. and Sibia Neurosciences Inc.

Eli Lilly and Co. (NYSE:LLY)

Aurora provided Lilly with a sublicense to Sibia¿s transcription-based functional bio-assay for drug screening to be used in conjunction with Aurora¿s fluorescent assay technologies and other drug screening services

ND

Aurora and Lilly signed a collaboration in 1/97 giving Lilly access to Aurora¿s technologies for use in its internal drug discovery program; Aurora and Sibia cross-licensed each other¿s drug screening technologies in 1/97 and Aurora has now granted Lilly a sublicense; Sibia got up-front payment, annual maintenance fees and royalties (1/98)

Aurora Biosciences Corp. and Sibia Neurosciences Inc.

Merck & Co. Inc. (NYSE:MRK)

Aurora provided Merck with a sublicense to Sibia¿s patent on high-throughput drug screening for use in conjunction with Aurora¿s fluorescent assay technologies and other drug screening services

ND

Aurora and Merck signed a collaboration in 12/97 giving Merck access to Aurora¿s technologies for use in its internal drug discovery program; Aurora and Sibia cross-licensed each other¿s drug screening technologies in 1/97 and Aurora has now granted Merck a sublicense; Sibia got up-front payment (1/98)

Axys Pharmaceuticals Inc.

Boehringer Mannheim GmbH (Germany)

Expansion of 5/95 collaborative research agreement to identify genes involved in osteoporosis

ND

This agreement was originally between Sequana Therapeutics Inc. (which merged with Arris Pharmaceutical Corp. in 1/98 to form Axys Pharmaceuticals) and Boehringer¿s parent company, Corange International Ltd.; the alliance has been expanded and scientists will accelerate efforts to identify areas in human genome that correspond to genetic regions linked to bone metabolism in primates that were identified by Sequana; further details ND (3/98)

Axys Pharmaceuticals Inc.

Merck & Co. Inc. (NYSE:MRK)

Extension of 11/96 collaboration on small-molecule inhibitors of cathepsin K (cysteine protease) as therapies for osteoporosis

ND

Original agreement signed by Arris Pharmaceutical Corp. (which merged with Sequana Therapeutics Inc. in 1/98 to form Axys); companies extended collaboration to 11/99; further details ND (12/98)

Cell Therapeutics Inc.

Ortho Biotech Inc./ The R.W. Johnson Pharmaceutical Research Institute (both are affiliates of Johnson & Johnson; NYSE:JNJ)

Restructuring of 11/96 R&D and marketing agreement on lisofylline (anti-inflammatory drug for reducing toxicities from radiation and chemotherapy in cancer patients)

ND

Due to negative results of 1st Phase III trial, the regulatory time line for this drug has been altered; Cell Therapeutics will now control and fund product development; Johnson & Johnson to pay its share through 12/31/98; if new Phase III trial is positive, Johnson & Johnson has option of resuming responsibility for product development and marketing; if it exercises option, Cell Therapeutics gets additional payments; if not, then Cell Therapeutics can license product to other 3rd parties (7/98)

Cima Labs Inc.

Novartis Consumer Health Inc. (division of Novartis AG; Switzerland)

Novartis exercised option under 12/97 agreement to license consumer products developed via OraSolv fast-dissolve technology

ND

ND (7/98)

Connetics Corp.

Soltec Research Pty. Ltd. (Australia)

Connetics exercised its option under 6/96 agreement to license clobetasol mousse for treating severe dermatoses (high-potency corticosteroid formulated as quick-break foam)

ND

Connetics gets exclusive rights to develop and market product in North America (1/98)

Corixa Corp.

Pasteur Merieux Connaught (unit of Rhone-Poulenc Group; France)

Extension and expansion of 3/97 collaboration on use of Corixa¿s protein adjuvant LeIF (Leishmania elongation initiation factor) in vaccines for infectious diseases; expanded to include comparisons of LeIF to other adjuvants

ND

Relationship stems from prior option agreement for Pasteur Merieux to license exclusive rights to LeIF as adjuvant; now, Pasteur Merieux has received new option to commercialize LeIF in same disease areas as previously; this option expires 6/30/98 (1/98)

Corixa Corp.

Pasteur Merieux Connaught (unit of Rhone-Poulenc Group; France)

Extension of 3/97 research agreement and license option on use of Corixa¿s protein adjuvant LeIF (Leishmania elongation initiation factor) in vaccines for infectious diseases

ND

This collaboration was already extended with new options in 1/98 but those options were to expire; Pasteur Merieux extended its options until 12/31/98 to license LeIF exclusively for use in influenza and respiratory syncytial virus vaccines and nonexclusively for use in HIV, tuberculosis and malaria vaccines (8/98)

Corixa Corp.

SmithKline Beecham Biologicals SA (Belgium; unit of SmithKline Beecham plc; NYSE:SBH; U.K.)

Extension of Smith-Kline¿s option under 3/97 cancer vaccine agreement to license early-stage antigen discovery program for an undisclosed cancer target

$2M

As part of 3/97 cancer vaccine collaboration, Corixa granted SmithKline 2 options for licensing its programs for vaccine development; SmtihKline paid $2M to extend the 1st option until 9/30/99 (the 2nd option must be acted on by 3Q:98) (2/98)

Corixa Corp.

SmithKline Beecham Biologicals SA (Belgium; unit of SmithKline Beecham plc; NYSE:SBH; U.K.)

Extension of 10/95 collaboration on T-cell-active recombinant subunit vaccines for infectious diseases, specifically tuberculosis

ND

SmithKline will provide additional research funding through 5/99 and gets exclusive option to license Corixa¿s tuberculosis antigens for use as vaccine through 8/99; if it exercises option, Corixa gets fee plus milestones; SmithKline gets exclusive worldwide rights except in Japan, where Corixa gets co-exclusive rights (8/98)

Corixa Corp.

SmithKline Beecham Biologicals SA (Belgium; unit of SmithKline Beecham plc; NYSE:SBH; U.K.)

Major expansion of 10/95 collaboration on T-cell-active vaccines for tuberculosis (amended 3/97 to include antigens for use in vaccines for breast and prostate cancer) to include vaccines for ovarian and colon carcinoma as well as for infectious diseases Chlamydia trachomatis and C. pneumoniae

$200M (equity; % ND)

Expanded agreement adds 5 new vaccine programs; SmithKline also has option to select 1 more application in future; 4-year collaboration; Smith-Kline licensed rights to Corixa¿s HER-2/neu vaccine for breast and ovarian cancer and its breast cancer antigen mammaglobin; except for tuberculosis vaccine, SmithKline gets exclusive worldwide rights to all vaccine products; SmithKline also has option on nonexclusive license to Corixa¿s LeIF adjuvant and its microsphere delivery technology; Corixa gets $49M committed funding over 4 years (which includes a $2.5M equity purchase now and $2.5M in the future, both at premium); Corixa gets milestones of $150M, as well as royalties; Corixa retains right to form non-vaccine partnerships for these antigens; transaction subject to antitrust considerations (10/98)

Corvas International Inc.

Ortho Clinical Diagnostics Inc. (unit of Johnson & Johnson; NYSE:JNJ)

Restructured agreement that supercedes 1992 agreement for license to Corvas¿ recombinant thromboplastin for use in diagnostics

$1M

Original 1992 agreement concerned supply of thromboplastin formulations to Ortho; Corvas has now licensed the diagnostic applications of its thrombo-plastin; Ortho also gets certain licenses related to production of recombinant tissue factor; Corvas gets $1M for these licenses and will continue to get royalties (12/98)

Corvas International Inc.

Schering-Plough Corp. (NYSE:SGP)

Extension of 6/97 collaboration on orally bioavailable inhibitors of serine protease necessary for replication of hepatitis C virus

$1.6M

Schering-Plough extended collaboration for 1 year and will provide additional $1.6M in funding through 5/99 (4/98)

Corvas International Inc.

Schering-Plough Corp. (NYSE:SGP)

Extension of 6/97 collaboration on oral anticoagulants based on protease inhibitors

$3M

Schering-Plough will support preclinical development through 9/99 and provide additional $3M in funding (12/98)

Cubist Pharmaceuticals Inc.

Merck & Co. Inc. (NYSE:MRK)

Expansion of 6/96 collaboration on compounds that inhibit function of amino acyl-tRNA synthetases for treating drug-resistant bacteria and fungi to include compounds discovered by Cubist

ND

This is 2nd expansion of agreement (1st was in 10/97); under new terms, compounds discovered independently by Cubist (plus the data) will be licensed by Merck for inclusion in the collaboration; Merck will fund R&D and pay milestones in return for access to Cubist¿s compounds; Cubist may conduct medicinal chemistry on and preclinical development of these compounds (5/98)

Cytel Corp.

Nextran unit of Baxter Healthcare Corp. (NYSE:BAX)

Expansion and extension of 10/96 collaboration on Cytel¿s alpha galactose carbohydrate product for use in antitransplant rejection device to include other carbohydrate products for treating rejection associated with xeno-transplantation

ND

New agreement allows for broader application of Cytel¿s carbohydrate products (made via sugar nucleotide cycling technology); Cytel has exclusive agreement to supply products to Nextran; Cytel gets milestones; Baxter invested $1M in Cytel¿s $8.4M private placement (12/97); Cytel will develop and manufacture products (2/98)

Desmos Inc.*

Baxter Healthcare Corp. (subsidiary of Baxter International Inc.; NYSE:BAX)

Renewal and extension of 9/97 collaboration on use of Desmos¿ extracellular matrix as biocoating for percutaneous implants used in renal therapy

ND

ND (7/98)

Emisphere Technologies Inc.

Eli Lilly and Co. (NYSE:LLY)

Expansion of 2/97 agreement to use Emisphere¿s technology for oral delivery of therapeutic proteins and exercise of 2 options to license technology for 2 specific proteins of Lilly (1 in osteoporosis; 1 in endocrinology, including growth disorders)

ND

Lilly executed 2 license agreements and made 2 milestone payments to Emisphere (both are part of the terms of the original agreement) (3/98)

Epimmune Inc. (subsidiary of Cytel Inc.)

G.D. Searle & Co. (wholly owned subsidiary of Monsanto Co.; NYSE:MTC)

Definitive agreement to collaborate on cancer vaccines developed via Epimmune¿s library of antigenic cancer epitopes and immunostimulant technology (PADRE)

$100M (13.4% equity)

Letter of intent signed 9/97, at which time Searle invested $5M in Cytel; in definitive agreement, Searle invested additional $3.9M in Cytel preferred stock and $6.1M in Epimmune preferred stock; Cytel simultaneously invested $3.9M in Epimmune preferred stock; Searle now owns 13.4% of Epimmune, while Cytel owns the rest; preclinical and clinical milestones could total $100M over next 10-12 years; Searle gets worldwide exclusive rights to Epimmune¿s epitope and PADRE technologies in cancer field (excluding rights previously granted elsewhere); Epimmune gets royalties (3/98)

Gene Logic Inc.

The Procter & Gamble Co. (NYSE:PG)

Expansion of 6/97 collaboration on therapeutic targets for heart failure (via Gene Logic¿s READS gene expression technology for database of differential gene expression) to include target in osteoporosis

ND

Expansion will result in doubling of Gene Logic¿s annual revenues from collaboration; Procter & Gamble gets access to databases and will pay annual fees; Gene Logic also gets milestones and royalties; the partners can now work together on any disease indication; Gene Logic can work with 3rd parties on specific indications (12/98)

Gene Logic Inc.

Rhone-Poulenc Rorer Inc. (subsidiary of Rhone-Poulenc SA; NYSE:RP; France)

Expansion of 9/97 alliance to conduct p53 testing for clinical trials of adenoviral p53 gene therapy for cancer

ND

The original agreement was between Rhone-Poulenc Rorer and OncorMed (which Gene Logic acquired in 9/98); this is expansion of alliance to analyze genes for gene therapy clinical trials; financial details ND (11/98)

GeneMedicine Inc.

Corange International Ltd. (unit of Roche Holdings Ltd.; Switzerland)

Expansion of 7/95 collaboration on non-viral gene therapies for certain cancers to cover all human cancer indications for gene medicines using genes for interleukin-2 (IL-2), interferonalpha (IFN-a) and interleukin-12 (IL-12); genes used alone or in combination

ND

Research term of collaboration extended until 2/02; companies will work exclusively together on gene therapies using the 3 genes; focus on Phase II trial of IL-2 in head and neck cancer and preclinical through Phase I/II trials of other 2 genes (same indication); on successful completion of 1 clinical trial, GeneMedicine has option to share development costs in exchange for 50% of profits or to get royalties on worldwide sales; Roche will convert additional equity payments under 7/95 agreement into research and milestone payments; GeneMedicine can partner with other firms in gene therapy for cancer using different genes (8/98)

GeneMedicine Inc.

Merck & Co. Inc. (NYSE:MRK)

Expansion of 12/97 collaboration to evaluate GeneMedicine¿s Gene-Switch technology (to control gene expression) with Merck¿s vector system for gene-based therapies

ND

Collaboration initially focused on 2 therapeutic applications; it has now been expanded to include 3 applications; further details ND (11/98)

Genome Therapeutics Corp.

Astra Research Center Boston (division of Astra AB; Sweden)

Extension of 9/95 R&D collaboration on anti-infectives and vaccines for Helicobacter pylori infection (peptic ulcers, gastritis, stomach cancer) based on sequence data from H. pylori genome

ND

This is 2nd extension of collaboration (1st was in 7/97); agreement now extended at least through 8/99; program has moved to high-throughput screening of molecules at Astra; financial terms ND (6/98)

Genome Therapeutics Corp.

Schering-Plough Corp. (NYSE:SGP)

Extension of 12/95 collaboration on antiinfective agents for drug-resistant bacteria, including Staphylococcus aureus, via Genome Therapeutics¿ genomics-based high-throughput screening, target validation and assay development

$7M

Collaboration extended through 3/31/00; guaranteed payments to Genome Therapeutics raised $13M to $20M (it can also get as much as $23.5M more in milestones) (3/98)

Genome Therapeutics Corp.

Schering-Plough Corp. (NYSE:SGP)

Acceleration of 12/96 collaboration to identify genes involved in susceptibility to asthma

ND

Asthma genetics program is ahead of schedule; companies have enlarged program substantially and have moved up the time lines (11/98)

Genset SA (France)

Synthelabo SA (unit of L¿Oreal SA; France)

Extension of 12/96 research alliance to discover and sequence genes involved in or associated with prostate cancer

ND

Genset has discovered 1 gene associated with prostate cancer and identified others that may be involved; to confirm the latter, Synthelabo has extended collaboration for 1 year; Genset will get additional research funds and milestone payments (4/98)

Genzyme Transgenics Corp.

Eli Lilly and Co. (NYSE:LLY)

Expansion of 3/98 feasibility agreement to produce a transgenic therapeutic protein

$22M

Lilly¿s option to license protein expires 12/99; until then, Genzyme Transgenics will get $1M development funding; on execution of option, Genzyme Transgenics gets funding and milestones of $22M; Lilly gets worldwide rights; Genzyme Transgenics will manufacture protein and gets royalties (7/98)

Human Genome Sciences Inc.

Takeda Chemical Industries Ltd. (Japan)

Takeda exercised option under 6/95 agreement to license Human Genome¿s genomics-derived product candidate myeloid progenitor inhibitory factor-1 (currently in U.S. Phase I trials for protecting hematopoietic progenitor cells from effects of chemotherapy)

ND

Takeda exercised its option to develop and commercialize product in Japan; Human Genome got option fee for these rights and will get milestones and royalties; further details ND (2/98)

Hybridon Inc. (OTC Bulletin Board:HYBN)

G.D. Searle & Co. (subsidiary of Monsanto Co.; NYSE: MTC)

Extension and expansion of 1/96 collaboration on antisense drugs for inflammatory disease to include more targets in cardiovascular disease and cancer, including MDM2 oncogene

ND

Searle will continue to support research through 1/00; Searle has option of designating additional molecular targets; companies also initiated program focused on MDM2 oncogene (inhibits apoptosis) (7/98)

ImClone Systems Inc.

Wyeth-Lederle Vaccines (division of American Home Products Corp.; NYSE:AHP)

Extension of 9/93 collaboration to develop anti-idiotype and recombinant vaccines for gonorrhea

ND

This agreement was originally between ImClone and American Cyanamid Co. (since acquired by American Home Products); Im-Clone will continue to get research support, milestone payments and royalties; Wyeth-Lederle retains worldwide manufacturing and marketing rights and is responsible for all preclinical, clinical and regulatory work (5/98)

Immunex Corp.

American Home Products Corp. (NYSE:AHP)

Restructuring of product rights agreements and termination of oncology agreement; especially concerns Leukine, Mobist (FLT-3 ligand), IL-15 and CD40 ligand

ND

Immunex no longer obligated to fund certain oncology R&D at American Home¿s subsidiary American Cyanamid; Immunex gets worldwide rights to Leukine and 3 drugs still in clinic (to which American Home had held rights outside North America); Immunex will pay royalties to American Home on ex-North American sales; American Home has option to acquire rights to 4 future Immunex products; Immunex can convert 2 of those calls and then pay American Home milestones and royalties; for exercised call, Immunex gets fees, milestones and royalties (7/98)

Incyte Pharmaceuticals Inc.

Johnson & Johnson (NYSE:JNJ)

Expansion of 1/96 database subscription agreement (which covered LifeSeq human genome sequence and expression database) to include Incyte¿s PathoSeq microbial genome database

ND

Incyte gets annual access fees and could get royalties on future sales; further details ND (3/98)

Incyte Pharmaceuticals Inc.

Novartis AG (Switzerland)

Expansion of 6/97 database partnership to include Incyte¿s LifeSeq gene sequence and expression database

ND

Novartis gets nonexclusive access to LifeSeq database in exchange for annual access fees; further details ND (1/98)

Incyte Pharmaceuticals Inc.

Novartis AG (Switzerland)

Expansion of 6/97 database partnership to include Incyte¿s gene expression microarray technology

ND

This is the 2nd expansion of the partnership; Novartis gets data from DNA microarrays from the UniGEM product line as well as data from custom microarrays; Incyte gets access fees and per-experiment fees (7/98)

Incyte Pharmaceuticals Inc.

Pfizer Inc. (NYSE:PFE)

Extension and expansion of 6/94 genomic database partnership to include LifeSeq FL database of full-length genes and LifeSeq GeneAlbum DNA clone set

ND

Pfizer will continue to have access to Incyte¿s databases, including its LifeSeq gene sequence and expression database as well as others; collaboration extended for 3 years (intent announced 12/97); financial details ND (2/98)

Incyte Pharmaceuticals Inc.

Pfizer Inc. (NYSE:PFE)

Expansion of 6/94 genomic database partnership to include Incyte¿s LifeTools bioinformatics software and LifeArray microarray data analysis and management software

ND

Companies already extended and expanded agreement in 2/98; now, Pfizer will use Incyte¿s LifeTools and LifeArray to support its global research programs; details ND (9/98)

Inhale Therapeutic Systems Inc.

Baxter International Inc. (NYSE:BAX)

Renegotiation of 3/96 strategic collaboration to use Inhale¿s dry-powder pulmonary delivery system as technology platform for non-peptide, nonprotein drug candidates of Baxter (not identified)

ND

Companies agreed to focus efforts on the 1 compound with largest commercial potential (completed Phase I trial); 2 additional compounds remain in collaboration and may be developed later; Inhale gets all rights to a 4th compound (currently in preclinical stages); Inhale will continue to be responsible for product development, which Baxter will fund; Baxter responsible for worldwide commercialization; other terms remain unchanged (4/98)

Inhale Therapeutic Systems Inc.

Baxter International Inc. (NYSE:BAX)

Amendment of terms of 3/96 collaboration to use Inhale¿s dry-powder pulmonary delivery system for non-peptide, nonprotein drug candidates

ND

Companies intend to find 3rd party to further develop and commercialize an undisclosed compound; Baxter will continue to provide funding in preparation for Phase II trials while 3rd party is identified; product falls outside Baxter¿s current business focus; other 2 compounds in collaboration will remain and may be developed in future (10/98)

LeukoSite Inc.

Kyowa Hakko Kogyo Co. Ltd. (Japan)

Extension of 4/97 agreement on small-molecule antagonists that block chemokine receptors CCR1 and CXCR3 on leukocytes as treatments for inflammation and autoimmune diseases

ND

This agreement (which is part of a multinational drug discovery alliance that also includes Warner-Lambert Co.) was expanded once in 11/97; LeukoSite has now identified lead compounds; Kyowa Hakko had option to continue work on 1 or 2 targets and chose both; further details ND (4/98)

LeukoSite Inc.

Warner-Lambert Co. (NYSE:WLA)

Extension of 11/96 collaboration on small-molecule antagonists to the CCR5 and CXCR4 receptors (chemokine co-receptors used by HIV to enter T cells)

ND

2-year extension of collaboration (already expanded once in 11/97) (1/98)

Ligand Pharmaceuticals Inc.

Eli Lilly and Co. (NYSE:LLY)

Extension of Ligand¿s option (under 11/97 alliance on metabolic diseases) to acquire selected rights to 1 of Lilly¿s specialty drugs in certain markets of interest to Ligand

$20M

Lilly extended Ligand¿s option so that Ligand has additional time to complete its evaluation and assessment of product; if Ligand exercises option, Lilly gets milestones of $20M in Ligand stock; if Ligand does not exercise option, it can elect to sell $20M in equity to Lilly at 20% premium to market (3/98)

Ligand Pharmaceuticals Inc.

SmithKline Beecham plc (NYSE:SBH; U.K.)

Expansion of 2/95 collaboration on small-molecule, orally available drugs to control hematopoiesis; use of Ligand¿s STAT technology (signal transducers and activators of transcription) to target hematopoietic growth factors

ND

The collaboration was expanded twice; in 2/97, SmithKline exercised its option to include a 3rd drug discovery target and bought $2.5M in Ligand stock; in 8/97, SmithKline extended the term of the collaboration and bought a $2.5M convertible note (although these events both occurred in 1997, Ligand only announced them in 1998) (3/98)

Medarex Inc.

Merck KGaA (Germany)

Option to expand 4/94 collaboration on Medarex¿s MDX-477 bispecific antibody for certain cancers (targets epidermal growth factor receptor; currently in Phase II trials for head and neck cancer)

$1.5M

Merck paid $1.5M to obtain exclusive option on worldwide licensing rights to product; Medarex would retain U.S. rights; Merck will fully fund Phase II trials (12/98)

MedImmune Inc.

SmithKline Beecham plc (NYSE:SBH; U.K.)

Finalized agreement (from 12/97) to develop human papillomavirus vaccines for preventing cervical cancer and genital warts

$85M

Agreement, proposed 12/97, was subject to clearance under anti-trust laws, which occurred (1/98)

Metabasis Therapeutics Inc. (majority-owned subsidiary of Gensia Sicor Inc.)

Pfizer Inc. (NYSE:PFE)

Extension of 5/96 research collaboration on use of adenosine regulating agents as broad-spectrum analgesic drugs for treating pain

ND

This agreement was originally between Gensia Inc. and Pfizer; Pfizer extended collaboration through 5/99; Metabasis gets additional research funding plus milestones and royalties (if Pfizer selects product for clinical development) (3/98)

Microcide Pharmaceuticals Inc.

Daiichi Pharmaceutical Co. Ltd. (Japan)

Extension of 11/95 joint research agreement on small-molecule drugs to prevent antibiotic resistance in Gram-negative bacteria, especially Pseudomonas aeruginosa, by over-coming efflux pump mechanism

$3.5M

Daiichi extended research agreement for 1 year, to 3/31/99, and will pay additional $3.5M in research funding (4/98)

Microcide Pharmaceuticals Inc.

Ortho-McNeil Pharmaceuticals and the R.W. Johnson Pharmaceutical Research Institute (units of Johnson & Johnson; NYSE:JNJ)

Extension of 10/95 collaboration on therapeutics for Gram-positive bacterial infections, especially drug-resistant strains; focus on beta-lactam compounds

ND

Companies will continue joint development of beta-lactam compounds; Johnson & Johnson will support research for additional 8-14 months; the duration and amount of funding will depend on selection of 1 additional compound for development by 12/31/98; Microcide regained rights to its antibiotic potentiator technologies and compounds (10/98)

Myriad Genetics Inc.

Bayer Corp. (unit of Bayer AG; Germany)

Extension of 9/95 alliance to discover genes that predispose individuals to obesity, osteoporosis and asthma

$12.2M

Bayer extended collaboration until 9/02; Myriad has made significant progress toward isolating disease-causing genes; Myriad will get additional $6.2M in committed research funds plus $6M in milestones over next 2 years (12/98)

Neurogen Corp.

Pfizer Inc. (NYSE:PFE)

Extension of 11/95 collaboration on drugs that work as neuropeptide Y antagonists for treating obesity and eating disorders

ND

Pfizer will fund research for an additional year, beginning 11/98; further details ND (5/98)

Neurogen Corp.

Pfizer Inc. (NYSE:PFE)

Extension and expansion of collaborations on small-molecule drugs that act on specific GABA receptors in brain, on drugs for anxiety and cognition (from 2/92) and drugs for sleep disorders (from 6/94); added depression as new target

$12.5M

Collaboration extended for 2 years; Neurogen gets $6.25M per year in additional research funds (11/98)

Onyx Pharmaceuticals Inc.

Parke-Davis (division of Warner-Lambert Co.; NYSE:WLA)

Extension of 5/95 collaboration on drugs that affect cell-cycle regulation; for treating cancer and hyper-proliferative diseases

$25M

Collaboration extended for 3 years; Onyx gets $25M in committed funding plus milestones; Warner-Lambert also gets marketing rights in Japan (as well as rest of world); Onyx gets milestones tied specifically to development efforts in Japan (1/98)

OSI Pharmaceuticals Inc.

Hoechst Marion Roussel Inc. (subsidiary of Hoechst AG; Germany)

Extension of 3/97 agreement on orally active small-molecule inducers of erythro-poietin gene expression (for treating anemia due to chronic renal failure or associated with chemotherapy in AIDS and cancer patients)

ND

Companies extended agreement for 6 months to allow researchers to follow up on preclinical data; Hoechst Marion Roussel will continue to fund research during this period (4/98)

OSI Pharmaceuticals Inc.

Wyeth-Ayerst Laboratories (division of American Home Products Corp.; NYSE:AHP)

Exercise of option to license series of small-molecule, gene-transcription-based compounds that modulate expression of phosphoenol pyruvate carboxykinase for treating Type II diabetes

ND

Wyeth-Ayerst gets exclusive worldwide license to compounds; further details ND (1/98)

Palatin Technologies Inc.

Competitive Technologies Inc. (AMEX:CTT)

Exercised 11/97 option to license peptide analogue PT-14 for diagnosing and treating male erectile dysfunction (hormone activates melanocortin receptors in brain)

ND

Palatin gets exclusive rights to develop and commercialize product worldwide (5/98)

Palatin Technologies Inc.

Nihon Medi-Physics Co. Ltd. (Japan)

Restructuring of 12/96 collaboration on diagnostic and therapeutic radio-pharmaceuticals based on Palatin¿s MIDAS peptide technology (for design and synthesis of peptide mimetics)

ND

The 1st agreement between the parties was terminated when both decided to change the emphasis; this new letter of intent should become finalized in 1Q:99; Palatin gets up-front payments and milestones; further details ND (12/98)

Pharmacopeia Inc.

Berlex Laboratories Inc. (subsidiary of Schering AG; Germany)

Expansion of 2/95 agreement on use of combinatorial chemistry and high-throughput screening for drug leads for multiple sclerosis to pursue chemical optimization of lead compound against additional target

ND

Pharmacopeia will get additional research funding, milestones and royalties (8/98)

Pharmacopeia Inc.

Organon NV (the Netherlands)

Expansion of 5/96 agreement on use of combinatorial chemistry and high-throughput screening for drug leads to include development of compound against additional target

ND

Pharmacopeia will get additional research funding, milestones and royalties (8/98)

Phytera Inc.*

Tsumura & Co. (Japan)

Extension and expansion of 6/96 collaboration on use of Phytera¿s plant cell culture extract libraries to screen for small molecules to treat rheumatoid arthritis and allergies; will now also screen Phytera¿s marine microorganism extract libraries

ND

Collaboration extended through 6/00; Phytera gets research funds and milestones; companies co-own products; Phytera gets exclusive rights in North America; Tsumura gets exclusive rights elsewhere; companies will pay each other royalties (8/98)

ProScript Inc.*

Hoechst Marion Roussel Inc. (subsidiary of Hoechst AG; Germany)

Extension of 11/95 research collaboration on orally active drugs for inflammatory diseases and cancer; developed via ProScript¿s technology for inhibiting key enzymes in ubiquitin-proteasome pathway (suppress activation of gene transcription factor NF-kB)

ND

Hoechst Marion Roussel has extended research phase of collaboration for 1 year and has option to continue for a 2nd year; terms remain unchanged (6/98)

Regeneron Pharmaceuticals Inc.

Sumitomo Pharmaceuticals Co. Ltd. (Japan)

Expansion of 6/94 collaboration on BDNF (brain-derived neurotrophic factor) for treating amyotrophic lateral sclerosis

$5M

Sumitomo licensed the product for developing in Japan; Regeneron gets initial $5M payment plus milestones and royalties (8/98)

Repligen Corp.

Glaxo Wellcome plc (NYSE:GLX; U.K.)

Extension of 11/94 collaboration on chemokine inhibitors; companies have jointly developed high-through-put screening assay to identify small molecules that block interaction of pro-inflammatory chemokine with its receptor

ND

1-year extension; Glaxo will use assay to screen its internal compound library; Repligen will supply Glaxo with one of its carbohydrate analogue combinatorial libraries for screening, too; Glaxo gets worldwide rights to any products; Repligen gets research support and royalties; Glaxo has option to acquire rights to active compounds from Repligen¿s library (1/98)

Ribozyme Pharmaceuticals Inc.

Parke-Davis (division of Warner-Lambert Co.; NYSE:WLA)

Definitive agreement on collaboration to evaluate specific disease-related genes for drug intervention using Ribozyme¿s target validation technology (involves use of ribozymes to discover gene function and validate gene targets)

ND

Letter of intent signed 12/97; Ribozyme Pharmaceuticals will design and synthesize ribozymes against target genes designated by Parke-Davis; financial terms ND (3/98)

Scriptgen Pharmaceuticals Inc.*

Eli Lilly and Co. (NYSE:LLY)

Expansion of 5/97 collaboration to use Scriptgen¿s ATLAS technology (any target ligand affinity screen) against drug targets identified by Lilly

ND

Expanded collaboration doubles the number of Lilly targets from 2 to 4; further details ND (6/98)

Trega Biosciences Inc.

Ono Pharmaceutical Co. Ltd. (Japan)

Expansion of 6/97 R&D agreement on orally active small-molecule agonists of melanocortin receptor subtype MC-1 for treating inflammatory diseases

ND

Collaboration will now include a completely different target of interest to Ono; Trega will create custom combinatorial libraries, optimize lead compounds discovered by Ono and screen them; Ono will fund research and pay milestones and royalties (letter of intent 2/98; final agreement 5/98)

Trega Biosciences Inc.

The Procter & Gamble Co. (NYSE:PG)

Exercise of option from 1/95 collaboration to license series of lead compounds (identified via Trega¿s combinatorial chemistry technology) active against a biological target of Procter & Gamble

ND

Procter & Gamble exercised its option on an exclusive worldwide license to further develop compounds (5/98)

VIMRx Pharmaceuticals Inc.

Baxter Healthcare Corp. (subsidiary of Baxter International Inc.; NYSE:BAX)

Official naming of new cell therapy company Nexell Therapeutics Inc. (formed in 1997 to develop cell therapies for cancer and other diseases by combining Baxter¿s ex vivo cellular selection and storage business with VIMRx¿s access to gene therapy and genomics technology)

$130M (equity; % ND)

Companies signed letter of intent to form the new company (which is 80% owned by VIMRx and 20% owned by Baxter) in 6/97; the definitive agreement was signed in 10/97 and VIMRx shareholders approved the deal in 12/97; Baxter and VIMRx together contributed $40M to fund Nexell; Baxter is responsible for manufacturing, sales, marketing and distribution of products; Nexell will focus on R&D, partnerships and marketing development (2/98)

Xenova Group plc (U.K.)

Parke-Davis (division of Warner-Lambert Co.; NYSE:WLA)

Extension of 5/97 drug discovery collaboration based on Xenova¿s NatChem natural products library

ND

Xenova provided natural product extracts for screening, which Parke-Davis has done, identifying potential hits from which Xenova will now isolate and identify active chemicals; Xenova gets certain additional payments (10/98)

II. Terminated Agreements

Biotech Company**

Pharma Company(Symbol)

Type/Product Area

Amount

Terms/Details (Month)

Alkermes Inc.

The R.W. Johnson Pharmaceutical Research Institute (unit of Johnson & Johnson; NYSE:JNJ)

Termination of 12/96 collaboration on use of Alkermes¿ ProLease drug delivery system to develop sustained-release formulation of undisclosed drug for treating hormone-mediated disorders

-

Companies reached mutual decision to terminate collaboration; Alkermes regains all rights licensed to Pharmaceutical Research Institute, which has discontinued product development (11/98)

Alkermes Inc.

Schering-Plough Corp. (NYSE:SGP)

Termination of 1/92 agreement on use of Alkermes¿ ProLease drug delivery system to develop sustained-release formulation of Intron A (recombinant interferon alfa-2b)

-

Companies reached mutual decision to terminate collaboration; Alkermes regains all rights licensed to Schering-Plough; further details ND (11/98)

Allelix Biopharmaceuticals Inc. (Canada)

Astra AB (Sweden)

Termination of 6/96 agreement to develop ALX1-11 (recombinant human parathyroid hormone) for treating osteoporosis (currently in Phase II trials)

-

As a result of corporate restructuring at Astra, this program no longer fits; Allelix reacquired all product rights, including assets, know-how and proprietary rights; Allelix will assume responsibility for product development (9/98)

Amylin Pharmaceuticals Inc.

Johnson & Johnson (NYSE:JNJ)

Termination of 6/95 collaboration on Pram-lintide (synthetic analogue of human hormone amylin) for treating types I and II diabetes (currently in Phase III trials)

-

Johnson & Johnson provided 6 months¿ notice of its intent to terminate the collaboration, saying it was no longer in its best interests; all product rights return to Amylin, which will restructure its operations and reduce work force by 25% so it can continue product development (3/98)

Anergen Inc.

Novo Nordisk A/S (NYSE:NVO; Denmark)

Termination of 8/93 collaboration on use of AnergiX technology (inactivates disease-related T cells) for various diseases, including multiple sclerosis (Phase I trial ongoing)

-

This collaboration was extended for 2 years in 4/96, but Novo has now terminated it, as part of its change in strategic direction; all product rights return to Anergen; Novo will reimburse Anergen for cost of ongoing clinical trial; Anergen has no future obligations to Novo; Anergen will restructure its operations and reduce work force (2/98)

Axys Pharmaceuticals Inc.

Glaxo Wellcome plc (NYSE:GLX; U.K.)

Termination of 7/94 collaboration to discover genes associated with Type II diabetes (expanded in 2/96 to include genes for obesity)

-

This agreement was originally between Sequana Therapeutics Inc. (which merged with Arris Pharmaceutical Corp. in 1/98 to form Axys Pharmaceuticals) and Glaxo; on dissolution of agreement, Axys gets exclusive rights to all obesity family samples and data; Axys gets nonexclusive rights to certain Type II diabetes samples and data while Glaxo retains exclusive rights to certain Type II diabetes samples and data (5/98)

Cambridge NeuroScience Inc.

Boehringer Ingelheim International GmbH (Germany)

Termination of 1/95 collaboration on Cerestat (NMDA ionchannel blocker) for traumatic brain injury and stroke

-

Based on further evaluation of negative Phase III interim results, companies have terminated collaboration; Cambridge NeuroScience retained full rights to product (7/98)

Celtrix Pharmaceuticals Inc.

Yoshitomi Pharmaceutical Industries Ltd. (Japan)

Termination of 7/94 agreement to develop SomatoKine (recombinant complex of insulin-like growth factor-1 and its binding protein, BP3) for treating osteoporosis

-

This agreement was originally between Celtrix and The Green Cross Corp. (which Yoshitomi acquired in 4/98); Yoshitomi cited certain development and financial aspects of the program as reason it decided to terminate the program; Celtrix regains product rights in Japan for treating osteoporosis (6/98)

CoCensys Inc.

G.D. Searle & Co. (subsidiary of Monsanto Co.; NYSE: MTC)

Termination of 5/96 collaboration on CCD 3693 (synthetic epalon, or neuroactive steroid) for treating insomnia (Phase I trials completed)

-

Searle ended agreement but provided no explanation; CoCensys retains all rights to compounds in this program (7/98)

Corvas International Inc.

Schering-Plough Corp. (NYSE:SGP)

Termination of 12/94 collaboration on orally bioavailable thrombin inhibitors for preventing and treating cardiovascular disorders

-

Companies terminated this program after disappointing results of a Phase I trial; the 2 other research programs (on inhibitors of Factor Xa and hepatitis C virus) remain intact (8/98)

Diatide Inc.

Nycomed Amersham plc (U.K.)

Termination of 8/95 option and development agreement on early-stage imaging products

-

Nycomed will discontinue R&D payments for early-stage products as of 1/31/99; Diatide regains U.S. rights to all non-optioned products; decision does not affect license and co-promotion agreements on AcuTect and P829 imaging products (8/98)

Ergo Science Corp.

The R.W. Johnson Pharmaceutical Research Institute and Ortho-McNeil Pharmaceutical Inc. (units of Johnson & Johnson; NYSE:JNJ)

Termination of 2/98 collaboration on Ergoset Tablets (bromocriptine mesylate; dopamine agonist) and other products for treating Type II diabetes and obesity

-

FDA denied approval of Ergoset in 11/98, after which Johnson & Johnson terminated collaboration (12/98)

Gilead Sciences Inc.

Glaxo Wellcome plc (NYSE:GLX; U.K.)

Termination of 7/90 collaboration on genetic code blockers (including antisense and triple-helix compounds)

-

The companies jointly decided to end this collaboration (under a 3/96 extension, Glaxo had option to terminate after 2 years); each company retains rights to jointly developed technology as well as its own research results (6/98)

Immusol Inc.*

Pfizer Inc. (NYSE:PFE)

Conclusion of 3/95 collaboration to develop ribozyme gene therapy for treating HIV infection (program was part of Pfizer¿s Pfizergen R&D initiative)

-

Partnership will not be renewed; Pfizer will fund program through 5/98, after which Immusol will continue product development (HIV gene therapy currently in Phase I trials) (3/98)

Inex Pharmaceuticals Corp. (TSE:IEX; Canada)

Schwarz Pharma AG (Germany)

Termination of 3/98 collaboration to develop antisense drug INX-3280 (blocks function of c-myc gene) for treating cardiovascular restenosis

-

Drug failed to show benefit in Phase II trial; companies discontinued development in Europe and North America; Inex will not continue product development on its own (10/98)

Intercardia Inc.

Astra Pharmaceuticals LP (formerly Astra Merck Inc.)

Termination of 12/95 agreement on Bextra (bucindolol HCl) for treating congestive heart failure (currently in Phase III trials)

-

As a result of corporate restructuring at Astra (it bought out Merck¿s share of Astra Merck), Astra¿s product line now includes a competing product (Toprol-XL); agreement terminated by mutual agreement, due to non-compete clause in terms of original deal; Intercardia regains all rights, material and information relating to product, plus termination fee (9/98)

Matritech Inc.

Bayer AG (Germany)

Termination of 6/95 product development and marketing agreement on cervical cancer detection system using Matritech¿s nuclear matrix protein (NMP) technology (especially NMP-179)

-

Matritech submitted preclinical data to Bayer in 12/97 and Bayer elected not to proceed; Bayer¿s option to develop an automated instrument for use with NMP-179 has terminated and Bayer has no further obligations (3/98)

MorphoSys GmbH* (Germany)

Pharmacia & Upjohn Inc. (NYSE:PNU; U.K.)

Termination of 3/97 research collaboration on use of MorphoSys¿ human antibody library and phage-based screening technology to identify lead compounds and therapeutic targets for inflammation and other diseases

-

Pharmacia & Upjohn made strategic decision to focus its research in areas other than inflammation; plans to continue into 2nd phase of collaboration were suspended (8/98)

NaPro BioTherapeutics Inc.

Baker Norton Pharmaceuticals Inc. (wholly owned subsidiary of Ivax Corp.; AMEX:IVX)

Termination of 1993 development and marketing agreement on paclitaxel (compound extracted from needles and limb stock of ornamental yew trees)

$14.5M

Partners terminated their agreement after the FDA ruled in 12/97 that Ivax¿s paclitaxel-based drug Paxene for treating AIDS-related Kaposi¿s sarcoma might not get marketing approval until 8/04; Ivax gets royalty-free, nonexclusive license to NaPro¿s pending patents on stable formulation of paclitaxel in U.S., Europe and certain other markets; NaPro gets $6M cash, $6.4M on issuance of patents and the return of 1.1M shares of its stock ($2.1M) held by Ivax; NaPro will supply a certain amount of paclitaxel to Ivax (3/98)

NeoRx Corp.

Janssen Pharmaceutica NV (Belgium; unit of Johnson & Johnson; NYSE:JNJ)

Termination of 8/97 collaboration on NeoRx¿s radioimmunotherapy product Avicidin (for treating solid tumors)

-

Janssen will terminate agreement at year-end 1998, but is currently completing Phase II trials in advanced colon and prostate cancer; patients exhibited high incidence of unacceptable diarrhea; all rights to product and underlying pretargeting technology revert to NeoRx, along with all data generated by study (9/98)

NeoRx Corp.

Schwarz Pharma AG (Germany)

Termination of 4/97 collaboration on NeoRx¿s Biostent (combination drug/device) for treating restenosis following balloon angioplasty (Phase I trials completed)

-

Schwarz ceased product development, citing need for more studies with a new catheter and delays in the project; NeoRx has no plans to conduct Phase II trials without a partner (11/98)

Neurogen Corp.

Schering-Plough Corp. (NYSE:SGP)

Conclusion of joint research phase of 6/95 collaboration on small-molecule drugs that modulate dopamine receptor subtypes for treating schizophrenia

-

Schering-Plough moved the research in-house; if drug candidates progress through clinic, Neurogen gets milestones and royalties; Neurogen retains option to manufacture products for U.S. market (7/98)

Ophidian Pharmaceuticals Inc.

Eli Lilly and Co. (NYSE:LLY)

Termination of 5/96 collaboration on avian polyclonal antibody to neutralize toxins secreted by Clostridium difficile (gastrointestinal infection; Phase I trial completed)

-

Lilly said it will discontinue program; Ophidian regains all rights to product (9/98)

Pangea Systems Inc.*

Roche Bioscience (division of Roche Holding Ltd.; Switzerland)

Completion of collaboration to design expression chips from Roche Bioscience¿s expressed sequence tag databases

-

ND (4/98)

Sonus Pharmaceuticals Inc.

Daiichi Pharmaceutical Co. Ltd. (Japan)

Termination of 3/95 license agreement on EchoGen ultrasound contrast agent for intravenous myocardial contrast echocardiography

-

Daiichi took product through Phase I trials in Japan, completed in 12/97, but no further clinical development since that time; Sonus terminated agreement and is seeking another development partner (11/98)


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