Free Claim Construction Opening Brief - District Court of Delaware - Delaware

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EXHIBIT 3

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

PHARMACIA

& UP JOHN COMPANY, Plaintiff, v.

LLC

Civil Action No. 04-833 KAJ INC.

SICOR, INC., and SICOR PHARMACEUTICALS,

Defendants.

EXPERT REPORT I, LAURA T. GUERRA, testify, hereby declare as follows: I.

OF LAURA T. GUERRA in all respects to

being over the age of eighteen and competent

STATEMENTOF QUALIFICATIONS vitae, which includes a listing of my publications, is attached to

A copy of my curriculum this report as Exhibit A. I am the Associate Program at US Oncology.

Director

for Research

Operations

for the Translational

Oncology College and

I received my A.S. in Nursing in 1973 from Galveston

became a registered nurse. In 1973, I served as a graduate nurse in the Department the University of Texas Medical Branch in Galveston, Texas. as a hospital staff nurse, outpatient chemotherapy

of Nursing at

Then, from 1974 to 2004, I served

nurse, clinical research nurse, and clinical Cancer Center in Houston, In those positions, I

research nurse supe_dsor Texas.

at the University

of Texas M.D. Anderson

During part of that time, I also moonlighted worked with and developed

at another hospital.

personally glycosides,

first-hand knowledge

of certain aspects of anthracycline

especially in relation to breast cancers.

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II.

BACKGROUND

AND COMPENSATION

I have not testified, compensated this litigation. ItI.
INFORMATION

either by deposition

or at trial, as an expert in any case.

I am being with

at the rate of $ 175.00 per hour, plus expenses, for my efforts in conjunction

CONSIDERED

AND ASSUMPTIONS

I have been retained by the law firm of McDonnell provide a historical review of the use of anthracycline

Boehnen Hulbert & Berghoff LLP to I understand that discovery in

glycosides.

the case is ongoing, and that I may be asked to address other related issues if further information becomes available. In forming my analysis and comparison, considered the following materials: a. U.S. Patent No. 6,107,285 ("the '285 patent"); Handling of Antineoplastic in addition to my personal knowledge, I have

b. Linda Kathryn Barry et al., Promoting the Responsible Agents in the Community, 12 Oncology Nursing F. 41 (1985); c. Antineoplastic Marsha M. Cloak et al., Occupational Exposure Agents, 12 Oncology Nursing F. 33 (1985);

of Nursing

Personnel

to

d. Kai Falck et al., Mutagenicity The Lancet, June 9, 1979, at 1250;

of Urine of Nurses Handling

Cyetostatic

Drugs,

e. Kari Hemminki et al., Spontaneous abortions and malformations in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other potential hazards in hospitals, based on registered #formation of outcome, 39 J. Epidemiology & Community Health 141 (1985); f. Bonnie Rogers, Work Practices of Nurses Who Handle Antineoplastie Agents, 35 AAOHN J. 24 (1987) (citing Olver, I. & Scharz, M., Use ofdimethyl sulfoxide in limiting tissue damage caused by extravasation of doxorubicin, 67 Cancer Treatment Rep. 407); g. Sherry G. Selevan et al., A Study of Occupational Drugs and Fetal Loss in Nurses, 313 New Eng. J. Med. 173 (1985); Exposure to Antineoplastie

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h. Eero A. Sotaniemi et aI., Liver Damage 214 Acta Med. Scandanavia 181 (1983);

in Nurses

Handling

Cytostatic

Agents,

i. Roger W. Anderson et al., Risk of handling Am. J. Hospital Pharmacy 1881 (1982); j. doxorubicin, 333 (1984); Genevibve anthracycline

injectable

antineoplastic

agents, 39

Aubel-Sadron & Danielle Londos-Gagliardi, antibiotics, a physicochemical and biological

Daunorubicin and review, 66 Biochimie

k. T. Balazs & V.J. Ferrans, Health Persp. 181 (1978); 1. R.J. Maral & M. Jouanne, Cancer Treatment Rep. 9 (1981); m. Antineoplastic

Cardiac

Lesions

Induced

by Chemicals,

26 Envtl.

Toxicology

of Daunorubicin

in Animals

and Man, 65

Tot V. Nguyen et al, Exposure Drugs, 42 Cancer Res. 4792 (1982);

of

Pharmacy

Personnel

to

Mutagenic

n. Marja Sorsa et al., Occupational real hazards, 154 Mutation Res. 135 (1985);

exposure

to anticancer

drugs--Potential

and

o. Miriam C. Vaughn & William D. Christensen, Occupational Exposure to Cancer Chemotherapeutic Drugs: A Literature Review, 46 Am. Indus. Hygiene Assoc. B-8 (1985); p. H. Waksvik et al., Chromosome 65 Cancer Treatement Rep. 607 (1981); Analyses of Nurses Handling Cytostatic Agents,

q. Dominic A. Sotimando & James P. Wilson, Demonstration of Skin Fluorescence Following Exposure to Doxorubicin, Cancer Nursing, August I983, at 313 (citing H. Marquadt et al., Tumorigenicity in vivo and introduction of malignant transformation and mutagenesis in cell cultures by Adriamycin and Daunomycin, 36 Cancer Res, 2065 (1979) and B.R. Harrison, Developing Guidelines for worla'ng with antineoplastic agents, 38 Am. J. Hospital Pharmacy 1686 (1981)); r. Guidelines for Handling Parenteral Antineoplastics, 253 JAMA 1590 (1985): (citing B.R. Harrison, Developing Guidelines for working with antineoplastic agents, 38 Am. J. Hospital Pharmacy 1686 (1981 )); s. Idamycin; t. u. The Physician's Desk Reference entries on Adriamycin PFS and RDF and

Declaration Declaration

under Rule 1.132 of William J. Dana; under Rule 1.132 of Mary Horstman; and

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v.

Declaration under Rule 1.132 of Debra Holton-Smith.

I incorporate these materials into this report and into my opinion.
IV, SUMMARY OF OPINIONS

Through both opinion and personal experience, I know that nurses and other medical personnel were growing concerned about the harmful health effects of anthracycline glycosides by 1985. It is my opinion that lyophilized anthracycline glycosides, as used in hospitals as of that time and reconstituted by nurses, presented a substantial health risk to nurses. It is also my opinion that most of that health risk was later avoided through the use of ready-to-use formulations of anthracycline glycosides in sealed containers. It is another opinion of mine that ready-to-use formulations of anthracycline glycosides provided other benefits, including both added safety for medical personnel and patients and convenience. I may also testify regarding

my experience with anthracycline glycosides, including their treatment for various cancers.
V. OPLNIONS

The University of Texas M.D. Anderson Cancer Center is one of the largest and most advanced cancer treatment centers in the world. During my employment as an oncology nurse with UT M.D. Anderson, I worked with anthracycline glycosides on a daily or near-daily basis, as well as related drugs. lyophilized form. My first exposure to anthracycline glycosides was in powdered,

One of the first anthracycline glycosides I worked with was doxorubicin, I later worked with other anthracycline glycosides, including solutions of anthracycline glycosides by

known at first as Adriamycin. epirubicin.

That work included reconstituting

dissolving the lyophilizate in water.

That is, I am personally familiar with the use and

reconstitution of anthracycline glycosides as part of a treatment regimen.

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Anthracycline cancers.

glycosides

are very powerful chemotherapy RDF (the lyophilized

drugs for a variety of different described in the

For example, Adriamycin

form of doxorubicin

PDR entry') and Adriamycin PDR entry) were indicated acute lymphoblastic tissue and bone

PFS (the ready-to-use

solution form of doxorubicin neoplastic

described in the such as soft

"to produce regression in disseminated acute myeloblastic breast carcinoma, leukemia, ovarian

conditions

leukemia, sarcomas,

Wilms'

tumor, neuroblastoma, transitional malignant

carcinoma, disease,

cell bladder lymphoma and

carcinoma, thyroid carcinoma, bronchogenic carcinoma

gastric carcinoma,

Hodgkin's

in which the small cell histologic type is the most responsive

compared I in

to other cell types." am most Adriamycin perhaps familiar

I also worked with epirubicin in clinical trials in metastatic breast cancer. with the use of doxorubicin, the active pharmaceutical ingredient

RDF and PFS, because it has been on the market used anthracycline

for many years and was (and is I used doxorubicin in the

still) the most commonly

glycoside.

treatment of acute lymphoblastic for a variety of malignancies field from 1977 to 1994. In 1985, oncology nurses

leukemia and acute myeloblastic

leukemia from 1974 to 1976, nurse and in the breast cancer

during my role as a chemotherapy

were just beginning

to become

generally

aware of just how

toxic lyophilized anthracycline

glycosides were. About that time, a study was performed at M.D. in Oncolo_¥ Nursing Forum. I contributed to that study. and

Anderson, with the results published The study accurately reflected

the tasks performed

by oncology nurses at M.D. Anderson, of those tasks:

the exposure to anthracycline

glycosides in the performance

During the 5 days at work, the 10 nurses in Group 1 handled 751 doses of antineoplastic agents. This represents a mean of 75.1 doses of antineoplastic agents handled by each nurse in the 5-day period. Specific agents handled by this group and their mutagenicity are listed in Table 2. Nurses performed more than one task (as previously identified) with a single dose. For example, a nurse primed the IV tubing with an agent, connected the tubing to an infusion system

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(administer), and, when the infusion was complete, disconnected the tubing and disposed of the container. At the time of this study, these nurses wore no protective clothing as they performed these tasks with antineoplastic agents. The nurses performed a total of 2155 manipulative tasks within this 5-day work week, or an average of 2.87 tasks with each dose. Accompanying these tasks were 207 self-detected skin contacts (Table 3); therefore 9.6% of the total tasks performed were associated with skin contact. Self-detected skin contacts were reported with all seven tasks performed by these 10 nurses. However, for each task at least one nurse reported no self-detected skin contacts, as evidenced by a bottom range of zero for each task. The greatest frequency of skin contact (26%) occurred when priming the I-MED Volumetric Infusion Pump TM. The frequency with all other tasks was lower and within a relatively narrow range (4.4%-10.6%). The three nurses in Group 2 who admixed and administered antineoplastic agents handled 94 doses during the 5 days at work, for a mean of 3t.1 doses of antineoplastic agents handled by each nurse. Specific agents handled within this group, along with their mutagenicity, are listed in Table 2. These nurses also performed more than one task with a single dose with a total of 259 manipulative tasks being recorded within the 5 day work week, averaging 2.76 tasks for each dose. Preparation of antineoplastic agents was done on an open counter. Through random observations made each day during the study week it was noted that two of the three nurses wore surgical gloves only when preparing antineoplastic agents. However, one of these two nurses by day 4 of the work week began wearing surgical latex gloves to perform all tasks involving antineoplastic agents. The nurses reported 13 self-detected skin contacts accompanying these tasks (Table 4), therefore 5% of the total tasks performed were associated with skin contact. No self-detected skin contacts were reported for four of the eight tasks. For the other four tasks, as in Group 1, at least one nurse reported no self-detected skin contacts, as reflected by a bottom range of zero for each task (Table 4). In Group 3, the seven LVNs and aides disposed of 305 specimens of excreta, during the 5 days at work for a mean of 43.5 specimens per person. Excreta included urine, emesis, and stool. Of the total number of specimens, 52 (17%) were from patients who had received an antineoplastic agent within the previous 32 hours. Antineoplastic agents received by these patients and their mutagenicity are listed in Table 2. For the 305 specimens handled, 54 self-detected skin contacts were reported, with a range of 0-35. Thus, 18% of the specimens disposed of were associated with self-detected skin contact. The nurses' actions, and the exposure to antineoplastic agents, observed in the 1985 Cloak

Oncology Nursing Forum article comported The reconstitution steps. of lyophilized

with my experience at M.D. Anderson. glycosides at that time involved several

anthracycline

First, water was withdrawn

from a bottle with a syringe.

Second, the water was injected

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into the vial reconstitution

containing

lyophilized

anthracycline

glycoside.

This

step was the one in because of the

most likely to lead to spilling

of the anthracycline

glycoside

pressure that had to be exerted in injecting the water and the withdrawal vial. Third, the mixture was agitated until all of the anthracycline anthracycline glycoside solution

of the syringe from the was in solution.

glycoside

Fourth, the reconstituted

was withdrawn

from the vial and Fifth, any

injected into a 50 ml bottle or bag of i.v. solution to be administered remaining anthracycline glycoside solution would be disposed of.

to the patient.

I was also aware, from my work at another hospital other hospitals had somewhat different protocols

in the Texas Medical anthracycline

Center, that glycosides.

for handling

Specifically,

physicians,

not nurses, administered

the drugs and pushed

the drugs into the i.v.

instead of an i.v. drip. However, to my knowledge, make the handling of anthracycline The articles I reviewed

those other protocols did not (and could not)

glycosides much safer. into this report) show what oncology nurses glycosides could be quite dangerous for Nursing Forum stated . . . have been was shown to be indicated that

(which I incorporate

learned in the mid- and late-1980's: the nurses themselves. both that "[d]irectly

that anthracycline

For example, the 1985 Barry article in Oncolo_v irritating effects of doxorubicin

[and] daunorubicin and that doxorubicin AAOHN Journal

documented teratogenic doxorubicin Selevan

in individuals in animal

who handle these agents," The 1987 Rogers

studies.

article

causes local toxic and allergic reactions in skin and mucous membranes. England Journal of Medicine article found a correlation between

The 1987 nurses'

New

occupational

exposure to antineoplastic

drugs (including doxorubicin)

and fetal loss. The article

in Oncoloey Nursing Forum, as well as the other Oncologv Nursing Forum article published that year, became relatively commonly (and co.ntemporaneously) known in the oncology nursing

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field.

In addition, I was personally

familiar with oncology

nurses having skin irritations due to sclerotic

and

allergic reactions, miscarrying,

losing hair, and becoming

infertile

ovaries, all

caused by the handling of these drugs. Since the introduction of ready-to-use formulations of anthracycline glycosides in sealed

containers, I believe that the handling my understanding, of patients. Horstman, incorporate glycoside disposal.

of anthracycline

glycosides

has become

far safer and, to

oncology nurses have suffered

far fewer adverse effects related to treatment in the declarations of William J. Dana, Mary and which I anthracycline or improper glycosides,

Many of these benefits are described and Debra Holton-Smith, into this report. formulations, which

comport

with my own experience ready-to-use sprayback,

Because there is no need to reformulate reduced risk of spilling,

there is a greatly

In addition, because oncology nurses do less handling of the anthracycline

there is inherently less risk of harm from exposure. There are numerous other benefits of ready-to-use formulations of anthracycline

glycosides in sealed containers described in the declarations and Debra Holton-Smith. error in reformulating ready-to-use benefits For example, those declarations glycosides

of William J. Dana, Mary Horstman, point out the greater risk of dosing and the far greater convenience of

lyophilized

anthracycline

formulations.

I agree with the statements formulations of anthracycline

made in those declarations glycosides, and

as to the those

of ready-to-use

incorporate

statements into this report as part of my potential testimony.

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Id_Im-e nder u penmty ofperjury theforegoing that is true con,'ct. _d Ex_cumd in Hot_ton_ T_.x_ onAuEo..qt _ 2005.

T. Cru_-rra

9

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Exhibit A

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CURRICULUM VITAE Name: Laura T. Esparza-Guerra, R.N., CCRC Present Title and Affiliation: Registered Nurse Research Nurse Supervisor Department of Breast Medical Oncology The University of Texas M. D. Anderson Cancer Center BIRTHDATE: June 29, 1953 PLACE OF BIRTH: Galveston, Texas SOCIAL SECURITY NUMBER:

LICENSURE: 2-29690 HOME ADDRESS: 1110 Prince Street Houston, Texas 77008 OFFICE ADDRESS: The University of Texas M. D. Anderson Cancer Center Department of Breast Medical Oncology 1515 Holcombe - Unit 424 Houston, TX 77030 FAXES: 713- 794-4385 OFFICE E-MAIL: [email protected] TELEPHONE: 713- 861-9673

TELEPHONE: 713-563-0764

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EDUCATION: 1971 Ball High School Galveston, Texas; National Honor Society Graduate Associate Degree of Science in Nursing, Galveston College, Galveston, Texas; Degree - R.N., A.D.N. Clinical Qncotogy Course in Cancer Prevention and Detection, University of Texas System Cancer Center, M. D. Anderson Cancer Center, Houston, TX. Texas Women's University Nursing School, Continuing Education Course, Houston, TX.

1973

1980

1980

BOARD CERTIFICATION: 2002 Clinical Research Coordinator Certification (CRCC)

PROFESSIONAL EXPERIENCE: 1982-Present Clinical Research Nurse Supervisor, Department of Medical Oncology, Medical Breast Service, University of Texas M. D. Anderson Cancer Center, Houston, TX. Clinical Nurse, Department of Nursing, part time In-patient Breast Oncology Unit or Melanoma/Sarcoma Unit, University of Texas M D. Anderson Cancer Center, Houston, TX. Clinical Research Nurse, Department of Medicine, Medical Breast Service, University of Texas M. D. Anderson Cancer Center, Houston, TX. Staff Nurse, Department of Nursing-Ambulatory Treatment Center, Chemotherapy and Emergencies, Universityof Texas M. D. Anderson Cancer Center, Houston, TX. Staff Nurse, Department of Nursing-In-patient, Leukemia Service, University of Texas M. D. Anderson Cancer Center, Houston, TX. Graduate Nurse, Department of Nursing-Pediatrics, University of Texas Medical Branch, Galveston, TX.

1990 -1995

1977-1982

1975-1977

1974-1975

1973

2

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ADMINISTRATIVE RESPONSIBILITIES: At the Universityof Texas M. D. Anderson Cancer Center: 1983-1986 1984-present 1990-1997 1993- 1996 1995-1996 1996-present 1997-present 1999-present 2001-present 2002-present 2001-present Data Centralization CommitteeSystem at UTMDACC Research Nurse Committee Development of the Patient Data Management

UT M. D. Anderson Cancer Center Preceptorship & Clinical Exchange Program Lecturer Breast Medical Oncotogy, Nurse Assessment Form Working Group Nurses role in the ambulatory setting, Position Description Working Group Women's Cancer Research Group Office of Protocol Research Scientific Advisory Committee, Nurse Representative Research Nurse Orientation Program Committee Member & Preceptor Research Nurse Compensation Working Group Clinical Research Nurse Committee, Founding Member UT M.D. Anderson Cancer Center Medical Exchange and Training Program & Education Seminars to Japan, Advisory Board Member, Lecturer, and Preceptor

PROFESSIONAL MEMBERSHIP: Oncotogy Nursing Society (ONS) American Society of Clinical Oncology (ASCO) National Association of Hispanic Nurses (NAHN) Association of Clinical Research Professionals (ACRP) Hispanic Women in Leadership (HWL)

EXTRAM URAL: 1991-1996 1991-1999 1993-1999 1994-2000 1994-present 1999-present 2000-2003 2000-2002 2001-present 2002-present 2004-present Glaxo Speakers Bureau BristoI-Meyers Visiting Professor Program Orthobiotech Speakers Bureau Oncology Nurse Advisory Board for Taxotere, Rhone-Poulenc Rorer Aventis Pharmaceuticals (formally Rhone-Poulenc Rorer) Nurse Speaker Program Novartis Oncology Representative for The Breast Cancer Support Network .... for Better Bone Health Oncology Nurse Advisory Board for Ellence & Aromasin, Phamacia Oncology Corporation Immunex Nurse Speaker Program Oncology Nursing Society Forum Moderator for ONS Online. Genentech Regional Nurse Advocate (RNA) Program and Oncology Nurse Advisory Board for Herceptin and Avastin Oncology Nurse Advisory Board member, Pfizer Oncology

VOLUNTEER ACTIVITIES 1984-present 1994-present 1998-present Cancerwise Community Speaker Bureau (CCSB) Race for the Cure, annual participant Pink Ribbon Project, annual participant

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CLINICAL RESEARCH EXPERIENCE: Multimodality Treatment of Primary Breast Cancer During Pregnancy, ID01-193 A Presurgical Study to Evaluate Molecular Alterations that Occur in Human Breast Cancer Tissue and Normal Skin After Short Term Exposure to ZD1839 (Iressa) and to Correlate These Alterations with Pharmacokinetic Parameters, BCIRG 103 Multi-center Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed By Docetaxel (AC-T) With Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (AC-TH) And With Docetaxel, Platinum Salt and Trastuzumab (TCH) In The Treatment of Node Positive and High Risk Node Negative Adjuvant Patients With Operable Breast Cancer Containing Her-2neu, BCIRG 006 Phase II, Single Arm, Single Institution Clinical Trial Of Docetaxel And Doxorubicin in Combination With Local Administration Of INGN201(Ad5CMV-p53) in Locally Advanced Breast Cancer, (adequate tumor tissue must be available to determine p53 mutation status by DNA sequencing, ID00-008 A Multicenter Phase Ill Randomized Trial Comparing Docetaxel (Taxotere) and Trastuzumab (Herceptin) W/Docetaxel, Platinum Salt (Cisplatin or Carboplatin) and Trastuzumab as First-Line Chemo For Patients W/Advanced Breast Cancer Containing The Her2 Gene Amplification, BCIRG 007 Phase II study of docetaxel plus trastuzumab for patients with HER-2 overexpressing metastatic breast cancer, ID99-190 A Phase II study of UFT + Leucovorin (Orzei) given as a two times per day regimen in the treatment of patients with recurrent metastatic breast cancer, DM99-110 Phase I Open-Label, Single-Center Pilot Study Of Weekly Paclitaxel And Doxorubicin In Patients With MBC, DMP99-010 Phase II, Open-Label, Extension Trial of Rapid Intravenous Infusion of Zoledronate vs Aredia in Cancer Patients with Osteolytic Bone Metastases, ID 99-159 Prospective study of signal transduction pathways associated with trastuzumab (Herceptin)-based therapy for patients with metastatic breast cancer, LAB99-046 Pilot Study of Subcutaneous Dalteparin (Fragmin) for Outpatient Treatment of Deep Venous Thrombosis (DVT) in Low Risk Breast Cancer Patients, DM98-231 A Randomized, Double-Blind, Multicenter, Comparative Trial of I.V. Zoledronate (4 mg or 8 mg) Versus IV Aredia (90 mg), as an Adjunct to Standard Therapies in the Treatment of Multiple Myeloma and Breast Cancer Patients with Cancer-related Lesions, DM98-264 A Phase II study of UFT + Leucovorin (Orzel) given as a Three-times per day regimen in the treatment of patients with recurrent metastatic breast cancer, DM98-318 A Pilot Study To Assess Toxicity Of Paclitaxel Or Docetaxel In MBC Patients With Impaired Liver Function Secondary To Hepatic Metastasis, ID98-024 Phase II open-label, single-center trial of primary chemotherapy with docetaxel and doxorubicin (TD), surgery, postoperative chemotherapy with cyclophosphamide, methotrexate and 5-FU (CMF), radiotherapy and tamoxifen in patients with locally advanced breast cancer, ID 97-099 Phase I open-label, single=center trial of chemotherapy with docetaxel and doxorubicin plus sargramostim (GM-CSF) in patients with metastatic breast cancer, DM 97-130 Multicenter, open-label, dose-ranging study for the evaluation of safety, tolerability, and efficacy of Neovastat administered orally for 12 weeks in patients with prostate or breast cancer refractory to

4

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standard therapies or for whom no standard therapies are available, URL97-223 A phase 1/11tudy of docetaxel (RP 56976) and cyclophosphamide combination chemotherapy in patients s with advanced solid tumors (phase 1)/breast cancer (phase II), DM 94-015 A pilot study of docetaxel (RP 56976) in patients with paclitaxel-resistant advanced breast cancer, DM 94-037 Phase II Study of Ct-958 in Patients with Metastatic Breast Cancer, DM94-085 Phase I and Phase II Study of Liposomat Annamycin In Anthracycline-Resistant Breast Cancer, DM94-046

Phase II study of Sialyl Tn-KLH with DETOX -B adjuvant combination with Interferon alpha-2a in the treatment of breast cancer, ID94-018 Phase tl trial of RP 56976 (Taxotere) in patients with metastatic breast cancer, DM 92-058 A double-blind comparison of the efficacy of two-dose regimen of oral granisetron (1 mg twice, 2 mg once) in prevention of acute emesis in patients receiving moderately emetogenic chemotherapy, DM92-077 Multimodality treatment of primary breast cancer occurring concomitant with pregnancy, DM92-002 Phase II study of ifosfamide and mesna in patients with metastatic breast cancer, DM90-110 Phase II study of CI-973 in patients with refractory advanced breast cancer, DM90-089 Phase II study of recombinant alpha interferon (rlFNa) and continuous-infusion 5-fluorouracil in metastatic breast cancer, DM90-019 Phase II trial of fazarabine (ARA-AC, arabinosyl-5-azacytosine) in metastatic breast cancer, DM89-052

Phase t Clinical and Pharmacology Evaluation of CI-973, A New Platinum Derivative. Single Dose Repeated Every 28 Days, DM88-138 Phase II study of recombinant alpha interferon and recombinant interleukin-2 in metastatic breast cancer, DM88-075 Double blind placebo controlled crossover study of Ativan as adjunctive anti-emetic and primary anxiotytic therapy in patients with metastatic breast cancer, DM88-134 An open label evaluation of three different doses of oral GR-C570/75 (Zofran) in the prevention of nausea and vomiting associated with doxorubicin, cyclophosphamide chemotherapy, DM88-048 DM87-095 Phase I-II MonAB B72.3-GYK-DTPA Phase I study of TCNP (Tricyclic Nucleotide Phosphate, Triciribine in sotid tumors, DM87-075 Phase I-II study of high dose Etoposide (VP-16-213) in patients with breast cancer, DM87-050 A Phase II study of Didemnin-B in patients with metastatic breast cancer, DM87-039 Leuprolide vs Leuprolide + Tamoxifen in premenopausal breast cancer patients with metastatic breast cancer, DM86-97 Intraartedal FAC (5-fluorouracil, adriamycin, cyclophosphamide) chemotherapy in the treatment of breast cancer metastatic to the liver, DM86-45 Concomitant 5-day continuous infusion of Vinblastine and 5-fluorouracil in the treatment of refractory metastatic breast cancer, DM86-21

5

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Phase II study of hormone-mediated chemosensitivity-modulation premarin), DM85-59

of untreated breast cancer (Fac-

A Phase II study of high-dose Mitoxantrone in patients with metastatic breast cancer, DM84-73 Peri-operative chemotherapy in patients with T1 to T3 with N1 or N2 operable breast cancer, DM83-83 Phase II clinical trial of 2-N-methyl-9-hydroxyellipicinium cancer, DM83-49 (Elliptinium) in patients with advanced breast

A comparative study of Megestrol Acetate vs Tamoxifen in advanced breast cancer, DM83-42 Phase II trial of oral 4-Demethoxydaunorubicin DM92-73 (idarubicin) administration to breast cancer patients,

A comparative study of adjuvant FAC(Adriamycin, Cytoxan, and 5-fluorouracil) vs control in Stage I breast cancer patients, DM82-27 A pilot study with a combination of Cytoxan, Mitoxantrone, 5-fluorouracil with a non-cross resistant reinduction program with continuous infusion Adriamycin, DM82-21 Phase II study of Peplomycin in the treatment of metastatic breast caner, MB-DT81-95 A comparative study of Bisantrene given as a single IV dose or intermittently daily for 5 days every three weeks or as a weekly IV dose schedule, DT81-58 A comparative study of a combination of continuous infusion Adriamycin, Cytoxan, and VP-16-213 with a combination of continuous infusion Adriamycin, Cytoxan, and 5-fluorouracil in patients with metastatic breast caner, DT81-57 Phase II study of VM-26 in patients with metastatic breast caner, MB-DT80-63 A comparative study of two different combination of anthracenedione (Mitoxantrone) and Vinblastine in patients with refractory breast cancer, MB-DT80-85 A phase II study of anthracenedione (Mitoxantrone) in breast cancer, MB DT80-37 Phase II study of Carm!nomycin in the treatment of advanced breast cancer, MB-DT80-30 Phase II study of VP-16 (Etoposide) continuous infusion versus intermittent bolus infusion in patients with metastatic breast cancer, MB-DT79-84 Phase li study of FAC (Adriamycin, Cytoxan, and 5-fluorouracit) + Tamoxifen in the treatment of metastatic breast cancer, MB-DT77-48

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PUBLICATIONS 1. Schell FC, Yap HY, Hortobagyi GN, Issetl B, Esparza L: Phase II study of VP 16-213 (etoposide) in refractory metastatic breast carcinoma. Cancer and Chemother and Pharm 7:223-225, 1982. Yap HY, Esparza L, Blumenschein GR, Hortobagyi GN, Bodey GP: Combination chemotherapy with cyciophosphamide, mitoxantrone and 5-fluorouracil in patients with metastatic breast cancer. Cancer Treat Revs 10:53-55, 1983. Aboud A, Yap HY, Esparza L, Blumenschein GR, Hortobagyi GN, Issetl B, Bodey GP: Carminomycin, a new anthracycline analog in the treatment of advanced breast cancer. Cancer 53(1 ): 9-12, 1984. Holmes FA, Yap HY, Esparza L, Buzdar AU, Hortobagyi GN, Blumenschein GR: Mitoxantrone, cyclophosphamide, and 5-fluorouracil in the treatment of hormonally unresponsive metastatic breast cancer. Proceedings of the Lederle Novantrone Canadian Launch Symposium, February 24, 1983. Sem Oncol 11:28-31, 1984. Holmes FA, Esparza L, Yap HY, Buzdar AU, Blumenschein GR, Hortobagyi GN: A comparative study of bisantrene given by two dose schedules in patients with metastatic breast cancer. Cancer Cherno and Pharmacoi 18(2): 157-161, 1986. Holmes FA, Yap HY, Esparza L, Buzdar AU, Blumenschein GR, Hug V, Hortobagyi GN: Mitoxantrone, cyclophosphamide, fluorouracil in metastatic breast cancer unresponsive to hormonal therapy. Cancer 59(12): 1992-1999, 1987. Ro J, Buzdar AU, Esparza L, Hortobagyi GN: Phase II study of peplomycin in advanced breast carcinoma. Cancer Treat Rep 71:777-778, 1987. Holmes FA, Esparza L, Yap HY, Fraschini G, Blumenschein GR, Jabboury K, Hortobagyi GN: A randomized phase II study of etoposide versus teniposide in refractory metastatic breast cancer. International Journal of Experimental & Clinical Chemotherapy 2:95-98, 1989. Hotmes FA, Esparza L, Yap HY, Buzdar AU, Blumenschein GR, Hortobagyi GN: A comparative study of bisantrene given by two dose schedules in patients with metastatic breast cancer. Cancer Chemother Pharmacol 18:157-161, 1986. Buzdar AU, Yap HY, Esparza L, Holmes F, Fraschini G, Hug V, Hortobagyi G: A comparative randomized trial of doxorubicin and cyclophosphamide in combination with fluorouracil (FAC) or etoposide (EAC) in metastatic breast cancer. Int J Exp Clin Chemother 1(1): 48-55, 1988. Holmes FA, Esparza L, Yap HY, Fraschini G, Blumenschein GR, Jabboury K, Hortobagyi GN: A randomized phase II study of etoposide versus teniposide in refractory metastatic breast cancer. International Journal of Experimental & Clinical Oncology 2:95-98, 1989. Buzdar AU, Hortobagyi GN, Esparza LT, Holmes FA, Ro JS, Fraschini G, Lichtiger B: EIIiptinium acetate in metastatic breast cancer- a Phase II study. Oncology 47:101-104, 1990. Fraschini G, Ciociola A, Esparza L, Templeton D, Holmes FA, Waiters RS, Hortobagyi GN: Evaluation of three oral dosages of ondansetron in the prevention of nausea and emesis associated with cyclophosphamide-doxorubicin chemotherapy. J Clin Oncol 9(7): 1268-1274, 1991. Lamki ML, Buzdar AU, Singletary SE, Rosenblum MG, Bhadkamkar V, Esparza L, Podoloff DA, Zukiwski A, McGuire RT, Hortobagyi GN, Murray JL: IN-111LabeledB72.3 monoclonal antibody in the detection and staging of breast cancer: A phase I study. J Nucl Med. 32:1326-1332, 1991. Fraschini G, Holmes FA, Esparza L, Theriault RL, Buzdar AU, Hortobagyi GN: Phase I-II study of high-dose etoposide in patients with refractory breast cancer. Invest New Drugs 9:365-367, 1991.

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Waiters RS, Theriault RL, Holmes FA, Hortobagyi GN, Esparza L: Phase II trial of fazarabine (ARAAC, arabinosyl-5-azacytosine) in metastatic breast cancer. Invest New Drugs 10:43-44, 1992. Benvenuto JA, Newman IRA,Bignami GS, Raybould TJG, Raber MN, Esparza L, Waiters RS. Phase I I clinical and pharmacological study of didemnin B in patients with metastatic breast cancer. Invest new Drugs 10:113-117, 1992. Theriault RL, Cohen IA, Esparza L, Kowal C, Raber MN: Phase I clinical evaluation of CI-973 ([SP-43(R)]-[1,1 -cyctobutanedicarboxylato (2-)] (2-methyl- 1,4-butanediam ine-N, N1 platinum in patients with ) metastatic solid tumors. Cancer Chemotherapy and Pharmacology 31:333-337, 1993. Buzdar A, Esparza L, Natale R, Cody R, Calzone K, Benson AB, Ill, Sheehan T, Berry W: Lorazepam-enhancement of dexamethasone's antiemetic efficacy: A placebo-controlled study. Am J Clin Onco117:417-421, 1994. Fraschini G, Esparza L, Booser DJ, Theriault RL, Holmes FA, Hortobagyi GN: Frontline Arterial Infusion Chemotherapy for Hepatic Metastases in Patients with Breast Cancer. N Einhorn J, Nord CE, Norrby SR (Eds.): Recent Advances in Chemotherapy: Proc 18th International Congress of Chemotherapy. American Society for Microbiology, 1994, pp.:980-981 Waiters RS, Theriault RL, Holmes FA, Esparza L, Hortobagyi GN: Phase II study of recombinant alpha interferon and recombinant interleukin-2 in metastatic breast cancer. J Immunotherapy 16:303305, 1994. Hoffman K, Holmes FA, Fraschini G, Esparza L, Frye D, Raber M, Newman R, Hortobagyi GN: Phase I-il Study: Triciribine (tricyclic nucleoside phosphate) for metastatic breast cancer. Cancer Chemo & Pharm 37:254-258, 1995. Valero V, Holmes FA, Waiters RS, Theriault RL, Esparza L, Fraschini G, Fonseca G, Bellet RE, Buzdar AU, Hortobagyi GN: Phase II trial of docetaxel (taxotere): A new highly effective antineoplastic agent in the management of patients with anthracyctine-resistant metastatic breast cancer. J Clin Onco113:2886-2894, 1995. Waiters RS, Theriault RL, Booser DJ, Esparza L, Hortobagyi GN: Phase II study of recombinant alpha interferon (rlFNa) and continuous-infusion 5-fluorouracil in metastatic breast cancer. J Immunotherapy 18(3) 185-187, 1995. Esparza-Guerra L: Docetaxel, Advancing the treatment of metastatic breast cancer. Cope, Oncology Forum & News for Professionals. Vol. 12, No. 3. May/June 1996 Valero V, Holmes FA, Waiters RS, Theriault RL, Esparza-Guerra L, Fraschini G, Fonseca GA, Bellet RE, Buzdar UA, Hortobagyi GN: Phase II Trial of Docetaxel: A New, Highly Effective Antineoplastic Agent in the Management of Patients with Anthracycline-Resistant Metastatic Breast Cancer. J Clin Oncol 13(12): 2886-2894, 1995. (Abstracted in Breast Diseases: A Year Book Quarterly 7 (3): 302-303, 1996). Rahman Z, Esparza-Guerra L, Yap HY, Fraschini G, Bodey G, Hortobagyi G: Chemotherapy-induced neutropenia and fever in patients with metastatic breast carcinoma receiving salvage chemotherapy. Amer Clin Oncol 1997; 79:1150-1157.

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Vatero V, Burris H Itl, Ravdin PM, Booser D, Esparza L, Holmes FA, Theriault R, Oldham B, Von Hoff DD, Hortobagyi G: Docetaxel in paclitaxel-resistant breast cancer: Study update. Rhone-Poulenc Rorer Oncology Taxotere Investigators Update 11(2): 2, Winter 1996. Waiters RS, Holmes FA, Vaiero V, Esparza-Guerra L, Hortobagyi GN: Phase II study of ifosfamide and mesna in patients with metastatic breast cancer. Cancer Am J. of CIin Onco11998 Valero V, Jones SE, Von Hoff DD, Booser DJ, Mennel RG, Ravdin PM, Holmes FA, Rahman Z, Schottstaedt MW, Erban JK, Esparza-Guerra L, Earhart RH, Hortobagy GN, Burris III HA: A phase II study of decetaxel (Taxotere) in patients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol 16:3362-3368:1998. Rivera E, Fraschini G, Esparza-Guerra L, Booser Daniel J, Theriault RL, Hortobagyi GN. Frontline arterial infusion chemotherapy for hepatic metastases in breast cancer patients. Cancer Therapeutics, 2:44-49, 1999. Cristofanilti M., Holmes FA, Esparza-Guerra L, Valero V, Buzdar AU, Neidhart JA, Hortobagyi GN. Phase 1/11 trial of high dose mitoxantrone in metastatic breast cancer: the M.D. Anderson Cancer Center experience. Breast Cancer Research & Treatment, 54(3):225-233, 1999. Booser DJ, Perez-Soler R, Esparza-Guerra L, Cossum P, Qing-Ping W, Zou Y, Priebe W, Hortobagyi GN. Phase I study of liposomal annamycin, 46:427-432, 2000. Valero V, Holmes F, Waiters R, Theriault R, Esparza-Guerra L, Fraschini G, Fonseca G, Bellet R, Buzdar A, Hortobagyi GN. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthraycline-resistant breast cancer. Classic Papers and Current Comments, Vol 5, No 4, pp759-768, 2001. Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Sneige N, Smith TL, Hortobagyi GN. Phase II study of weekly docetaxel (Taxotere; Txt) and trastuzumab (Herceptin; H) for patients with HER-2 overexpressing (HER2+) metastatic breast cancer (MBC). Euro J Cancer 37:A193, 2001. Esmaeli B, Hortobagyi GN, Esteva FJ, Booser DJ, Ahmadi AM, Rivera E, Arbuckle R, Delpassand E, Esparza-Guerra L, Valero V. Canalicular stenosis secondary to weekly vs. every-three weeks docetaxet in patients with metastatic breast cancer. Ophtalmology 109(6):1188-1191,2001. Esteva FJ, Valero V, Booser D, Guerra L, Hortobagyi GN. A phase II trial of trastuzumab monoctonal antibody therapy plus weekly docetaxel for patients with HER-2 overexpressing metastatic breast cancer. J Investig Med 49:A196, 2001 Esteva FJ, Valero V, Booser D, Esparza-Guerra L, Murray JL, Pusztai L, Cristofanilti M, Fritsche H, Sneige N, Smith TL, Hortobagyi GN. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2 overexpressing metastatic breast cancer. Journal of Clinical Oncology, Vol 20, No 7, pp1800-1808, 2002. Booser DJ, Esteva FJ, Rivera E, Esparza-Guerra L, Priebe W, Valero V, Hortobagyi GN Phase II study of liposomal annamycin in the treatment of doxorubicin-resistant breast cancer. Cancer Chemotherapy Pharrnacol, 46:427-432, 2002. Trent JC, Valero V, Booser DJ, Esparza-Guerra L, Ibrahim N, Rahman Z, Vernillet L, Patel S, David CL, Murray JL, Cristofanitli M, Hortobagyi GN. Combination chemotherapy with cyclophosphamide and docetaxel: A phase I and pharmacokinetic study with and without G-CSF in patients with solid tumors followed by a phase It study as first-line treatment for metastatic breast cancer Clin Cancer Res 9(7):2426-2434, 2003.

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BOOKS AND CHAPTERS 1. Holmes FA, Yap HY, Esparza L, Buzdar AU, Hortobagyi GN, Blumenschein GR: Mitoxantrone, cyctophosphamide, and 5-fluorouracil in the treatment of hormonally unresponsive metastatic breast cancer. IN New Perspectives in Chemotherapy: Focus on Novantrone, Seminars in Oncology XI (3) Suppl. 1, 1984, pp. 28-31. Esparza-Guerra 201-213. L: Oncology Nursing, Textbook on Breast Cancer Care. Tokyo, Japan, 2003, pp.

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INVITED ARTICLES t. Yap HY, Esparza L, Blumenschein GR, Hortobagyi GN, Bodey GP: Combination chemotherapy with cyctophosphamide, mitoxantrone and 5-fluorouracil in patients with metastatic breast cancer. Cancer Treat Rev 10 (Suppl.): 53-55, 1983. Holmes FA, Yap HY, Esparza L, Buzdar AU, Hortobagyi GN, Blumenschein GR: Mitoxantrone, cyclophosphamide, & fluorouracil in the treatment of hormonally unresponsive metastatic breast cancer, Proceedings of the Lederle Novantrone Launch Symposium, Seminars in Oncology 11(3): 28-31, 1984. Ezparza-Guerra L, Beschorner J, Cook GA, Paquette P, Troutner K: Nursing Consideration Guide. A step-by-step reference guide for nurses. Rhone-Poulenc Rorer Pharmaceuticals, Inc., 1996. Valero V, Esparza-Guerra L, Kane M, Merwin P, Staats D: Two Women's Experience, Series I Case Studies, Breast cancer therapy after neoadjuvant or adjuvant anthracycline failure. Phone-Poulenc Rorer Pharmaceuticals Inc. 1998. Esparza-Guerra L, Beschorner J, Cook GA, Paquette P, Trounter K: Treating Patients with Taxotere. What Nurses Need to Know. A step-by-step reference guide for nurses. Aventis Pharmaceuticals, Inc. 1999. Esparza-Guerra L, Dolbey C: Oncology, April 2002 A Comprehensive Guide for Nurses, Only Ellence. Pharmacia

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ABSTRACTS t. Schell F, Yap HY, Hortobagyi GN, Buzdar AU, Blumenschein GR, Issell B, Esparza L, Phase II Studyof VP16-213 (etoposide) in refractory metastatic breast carcinoma. Proceedings of the American Society Clinical Oncology, April 30-May 2, 22:357 (C-97), 1981. Aboud A, Yap HY, Esparza L, Blumenschein GR, Hortobagyi GN, Isselt B, Bodey GP: A phase Ii study of carminomycin in patients with stage IV breast cancer who have failed prior therapy with CMF. Proceedings of the 13th International Cancer Congress, Seattle, Washington, September 8-15, p.287 (abstract #1638), 1982. Esparza L, Yap HY, Smith T, Blumenschein GR, Bodey GP: Quantitative relationship between degree of myelosuppression and infection in patients with metastatic breast cancer. Proceedings ASCO/AACR (C348), 1983. Yap HY, Esparza L, Blumenschein GR, Hortobagyi GN, Bodey GP: Combination chemotherapy with cyclophosphamide, mitoxantrone, 5-FU in patients with metastatic breast cancer. Proceedings 13th Intl. Cancer Congress, Vienna, Austria, p. 150, (Abstract SY85-8), 1983. Holmes FA, Yap HY, Buzdar AU, Esparza L, Hortobagyi GN, Blumenschein GR, Ho D, Bodey GP: Sequential chemotherapy with mitoxantrone, cyclophosphamide and fluorouracil followed by doxorubicin and vinblastine in advanced breast cancer: An update. Proceedings ASCOIAACR (C-485), 3:124, 1984. Holmes FA, Yap HY, Buzdar AU, Esparza L, Hortobagyi GN, Blumenschein GR, Bodey GP: Sequential chemotherapy with mitoxantrone, cyclophosphamide, and fluorouracil followed by doxorubicin and vinblastine in hormone unresponsive advanced breast cancer (C-485). Proceedings of the 20th Annual Meeting of American Society of Clinical Oncology, 3:124, December 7-8, 1984. Buzdar AU, Esparza L, Blumenschein GR, Hortobagyi GN: Peplomycin in treatment of advanced metastatic breast cancer - A phase II study. Proceedings American Association for Cancer Research 26:165, (655), 1985. Holmes FA, Esparza L, Yap H, Buzdar AU, Blumenschein G, Hortobagyi GN: A comparative study of bisantrene (B) given by single IV dose (S) vs daily for five days (Dx5) in patients with metastatic breast cancer. Proceedings of the 8th Annual San Antonio Breast Cancer Symposium (Abstract 27), and Breast Cancer Research & Treatment 6(2): 170, November 7-8, 1985. Buzdar AU, Esparza L, Hortobagyi GN: A comparative randomized trial ofdoxorubicin, cyclophosphamide in combination with fluorouracil (FAC) or etoposide (EAC) in metastatic breast cancer. 14th International Cancer Congress, Budapest, Hungary, Aug. 21-27, 2:736 (2830), 1986.

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10. Holmes FA, Esparza L, Yap HY, Buzdar AU, Blumenschein GR, Hortobagyi GN: A comparative study of etoposide and teniposide in refractory metastatic breast cancer. Proceedings of the 9th Annual San Antonio Breast Cancer Symposium, October 31- November 1, 1986 (abstract 10). 11, Holmes FA, Neidhart JA, Hortobagyi GN, Esparza L, Buzdar AU, Jabboury K: High dose mitoxantrone in patients with metastatic breast cancer. Proceedings of American Society Clinical Oncology, May 17-19, 6:64, (248), 1987. 12. Hug V, Esparza L, Hortobagyi GN: Premarin can effectively modulate the hormonal tumor environment in vivo. Proceedings of American Society Clinical Oncology (abstract 939), 28:237, May 20-23, 1987. 13. Fraschini G, Esparza L, Tashima C, Jabboury K, Hortobagyi G: Simultaneous 5-day continuous infusion (CI)ofvinblastine and 5-fluorouracilfor the treatment of refractory metastatic breast cancer. Proceedings of the 78th Annual Meeting of the American Association for Cancer Research, 28:196, (abstract 779), May 20-23, 1987.

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14. Hug V, Esparza L, Hortobagyi G: Use of estrogens to increase the cell kill potential of chemotherapy. Proceedings of the 3rd International Congress on Hormones and Cancer, Hamburg, Federal Republic of Germany, September 6-11, 1987, J Steroid Biochemistry 28:115S (Abstract C-051 ). 15. Holmes FA, Neidhart JA, Hortobagyi GN, Esparza L, Buzdar AU, Tashima C, Ro JS: High dose mitoxantrone for metastatic breast cancer. 10th Annual San Antonio Breast Cancer Symposium, December 11-12, 1987, Breast Cancer Research and Treatment 10:109 (abstract 98). 16. Fraschini G, Esparza L, Tashima CK, Jabboury K, Ro JS, Hortobagyi GN: Evaluation of concomitant 5day continuous infusion of vinblastine and 5-fluorouracil in patients with refractory breast carcinoma. Proceedings of the 10th Annual San Antonio Breast Cancer Symposium, December 11-12, Breast Cancer Research & Treatment l 0:107, 1987 (abstract #53).

17. Fraschini G, Esparza L, Tashima C, Jabboury K, Hortobagyi G: Simultaneous 5-day continuous infusion of vinblastine and 5-fluorouracil for the treatment of refractory metastatic breast cancer. Proceedings of the 78th Annual Meeting of the American Association for Cancer Research, May 20-23, 1987, 28:196 abstract 779. 18. Holmes FA, Neidhart JA, Hortobagyi GN, Esparza L, Buzdar AU, Tashima C, Ro JS. High dose mitoxantrone for metastatic breast cancer. 10th Annual San Antonio Breast Cancer Symposium, December 11-12, Breast Cancer Res & Treat 10(1): 109 (98), 1987. 19. Buzdar AU, Esparza L, Hortobagyi GN, Lichtiger B, Holmes FA, Hug V, Fraschini G: Elliptinium acetate in treatment of advanced breast cancer - A phase II study. In Proceedings of the 79th American Association for Cancer Research Meeting, 29:200 (794), New Orleans, LA, May 25-28, 1988. 20. Buzdar A, Lamki L, Podotoff D, Esparza L, Theriault R, Holmes F, Singletary S, Ro J, Zukiwski A, Hortobagyi G: Phase I-II Clinical Study of Monoclonal Antibody (MONAB B72.3-GYK-DTPA-1111N) Imaging in Patients with Breast Cancer. Breast Cancer Research and Treatment 12(1): 116 (Abst. 38), 1988. 21. Hug V, Esparza L, Clark J, Tashima C, Holmes F, Hortobagyi G, Vogel V: Properly used hormonal modulation of chemotherapy is effective and safe. IN Proceedings of the 24th Annual American Society of Clinical Oncology Meeting 7:92 (349), New Orleans, LA, May 22-24, 1988. 22. Lamki LM, Buzdar A, Singletary E, Rosenblum M, Podotoff D, Esparza L, Bhadkamkar V, McGuire R, Murray JL: Breast cancer detection, pharmacokinetics and tissue localization studies using IN-111GYK-DTPA-B72.3 Monoclonal antibody (MoAB). The Society of Nuclear Medicine 36th Annual Meeting, June 13-15, 1989. 23. Fraschini G, Esparza L, Holmes F, Tashima C, Theriault R, Hortobagyi G: High-dose etoposide in metastatic breast cancer. 12th Annual San Antonio Breast Cancer Symposium, December 7-9, 1989, Breast Cancer Research and Treatment 14:142 (abstract 39), 1989. 24. Buzdar A, Esparza L, Singletary E, Lamki L, Murray J, Ro JY, Zukiwski A, Hortobagyi G: Phase I-II study of monoclonal antibody (Monab B72.3) in patients with breast cancer. Fourth International Conference on Monoclonat Antibody Immunoconjugates for Cancer, (Abst. #41) p 125, March 30-April 1, 1989. 25. Fraschini G, Yap HY, Smith T, Espar-za L, Hortobagyi G: Multivariate analysis of factors predicting response in breast cancer patients undergoing second-line chemotherapy. Proceedings of the 18th Annual American Association for Cancer Research Meeting, May 24, 27, 1989, 30:255, abstract 1013. 26. Murray JL, Lamki LM, Buzdar AU, Esparza L, Theriault RL, Holmes F, Singletary SE, Ro JY, Zukiwski AA, McGuire RT, Hortobagyi GN, Rosenblum MG: Imaging, radiolocalization index, and pharmacokinetics of monoclonal antibody B72.3-GYK- DTPA-111 In in patients with primary breast cancer. Proceedings of the American Association for Cancer Research 30:403 (1599), 1989.

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27. Esparza L, Hug V, Clark J, Tashima C, Holmes F, Hortobagyi GN: Effect of chronic and acute estrogen stimulation on ER-positive breast tumors. Proceedings of American Society of Clinical Oncology 8:45 (171), 1989. 28. Esparza L, Fraschini G, Kau S, Tashima C, Holmes F, Frye D, Hortobagyi G: Independent validation of a model for prediction of response to second-line chemotherapy in breast cancer patients. Proceedings of the American Association for Cancer Research 30:254 (1012), 1989. 29. Fraschini G, Esparza L, Ciociola A, Holmes F, Templeton D, Hortobagyi G: Evaluation of three oral dosages of ondansetron (CR 38032F) in the prevention of emesis associated with doxorubicincyclophosphamide chemotherapy. Program/Proceedings of the Twenty-Sixth Annual Meeting of the American Society of Clinical Oncology, May 20-22, 1990, Washington, DC, 9:328 (Abstract 1267), 1990. 30. Fraschini G, Esparza L, Ciociola A, Templeton D, Waiters R, Hortobagyi G: Antiemetic activity of three oral dosages of ondansetron in patients receiving doxorubicin and cyclophosphamide. J Cancer Res Clin Oncol 116 (Suppl. Part I): 640 (Abstract A5.280.16), 1990. 31. Theriault RL, Esparza L, Raber M, Newman R, Krakoff I, Cohen 1,Kowal C: Phase I evaluation of [SP-43-(R)]-[1,1-cyctobutaneidicarboxylato (2-)] (2-methyl-l,4-butahedl'amine-N,N') platinum (CI-973). Proceedings of the 81st Annual American Association for Cancer Research Meeting, May 23-26, 1990. 32. Cody R, Natate R, Calzone K, Buzdar A, Esparza L, Benson A III, Sheehan T: Ativan as adjunctive antiemetic and primary anxiolytic therapy in patients receiving cancer chemotherapy (Abstract 1205). Proceedings of the American Society of Clinical Oncology, 10:340, 1991. 33. Waiters R, Parkinson D, Talpaz M, Esparza L, Holmes F, Tashima C, Hortobagyi G: A phase II trial of recombinant interleukin-2 (rlL-2, Hoffrnan-LaRoche) (rlFN-1)in metastatic breast cancer. Proceedings of the 26th Annual American Society of Clinical Oncology Meeting, May 20-22, 1990, 9:36, abstract 134. 34. Theriault R, Esparza L, Raber M, Newman R, Krakoff I, Kowal C, Cohen I: Phase I clinical evaluation of CI-973, a novel platinum analog, in patients with solid tumors. Proceedings of the 82rid Annual tumors. Proceedings of the 82nd Annual American Association for Cancer Research, May 15-18, 1991, Houston, TX (Abst No.: 1194). 35. Waiters RS, Esparza L, Theriault RT, Booser DJ, Hortobagyi GN: The impact of the addition of recombinant alpha interferon to 5-fluorouracit in patients with metastatic breast cancer. Proceedings of the 27th Annual Meeting of the American Society of Clinical Oncology, May 19-21,1991,10:58, abstract 107. 36. Benvenuto JA, Newman RA, Raber MN, Raybould RJG, Bignami GS, Esparza I.., Waiters RS: A clinical and pharmacokinetic study of didemnin B (Abstract 3189). Proceedings of the American Association for Cancer Research, 33:533, 1992. 37. Theriault R, Esparza L, Waiters R, Cohen I, Kowel C, Hortobagyi G: Phase II evaluation of CI-973 in patients with metastatic breast cancer (Abstract 1290). Proceedings of the American Association for Cancer Research, 33:215, 1992. 38. Fraschini G, Esparza L, Theriault RL, Booser DJ, Hortobagyi GN: Front.line arterial infusion chemotherapy in breast cancer patients with liver metastases (Abstract 1562). Proceedings of the American Association for Cancer Research, 33:261, 1992. 39. Dhingra K, Esparza L, Valero V, Booser D, Waiters R, Holmes F, BuzdarA, Hortobagyi G: Neoadjuvant chemotherapy of breast cancer impact of G-CSF on received dose intensity (Abst. #182). Proceedings of the American Society of Clinical Oncology 12:95, 1993. 40. Valero V, Esparza L, Holmes F, Waiters R, Fraschini G, Theriault R, Dhingra K, Buzdar A, Bellet R, Slattery A, Pazdur R, Raber M, Bayssas M, Hortobagyi G: Phase II study of taxotere in refractory metastatic beast cancer (Abst. 184). Proceedings American Society Clinicat Oncology, 12:96, 1993. 14

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41. Valero V, Esparza L, Theriault RI, Esparza L, Fraschini G, Holmes F, Waiters R, Buzdar A, Raber M, Pazdur R, Beltet R, Bayssas M, Hortobagyi G: Phase It study of taxotere in patients with anthracyclineresistant metastatic breast cancer, lntl Cong of Chemotherapy (18t_: 1993:Stockholm, Sweden) Recent Advances in Chemotherapy: Proc of the 18 Intl Cong of Chemotherapy, Stockholm, Sweden, June 27July 2, 1993, p. 844. 42. Valero V, Waiters R, Theriault R, Esparza L, Fraschini G, Holmes F, Buzdar A, Bellet R, Bayssas M, Hortobagyi G: Phase II study of taxotere in refractory metastatic breast cancer (RMBC). (abst 437). Seventh European Conference on Clinical Oncology and Cancer Nursing, Jerusalem, Israel, November 14-18, 1993, p. $83. 43. Valero V, Waiters R, Theriault R, Esparza L, Fraschini G, Holmes F, Buzdar A, Belier R, Byssas M, Hortobagyi G: Phase II Study of Taxotere in refractory metastatic breast cancer. Eur J Cancer 29A [Suppl. 6]: $83 [Abst. No. 437]. 44. Valero V, Waiters R, Theriault R, Esparza L, Holmes F, Fraschini G, Buzdar A, Raber M, Bellet R, Bayssas M, Hortobagyi G: Phase II Study of TaxotereTM in anthracycline- refractory metastatic breast cancer. Prog and Abst 8th NCI-EORTC Symposium on New Drugs in Cancer Therapy, March 15-18, 1994, Amsterdam, p 202 (Abst. 507). 45. Valero V, Waiters R, Theriault R, Esparza L, Holmes F, Fraschini G, Plasse T, Bellet R, Raber M, Buzdar A, Hortobagyi G: Phase II study of docetaxel (taxotere) in anthracycline-refractory metastatic cancer (ARMBC) (Abst. 1636). Proceeding of American Society of Clinical Oncology 13:470, t994. 46, Esparza L, Valero V, Hortobagyi GN: Docetaxel (taxotere): A therapeutic advance in the treatment of anthracycline refractory metastatic breast cancer. Oncology Nursing Society 20th Annual Congress, Anaheim, CA (April 26-29, 1995), Oncology Nursing Forum 22(2):394, March 1995 (Abst. 191). 47. Valero V, Esparza L, Patel S, Theriault R, Pazdur R, Ayoub JP, Qasim M, Rodriguez E, Bellet R, Hortobagyi G: Phase I Study of Cyciophosphamide and Docetaxel (Taxotere) in Solid Tumors. ECCO 1995. (Submitted) 48. Valero V, Booser D, Theriault R, Esparza L, Gagnon S, Hortobagyi G: Pilot study of taxotere in taxolresistance metastatic breast cancer (TRMBC). (Abst 384). Eur J Cancer 31A(suppl 5): $84; 1995. 49. Dhingra K, Singletary E, Strom E, Sahin A, Esparza L, Valero V, Booser D, Waiters R, Hortobagyi G: Randomized trial of G-CSF (filgrastim)-supported dose-intense neoadjuvant (neo) chemotherapy (CT) in locally advanced breast cancer (LABC). (Abst 76)° Proc Am Soc Clin Oncol 14:94; 1995. 50. Valero V, Burris H, Ravdin P, Booser D, Esparza L, Holmes F, Theriault R, Oldham B, Von Hoff D, Hortobagyi G: Docetaxel (Taxotere7) Therapy in PaclitaxeI-Resistant Metastatic Breast Cancer (RMBC). 18th Annual San Antonio Breast Cancer Symposium, December 10-13, 1995. (Abst 310) Breast Cancer Research and Treatment 37 (Suppl): 90, 1996. 51. Valero V, Burris III HA, Jones SE, Booser DJ, Ravdin P, Mennel R, Schottstaedt M, Esparza-Guerra L, Kwiecinski C, Earhart R, Von Hoff D, Hortobagyi GN: Multicenter Pilot Study of Taxotere in TaxolResistant Metastatic Breast Cancer (MBC). (Abst 95). Proc Amer Soc Clin Oncol 15:107, 1996. 52. Booser DJ, Esparza-Guerra L, Zou Y, Priebe W, Perez-Soler R, Liposomal annamycin. Phase Iclinical and pharmacological study. (Abst 762). Amer Soc of Clin Oncol 16:217a, 1997. 53. Valero V, Esparza-Guerra L, Rahman Z, Ibrahim N, Booser DL, Patel S, Holmes FA, Qasim M, Hoff P, Beltet R, Hortobagyi G: Phase I study of docetaxel (Taxotere)and cyclophosphamide without and with GCSF in previously treated and untreated solid tumors. (Abst 772). Amer Soc of Clin Oncol 16.220a, 1997.

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54. Dhingra K, Esparza-Guerra L, Valero V, Booser D, Theriault R, Singletary E, Strom E, McNeese M, Buzdar A, Sahin A, Hunt K, Martinez N, Hortobagyi G: M.D. Anderson Cancer Center, Houston, Texas 77030. Phase tll randomized trial of dose-intensive adjuvant 5fu doxorubicin, cyctophosphomide (FAC) wit G-CSF (Fitgrastim) in locally advanced breast cancer (LABC) - efficacy and safety data. (Abst 278). Amer Soc of Clin Oncol 18:74a, 1999. 55. Trent JC, Valero V, Buzdar AU, Esparza-Guerra L, Booser DJ, Cristofanilli M, David CL, Esteva FJ, Murray JL, Rosales MF, Bellet RE, Hortobagyi GN. Phase II study of docetaxel and cyclophosphamide combination chemotherapy as first-line treatment for metastatic breast cancer. Proc Am Soc Clin Oncol 19:108 (Abstr 416), 2000. 56. Vatero V, Esteva FJ, Rosales MF, Esparza-Guerra L, Sahin AA, Strom EA, Ross Mt, Booser DJ, Ibrahim NK, Cristofanilli M, Hunt KK, Hortobagyi GN. Phase II trial of primary chemotherapy with docetaxel and doxorubicin in locally advanced breast cancer: clinical and pathological results. Proc Am Soc Clin Oncol 19:132 (Abstr 519), 2000. 57. Valero V, Esteva Francisco J, Sahin AA, Booser DJ, Strom EA, Esparza-Guerra LT, Ross MI, Rosales MF, Ibrahim NK, Cristofanilli M, Buchholz TA, Hunt KK, Hortobagyi GN. Phase II trial of neoadjuvant chemotherapy with docetaxel and doxorubicin, surgery, adjuvant CMF, and radiotherapy +/- tamoxifen in locally advanced breast cancer. 23rd Annual. San Antonio Breast Cancer Symposium, Breast Cancer Res Treat 64:A253, 2000. 58. Esteva FJ, Valero V, Booser D, Esparza-Guerra L, Hortobagyi GN. A phase II trial of trastuzumab monoclonal antibody therapy plus weekly docetaxel for patients with HER-2 overexpressing metastatic breast cancer. Clinical Research 2001. J Investigative Med 196A (Abstr80), 2001. 59. Esparza-Guerra L, Buzdar A: Anastrazole "Arimidex" does not impair adrenal cor_isol or aldosterone synthesis in postmenopausal women with advanced breast cancer. Proceedings of ASCO Vol 20 (Abstr 1954), 2001. 60. Esteva FJ, Valero V, Booser D, Esparza-Guerra L, Manuel N, Smith TL, Cristofanilli M, Pusztai L, Ibrahim N, Murray JL, Hortobagyi GN. A phase II trial of weekly docetaxel (D) and herceptin (H) for patients with HER-2 overexpressing (HER-2) (sHERS) levels. Proceedings of ASCO, Vol 20 (Abstr 2019), 2001. 61. Vatero V, Esparza-Guerra L, Murray JL, Rosales M, Booser D, Hortobagyi G. Phase I study of docetaxel (Taxotere) and Doxorubicin every 14 days with GM-CSF (Leukine) and without GM-CSF in patients with anthraycline-naYvemetastatic breast cancer. Proceedings of ASCO, Vol 20 (Abstr 2042), 2001. 62. Esteva FJ, Booser D, Esparza-Guerra L, Murray JL, Pusztai L, Cristofanilli M, Sneige N, Smith TL, Hortobagyi GN. The University of Texas M.D. Anderson Cancer Center, Breast Medical Oncology, Houston, Texas, USA. EJC, ECCO 11, The European Cancer Conference, Vol 37 Supplement 6, (Abstr 706), October 21-25, 2001. 63. Rosenthal SI, Valero V, Middleton LP, Strom EA, Esparza-Guerra LT, Fuller GN, Cohen DS, Sahin AA. Analysis of topoisomerase I1_detecting using chromogenic in-situ hybridization and immunohistochemistry to predict the pathologic response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. M.D. Anderson Cancer Center, Houston, Texas, United States. US and Canadian Acad of Pathology Annual Meeting: (Abs 451452), 2001. 64. Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Sneige N, Fritsche H, Smith TL, Hortobagyi GN: Phase II Study of Weekly Docetaxet and Trastuzumab for Patients with HER-2-Overexpressing Metastatic Breast Cancer. Abst Innovators in Breast Cancer, Coral Gables FL, Dec 7-8, 2001, p.8.

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65. Cristofanilli M, Khrisnamurthy S, Guerra L, Bistooni K, Arun B, Waiters R, Booser D, Coffee K, Valero V, Hortobagyi GN: Ad%CMV-p53 combined with docetaxel and doxorubicin as induction chemotherapy for patients with locally advanced breast cancer: Preliminary report of safety and efficacy. Proceedings of ASCO, Vol 22 (Abstr 967), 2003. 66. Esparza-Guerra L, Lassere Y, Frances D, Chaney H, Jenkins J, Frye D: First Year Evaluation of the Research Nurse Development Model (RNDM): a Competency-Based Professional Model for Research Nurses Abst..# 196 presented at the Oncotogy Nursing Society Conference, 2004.

Lguerra: revised Aug10,04

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CERTIFICATE

OF SERVICE

I hereby certify that copies of the forgoing were caused to be served this 15tu day of August, 2005 upon the following in the manner indicated: BY HAND DELIVERY Steven J. Balick John G. Day ASHBY & GEDDES 222 Delaware Avenue P.O. Box 1150 Wilmington, DE 19899

BY FEDERAL Reid L. Ashinoff

EXPRESS

Brian T. Moriarty William J. Sipio David R. Baum SONNENSCHEIN NATH & ROSENTHAL 1221 Avenue of the Americas New York, NY 10020

LLP

.... J-2 S
;_es W_rrett, ( ...... ...JJr. .t------- .... --_/ )

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE
............................................................... X

)
PHARMACIA & UP JOHN COMPANY LLC, Plaintiff, v. SICOR INC. and SICOR PHARMACEUTICALS, Defendants.
...............................................................

) )

)
)

)
) Civil Action No. 04-833 (KAJ)

)
INC., ) )

)
)
X

NOTICE The undersigned

OF SERVICE Response to Sicor, III and

hereby certifies that copies of Plaintiffs

Inc.'s Second Set of Requests for Production,

Expert Report of Joseph O. Falkinham,

Expert Report of Laura T. Guerra were caused to be served on August following in the manner indicated: BY HAND DELIVERY Steven J. Balick John G. Day Ashby & Geddes 222 Delaware Avenue P.O. Box 1150 Wilmington, DE 19899 BY FEDERAL EXPRESS

15, 2005 upon the

Reid L. Ashinoff Brian T. Moriarty William J. Sipio David R. Baum Sonnenschein Nath & Rosenthal LLP 1221 Avenue of the Americas New York, NY 10020

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MORRIS, NICHOLS, ARSHT & TUNNELL

/s/ James W. Parrett, Jr. Jack B. Blumenfeld (# 1014) Maryellen Noreika (#3208) James W. Parrett, Jr. (#4292) 1201 N. Market Street P.O. Box 1347 Wilmington, DE 19899-1347 (302) 658-9200 Attorneys for Plaintiff Pharmacia & Upjohn Company, LLC OF COUNSEL: Daniel A. Boehnen Joshua R. Rich Lara V. Fleishman MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP 300 S. Wacker Drive Chicago, IL 60606 (312) 913-0001 August 15, 2005

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CERTIFICATE

OF SERVICE

I, James W. Parrett, Jr., hereby certify that on August 15th, 2005 I electronically filed the foregoing Notice of Service with the Clerk of the Court using CM/ECF, which will send notification of such filing(s) to the following:

Steven J. Balick, Esquire John G. Day, Esquire ASHBY & GEDDES I also certify that copies were caused to be served on August 15th, 2005 upon the following in the manner indicated:

BY HAND Steven J. Balick, Esquire John G. Day, Esquire Ashby & Geddes 222 Delaware Avenue Wilmington, DE 19801

BY FEDERAL EXPRESS Reid L. Ashinoff, Esquire Brian T. Moriarty, Esquire William J. Sipio, Esquire David R. Baum, Esquire Sonnenschein Nath & Rosenthal LLP 1221 Avenue of the Americas New York, NY 10020

/s/ James W. Parrett, Jr. James W. Parrett, Jr. (#4292) Morris, Nichols, Arsht & Tunnell (302) 658-9200 [email protected]