IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Patent Docket P1256Rl
`
`THEl\T.~dJ'.:NT. \Vl.TH ANTI, EfoH2
`/\NT1l1(JDJES
`
`DECLARATION UNDER 37 CFR §1.132
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`Sir:
`
`I, Susan D. HeJJmann, M.D., M.P.H., do hereby declare and say as follows:
`
`1. I am an inventor of the above application and an employee of Genentech, Inc., the assignee of the
`
`above application. I am currently Executive Vice President, Development and Product Operations and
`
`Chief Medical Officer At Genentech, Inc. In this capacity, I am responsible for Genentech's Medical
`
`Affairs, Regulatory Affairs, Product Development and Pharmacological Sciences, as well as
`
`Manufacturing, Process Sciences, Quality, and Engineering. I am a member of Genentech's Executive
`
`Committee. Prior to joining Genentech, I was Associate Director of Clinical Cancer Research at
`
`Bristol-Myers Squibb Pharmaceutical Research Institute and the Project Team Leader for paclitaxel
`
`(TAXOL®). I am currently Adjunct Associate Professor, Epidemiology and Biostatistics at the
`
`University of California, San Francisco; I was formerly Assistant Professor, Hematology-Oncology, also
`
`at UCSF. I have won various honors and awards since 1980 for my work in Oncology and AIDS research
`
`and have published more than 35 articles and abstracts. I hold bachelor and medical degrees from the
`.....
`Univ.e,rsity of Nevada, Reno and a master's degree in epidemiology and biostatistics from the University
`of California, Berkeley School of Public Health. I am board-certified in Internal Medicine and Medical
`
`Oncology following my clinical training at the University of California, San Francisco. During my nine
`
`years of training in internal medicine and oncology, I spent two years as visiting faculty at the Uganda
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`Cancer Institute studying AIDS and cancer. I also spent two years in private practice before returning to
`research. A copy of my resume is attached as Exhibit A
`
`2. I have read pending claim 1 of the above patent application which recites "A method for the treatment
`of a human patient with a disorder characterized by overexpression of ErbB2 receptor, comprising
`administering a combination of an anti-ErbB2 antibody and a taxoid, in the absence of an anthracycline
`derivative, to the human patient in an amount effective to extend the time to disease progression in said
`
`human patient."
`
`3. I have reviewed human clinical data generated by the above method which shows that the method
`produces results which would have been unexpected at the time of filing the provisional application upon
`which the above application is based on December 12, 1997. I will explain those surprising results in
`
`paragraphs 4 to 6 below.
`
`4. Prior to the filing of the above application, oncologists recognized that combining different
`chemotherapeutic agents would exacerbate the overall negative side effects of those agents. However, as
`demonstrated in the Example of the above patent application, and confirmed by subsequent clinical data
`that we have accumulated and reviewed since the filing of the patent application, combining an anti(cid:173)
`ErbB2 antibody (HERCEPTIN®) and paclitaxel does not seriously exacerbate the toxic side effects of
`those drugs. However, this was not the case with the anti-ErbB2 antibody combined with
`anthracycline/cyclophosphomide (AC) treatment. That combination therapy resulted in a syndrome of
`myocardial dysfunction (similar to that observed with anthracyclines) substantially more commonly than
`with AC alone. See page 43 of the above application.
`
`5. Thus, the combination of an anti-ErbB2 antibody and a taxoid in an amount effective to extend time to
`disease progression (TIP) has the unexpected advantage of avoiding the overall adverse side effects
`associated with other cancer drug combinations, such as an anti-ErbB2 antibody/anthracycline derivative
`
`combination.
`
`6. In addition to the unexpected result noted in paragraphs 4 and 5 above, the presently claimed method
`produces a further surprising result with respect to extending the TIP. The Example of the above
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`application shows that an anti-ErbB2 antibody significantly augmented the ability of paclitaxel to extend
`TIP in patients treated with this combination. In an ongoing analysis of the TIP data for patients treated
`with the combination of HERCEPTIN® and paclitaxel as described in the Example of the above patent
`application, we have seen that the combination of an anti-ErbB2 antibody and paclitaxel is synergistic
`(see page 37, lines 17-18 of the application), i.e. the combination achieves a therapeutic effect in terms of
`TIP which is greater than that expected by the simple addition of the effects of the component drugs. A
`statistical analysis of the data that shows such synergy is attached in Exhibits B and C. Exhibit B
`provides the results of the H0648 trial in which patients who had received prior anthracycline were
`treated with HERCEPTIN® and paclitaxel as described in the Example of the above application. Exhibit
`C provides the results of the H0650 study, in which patients who had received prior anthracyline were
`treated with HERCEPTIN® as a single agent at the same dose as in the H0648 trial. These data show
`that paclitaxel alone extended TfP by 2.8 months and HERCEPTIN® alone extended TfP by 3.5
`months, whereas the combination of HERCEPTIN® and paclitaxel extended TIP by 6.9 months. Thus,
`the combination is surprisingly synergistic with respect to extending TIP.
`
`7. Aside from paclitaxel, the above application describes the other taxoid, docetaxel (see page 16, lines
`3-5 of the application). Docetaxel has been combined with the anti-ErbB2 antibody HERCEPTIN® in
`human clinical trials (see Raefsky et al. Proc. Of ASCO 18:137a Abstract 523 (1999); of record).
`Preliminary clinical trial results indicate that the combination of docetaxel and HERCEPTIN®, like the
`paclitaxel and HERCEPTIN® combination, is well tolerated and without serious toxicities. Because of
`the similar structures and mechanisms of action of these two taxoids (see the package inserts for
`paclitaxel and docetaxel attached as Exhibits D and E, respectively), it is reasonable to conclude from
`reading the above patent application, that the combination of docetaxel and HERCEPTIN® will achieve
`the same results discussed above with respect to extending the TTP and avoiding the extent of the
`unwanted side effects resulting from an anti-ErbB2 antibody/anthracycline combination. I also consider
`paclitaxel to be representative of the taxoid class of chemotherapeutic agents, such that other members of
`this class would also behave similarly to paclitaxel when combined with an anti-ErbB2 antibody.
`
`8. The invention claimed in the above patent application has resulted in a dramatic change in the way
`oncologists treat human patients with ErbB2 overexpressing metastatic breast cancer. Indeed, a recent
`analysis by Genentech's marketing department has shown that therapy with the combination of an anti-
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`ErbB2 antibody and a taxoid as claimed in the above patent application is the most preferred method of
`therapy for such patients in this country, with such combination therapy exceeding anthracycline use by a
`factor of two.
`I declare further that all statements made herein of my own knowledge are true and that all statements
`made on information and belief are believed to be true; and further that these statements were made with
`the knowledge that willful false statements and the like so made are punishable by fine or imprisonment
`or both, under Section 1001 of Title 18 of the United States Code and that willful false statements may
`jeopardize the validity of the application or any patent issued thereon.
`
`Date: _ _ t-1/r-J_.3..,../1>0 _____ , ,...; ~
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`CURRICULUM VITAE
`Susan Diane Desmond-Hellmann, M.D., M.P.H.
`
`Home:
`139 Kings Court
`San Carlos, CA 94070
`Telephone: (650) 595-4573
`Fax: (650) 595-4679
`
`Office:
`Genentech, Inc.
`1 DNA Way
`South San Francisco, CA 94080
`Telephone (650) 225-5890/225-6003
`Fax: (650) 225-6587
`email address: hellmann.sue@gene.com
`
`PROFESSIONAL EXPERIENCE
`
`Genentech, Inc.
`South San Francisco, California
`1999 Executive Vice President, Development & Product Operations
`and Chief Medical Officer
`Responsibilities: Expanded responsibilities including Manufacturing, Process
`Sciences. Directs Senior Vice President, Product Operations (organization of
`approximately 2300 employees) in addition to existing Development leadership and
`management responsibilities.
`
`1997 Senior Vice President, Development & Chief Medical Officer
`Res~onsibilities: Leads the development organization with approximately 600
`emp oyees, serves as Chair of Product Development and member of the Executive
`Committee. Manages the annual development budget of approximately $400
`million. Directs management including five Vice Presidents and three Senior
`Directors responsible for Medical Affairs, Regulatory Affairs, Pharmaceutical
`Sciences and Product Development.
`
`1996 Additional title: Chief Medical Officer
`
`1996 Vice President, Medical Affairs
`Responsibilities: Led a department of more than 300 employees and nine direct
`reports. Managed an annual budget greater than $100 million in the areas of clinical
`research, biostatatistics, postmarketing and drug safety. Served on the Executive
`Committee and Product Development Committee.
`
`1996 Senior Director, Clinical Science
`Responsibilities: Led all clinical trial efforts, directly managed all clinical science
`directors. Served on the Product Development Committee.
`
`Aug. 1995
`
`Associate Director, Clinical Oncology
`Responsibilities: Led Clinical Oncology Center and assured success of all oncology
`projects. Managed four clinical scientists and one administrative assistant.
`
`March 1995 Clinical Scientist, Medical Affairs
`Responsibilities: Clinical leader, Tirrombopoietin project
`
`EXHIBIT A
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`Susan Diane Desmond-Hellmann, M.D., M.P.H.
`Curriculum Vitae
`
`PROFESSIONAL EXPERIENCE (continued)
`Bristol-Myers Squibb
`Pharmaceutical Research Institute
`Wallingford, Connecticut
`
`April 1993- Associate Director, Clinical Cancer Research
`Feb.
`1994 Project Team Leader Taxol (paclitaxel)
`
`Lexington Oncology Association
`Central Baptist Hospital
`(Lexington, Kentucky)
`
`June 1991- Private Practice, Medical Oncology and Hematology
`March 1993
`ACADEMIC APPOINTMENTS
`University of California, San Francisco
`(San Francisco, California)
`March 1999- Adjunct Associate Professor, Department of Epidemiology & Biostatistics
`June 1989- Assistant Clinical Professor, Department of Internal Medicine
`June 1991 Project Co-Director, Makerere University/ University
`of California, San Francisco Collaborative Health Project
`(Uganda, East Africa)
`1987- Clinical Instructor- Department oflnternal Medicine, Staff Physician,
`1989 AIDS Clinic/Oncology Clinic
`
`July
`Jan.
`
`BOARD MEMBERSHIPS (all current)
`
`University of California, Davis, School of Medicine - Board of Visitors
`American Federation for Medical Research Foundation Washington, D.C.- Board of Trustees
`Healthcare Leadership Council Washington, D.C. - Member
`California Heathcare Institute, La Jolla - Board of Directors
`
`EDUCATION
`
`Epidemiology and Biostatistics
`1988-89
`University of California, Berkeley School of Public Health
`Degree: M.P .H., 5/89
`
`Medical School:
`1978-82
`University of Nevada, Reno School Of Medicine
`Degree: M.D. 5/82
`
`Undergraduate:
`1975-78
`University of Nevada, Reno
`Degree: B.S. Pre-Med 5/78, University of Nevada, Reno
`POSTDOCTORAL TRAINING
`Fellowship: University of California, San Francisco
`1986-88
`Subspecialty: Hematology/Oncology
`Chief: Edwin Cadman, M.D.; Marc Shuman, M.D.
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`Susan Diane Desmond-Hetlmann, M.D., M.P.H.
`Curriculum Vitae
`
`CHIEF RESIDENCY
`1985-86
`University of California, San Francisco
`Specialty: Internal Medicine
`Chairman: Richard K. Root, M.D.
`
`RESIDENCY
`1982-85
`
`University of California, San Francisco
`Specialty: Internal Medicine
`Chairman: Lloyd H. Smith, M.D.
`
`MAJOR RESEARCH INTERESTS
`
`Clinical Trials Methodology.
`Therapy of Breast Cancer, Epidemiology of Kaposi's sarcoma and a putative sexually(cid:173)
`transmitted Kaposi's sarcoma agent, Epidemiology of non-Hodgkin's lymphoma,
`Epidemiology of Breast Cancer, AIDS-related oncogenesis, Epidemiology of Heterosexual
`Transmission of HIV infection, Diet and Cancer.
`
`CERTIFICATION AND LICENSURE
`
`1991
`1985
`1983
`
`1993
`1991
`1989
`1984
`
`Board Certified, Medical Oncology, 11191
`Diplomate, American Board of Internal Medicine 9/11185
`Diplomate, National Board of Medical Examiners 7/1/83
`
`Licensed Physician, State of Connecticut 4/2/93 (current)
`Licensed Physician, State of Kentucky, 6/91 (inactive)
`Licensed Physician, Uganda, East Afiica 3/89
`Licensed Physician, State of California 4/2184 (current)
`
`HONORS AND AW ARDS
`
`1994
`1992
`1990
`
`1989
`1988
`1982
`
`1982
`1982
`1982
`1980
`
`Bristol-Myers Squibb Presidential Award
`Alpha Omega Alpha, University of Nevada, Reno
`George Wellman Young Faculty Development Award (for UCSF
`faculty member showing outstanding ability in Oncology/ AIDS Research)
`George Wellman Young Faculty Development Award
`George Wellman Young Faculty Development Award
`University of Nevada School of Medicine Dean's Award (for top
`grade point average in medical school class)
`Outstanding Medical Student Clerk, Internal Medicine
`Outstanding Medical Student Clerk, Psychiatry
`Outstanding Medical Student Clerk, Pediatrics
`Lange Book Award for Outstanding Basic Sciences Student
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`Susan Diane Desmond-Hellmann, M.D., M.P.H.
`Curriculum Vitae
`
`PUBLICATIONS
`
`I. Masters Thesis
`The Epidemiology ofNasopharyngeal Carcinoma (University of California, Berkeley; 1988)
`
`II. Book Chapters.
`1. Onetto N, Dougan M, Hellmann S, Gustafson N, Burroughs J, Florczy KA,Canetta R,
`Rozencweig R. "Safety Profile" in Paclitaxel in Cancer Treatment. McGuire WP, Rominsky
`EK, eds. Marcel Dekker Inc., New York, 1995.
`2. Fischman ML, Cadman EC, Desmond SD. "Occupational Cancer", in Occupational Medicine.
`LaDou J, Editor. 1990 Appleton and Lange, East Norwalk, CT, pp 182-208.
`3. Desmond SD [Hellmann], Tseng A. "Cancer Screening and Staging", in Handbook of Medical
`Treatment Skatch W, Daley CL, Forsmark CE, Editors. 1988 Yearbook Medical Publishers
`Inc. Chicago, IL. pp 201-213.
`4. Amend W, Desmond SD [Hellmann], Long CS (eds). Advances in Internal Medicine, University
`of California, San Francisco, 1986.
`
`III. Journal Articles.
`1. Somlo G, Sniecinski I, ter Veer A, Longmate J, Knutson G, Yuk-Pavlovic S, Bhatia R, Chow W,
`Leong L, Morgan R, Margolin K, Raschko J, Shibata S, TetefM, Yen Y, Forman S, Jones D,
`Ashby M, Fyfe G, Hellmann S, Doroshow J. Recombinant human thrombop<>ietin in
`combination with
`uloc e colon -stimulatin factor enhances mobilization of
`· heral
`__________ J?.!Qg~tor eel s, incr~~J~~!!P ......... -~-------J~ .. !J:!~.~-~~centration, an acce crates
`hematopoietic recovery following high-dose chemotherapy. BlocKL 93(9):2798-2806, 1999 May
`
`2. Abrams, JS, Vena DA, Baltz J, Adams J, Montello M, Christian M. Onetto N, Desmond(cid:173)
`Hellmann S, Canetta R, Friedman MA, et al. Paclitaxel activity in hea"jgjretreated breast
`cancer; a National Cancer Institute Treatment Referral Center trial. Jo
`of CliniCat
`Oncology. 13(8): 2056-65, 1995 Aug.
`
`3. Hellmann, NS, Nsubuga PS, Baingana-Baingi DJ, Desmond-Hellmann, SD, Mbidde, EK,
`Granowitz CB, Sande MA. Single-dose am~cillin/sulbactam verses ce:friaxone as treatment
`for uncomplilcated gonorrheo in a U gandanTD cliiiic population with a prevalence of
`PPNG infection. Journal ofTropicaI Medicine and Hygiene. 98(2):95-100, 1995 Apr.
`
`4. Basler GA, Desmond-Hellmann S, Florczyk AP, Paclitaxel-induced recall soft tissue injury.
`Journal of Clinical Oncology. 13(2):531, 1995 Feb.
`
`5. Rudis C, Riccio L, Holmes F, Seidman A, Baselga J, Currie V, Fennelly D, Gilewski T,
`Moyanhan M,Raptis G, Sklarin N, Surbome A, Uhlenhopp M. Maickel N. Yao TJ.
`Hellmann S, Usakeicz J, Hortobagyi G, Norton L. Phase II study of semisynthetic
`paclitaxel in metatastic breast cancer. {Clinical Trial. ClinicaI TriaI, Phase II Journal
`Article} European Journal of Cancer. 33 (13):2198-202, 1997 Nov.
`
`6. Dieras V, Marty M, Tubiana N, Corette L, Morvan F, Serin D, Mignot L, Chazard M, Garet F~
`Onetto N, Hellmann S, Pouillart P. Phase II randomized trial ofpaclitaxel versus
`mitomycin in advanced breast cancer: A Nationat Cancer Institute Treatment Referral
`Center Trial. Sem. Oncol. 1995; 22 (No. 4, Supp 8): 33-39
`
`Susan Diane Desmond-Hellmann, M.D., M.P.H.
`Curriculum Vitae
`
`PUBLICATIONS
`7. Vadhan-Raj S, Murray U, Beuso-Ramos C, Shreyaskumar P, Reddy SP, Hoots WK, Johnston
`T, Papadopolous NE, Hittelman WN, Johnston DA, Yang TA, Paton VA, Cohen RL,
`
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`Hellmann, SD, BenJamin RS, Broxmeyer HE. Stimulation ll~ Me~oc~ and Platelet
`Producti~ Single Dose of Reco':11~inant Human ThiombOpoietin m Patients with
`of IntemaI Med. 126,9. 673-681, 1997.
`Cancer.
`
`8. Abrams JS, Vena DA, Baltz J, Adams J, Montello M, Christian M, Onetto N, Desmond(cid:173)
`Hellmann S, Canetta R, Friedman ~ Arbuck SG. Paclitaxel Activity in heavily
`pretreated breast cancer: An NCI treatment referral center tri81. J. Clin. Oricol. 13;2056-
`2065, 1995.
`
`10. Basler GA, Desmond-Hellmann SD, Florczyk AP. In Reply: Paclitaxel-Inducted "Recall" Soft
`Tissue Injury. JCO 1995; 531.
`
`11. Canetta R, Onetto N, Desmond-Hellmann S, Carter SK. Future Directions for Paclitaxel
`(Taxol) in Gynecologic Malignancies. Int J Gynecol Cancer 1994, 4 (Suppl 1), 23-26.
`
`12. Desmond-Hellmann SD, Katongole-Mbidde E. Kaposi's sarcoma: Recent Developments. AIDS
`1991, 5(suppl 1): S135-S142.
`
`13. Desmond-Hellmann SD, Mbidde EK, Kizito A, Hellmann NS, Ziegler JL. The Value of A
`Clinical Definition for Epidemic KS in Predicting HIV Seropositivity in Africa. J. AIDS
`1991; 4: 647-651.
`
`14. Desmond SD. Diet and Cancer: Should We Change What We Eat? West. J. of Med. 146
`73-78, 1986.
`
`IV. Abstracts
`1. Berstein SH, Nademanee AP, Vose JM, Tricot G, Fay JW, Negrin RS, DiPersio J, Rondon G,
`Champlin, R, Barnett, MJ, Cornetta K, Herzig GP, Vaughan W, Geils G Jr, Keating A,
`Messner H, Wolff SN, Miller KB, Linker C, Cairo M, Hellmann S, Ashby M, Stryker S,
`Nash RA. A multicenter study of platelet recovery and utilization in patients after
`myeloablative therapy and hematopoietic stem cell transplantation.
`Blood.91(9):3509-17, 1998 May 1.
`
`2. Shepherd F, Latreille J, Eisenhauer E, Fisher B, Hellmann S, Balcer M. Phase I trial ofpaclitaxel
`{Taxol) and ifosfamide in previously untreated patients with non-small cell lung cancer
`(NSCLC). Proc. Am. Soc. Clin. Oncol. 1995; 14:373
`
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`Susan Diane Desmond-Hellmann, M.D., M.P.H.
`Curriculum Vitae
`
`IV. Abstracts (continued)
`
`3. Gelmon K, Nabholtz JM, Bontenbal M, Spielmann M, Conte P, Klaassen U, Catimel G, Namer
`M, Fumoleau J, Bonneterre P, Sulk.es A, Sauter Ch, Roche H, Clavert H, Kaufinann J,
`Chaz.ard M, Diergarten K, Gallant G, Thompson M, Winograd B, Hellmann S. Randomized
`Trial of Two doses of Paclitaxel in Metastatic Breast Cancer After Failure of Standard
`Therapy. Proc. 8th NCI-EORTC Symposium on New Drugs in Cancer Therapy, 1994.
`(Abstract #493).
`
`4. Dieras V, Marty M, Morvan F, Tubiana N, Corette L, Mignot L, Serin D, Chaz.ard M, Garet F,
`Onetto N, Hellmann S, Pouillart P. A Phase II Randomized Study ofTaxol versus
`Mitomycin-C in Patients with Advanced Breast Cancer: Interim Analysis. Proc. Am. Soc.
`Clin. Oncol. 1994; 13:112. (Abstract #1683).
`
`5. Shephard F, Eisenhauer E, Latreille J, Fisher B, Hellmann S. Phase I Trial of Paclitaxel plus
`Ifosfamide in Previously Untreated Patients with Non-Small Cell Lung Cancer. Ann.
`Oncol. 1994; 5 (supp 8): 179 (Abstract# 0908).
`
`6. Sturgeon J, Ayoub J, Drouin P, Swenerton KD, Fung Kee Fung M, Lotocki RJ, Stuart G, Jeffrey
`J, Grimshaw R, Ghatage P, Healey D, Hellmann S, Onetto N, Gallant G, Dulude H. A
`Phase II, Multicenter, Non-Randomized Study of Taxol in Patients with Ovarian Cancer
`Previously Treated with Platinum Therapy. Abstract submitted to the Bristol-Myers Squibb
`Research Seminar, 1994.
`
`7. Hellmann S, Quist M, Basler G, Burroughs J, Florczyk A, Onetto N, Canetta R. Hematological
`Safety Profile of Taxol (paclitaxel) in Patients with Metastatic Breast Cancer (MBC) and
`Ovarian Cancer (OV). Abstract submitted to The American Society of Hematology, 36th
`Annual Meeting, Nashville, TN, December 1994.
`
`8. Louie L, Desmond SD, Katongole-Mbidde E, Hellmann N, Tager I. Kaposi's sarcoma may not be
`an STD in Uganda. VII Int. Conf on AIDS. Amsterdam, the Netherlands, July, 1992.
`
`9. Desmond-Hellmann SD, Mbidde EK, Kizito A, Hellmann N. Sexual Risk Behaviors in
`Heterosexual African Women with Kaposi's sarcoma. VII Int Conf on AIDS, Florence Italy
`16-21July,1991.
`
`10. Hellmann N, Desmond-Hellmann SD, Nsubuga PSJ, Baingana-Baingi, Mbidde EK, Tager I.
`Genital Trauma during Sex is a Risk Factor for HIV Infection in Uganda. VII Int Conf on
`AIDS, Florence Italy 16-21July,1991.
`
`1 Hellmann N, Desmond-Hellmann SD, Nsubuga PSJ, Mbidde EK, Baingana-Baingi. Risk
`Factors for HIV Infection Among Ugandan Couples. VII Int Conf on AIDS, Florence Italy
`16-21 July, 1991.
`
`12. Katongole-Mbidde E, Kazura JW, Banura C, Desmond-Hellmann SD, Kizito A, Hellmann N,
`Hom D, Kataaha P. Latency Period to the Development of Childhood AIDS-Associated
`Kaposi's sarcoma in African Children. VII Int Conf on AIDS, Florence Italy 16-21 July,
`1991.
`
`6
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`Susan Diane Desmond-Betlmann, M.D., M.P.H.
`Curriculum Vitae
`
`IV. Abstracts (continued)
`
`13. Nsubuga PSI, Hellmann NS, Baingana-Baingi, Mbidde EK, Desmond-Hellmann SD. The
`Association between Syphilis and HIV at a Uganda STD Clinic. 7th African Union for
`Venereal Diseases and Treponematoses (AUVDT) Conference, Lusaka, Zambia, 17-20.
`March, 1991.
`
`14. Desmond-Hellmann SD, Mbidde ED, Kizito A, Hellmann NS. Is Kaposi's sarcoma a sexually
`transmitted disease? Evidence from a case-control study. Oral Presentation/Abstract 5th Int.
`Conference on AIDS in Africa. Kinshasa, Zaire Oct 10-12, 1990.
`
`15. Desmond-Hellmann SD, Hellmann NS, Kataaha P, Nsubuga PSJ, K.abengera S, Mbidde EK.
`Low Prevalence of HIV-I Antigenemia in Ugandan Patients with HIV-I Infection. 5th Int.
`Conference on AIDS in Africa. Kinshasa, Zaire Oct 10-12, 1990.
`
`16. Mbidde EK, Banura C, Kazura J, Desmond-Hellmann SD, Kizito A, Hellmann NS. Non(cid:173)
`Hodgkin's lymphoma and HIV infection in Uganda. 5th Int Conference on AIDS in Africa.
`Kinshasa, Zaire Oct 10-12, 1990.
`
`17. Hellmann NS, Nsubuga PSJ, Baingana B, Mbidde EK, Desmond-Hellmann S. Is HIV a risk
`factor for sexually transmitted diseases? Data from Uganda. 5th Int. Conference on AIDS in
`Africa. Kinshasa, Zaire Oct 10-12, 1990.
`
`18. Mbidde EK, Banura C, Desmond-Hellmann SD, Kizito A, Hellmann NS. African Burkitt's
`Lymphoma and HIV Infection. VI International Conference on AIDS. San Francisco June
`1990.
`
`19. Hellmann NS, Nsubuga P, Mbidde EK, Desmond-Hellmann SD. Specific Heterosexual Risk
`Behaviors and HIV Seropositivity in a Uganda STD Clinic. VI International Conference on
`AIDS. San Francisco June 1990.
`
`20. Hellmann NS, Nsubuga P, Baingana B, Mbidde EK, Desmond-Hellmann SD. HIV Infection
`among Patients in a Uganda STD Clinic. VI International Conference on AIDS. San
`Francisco June 1990.
`
`21. Desmond-Hellmann SD, Mbidde EK, Kizito A, Hellmann NS. The Epidemiology and Clinical
`Features of Kaposi's Sarcoma (KS) in African Women with HIV Infection. VI International
`Conference on AIDS. San Francisco June 1990.
`
`22. Desmond-Hellmann SD, Mbidde EK, Kizito A, Hellmann NS. A Clinical Case Definition for
`HIV Infection among Ugandan Patients with Kaposi's Sarcoma. VI International Conference
`on AIDS. San Francisco June 1990.
`
`23. Mbidde EK, Desmond-Hellmann S, Kazura J, Kizito A, Hellmann N, and Banura C. The impact
`of AIDS on adult Kaposi's sarcoma at the Uganda Cancer Institute. Abstract# 227. IV
`Conference on AIDS and Associated Cancers in Africa, Marseille, France, 18-20 Oct. 1989.
`
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`

`

`Susan Diane Desmond-Hellmann, M.D., M.P.H.
`Cuniculum Vitae
`
`IV. Abstracts (continued)
`
`24. Mbidde EK, Kazura J, Brumra C, Hom D, Hellmann SD, Kizito A, and Hellmann N. Changing
`pattern of childhood Kaposi's sarcoma Abstract # 228. IV Conference on AIDS and
`Associated Cancers in Africa, Marseille, France, 18-20 Oct. 1989.
`
`25. Louie L, Desmond S, Gilles K, Newman B, King MC. Genetic Epidemiology of AIDS. Abstract
`# ThAP 83, V Int Conf. on AIDS. Montreal Canada, June 4-9, 1989. page 154.
`
`26. Heyer DM, Desmond SD, Volberding P, Kahn J. Changing Prevalence of Malignancies in Men
`at San Francisco General Hospital During the HIV Epidemic. Abstract# WBO 19, V Int.
`Conference on AIDS. Montreal Canada, June 4-9, 1989. page 206.
`
`27. Kahn J, Desmond S, Bottles K, Kaplan L. Incidence of Malignancies in Men at San Francisco
`General Hospital during the AIDS Epidemic. Abstract# 7613, IV Int. Conference on AIDS.
`Stockholm Sweden, June 13-16, 1988, page 328.
`
`8
`
`12 of 14
`
`Celltrion, Inc., Exhibit 1008
`
`

`

`Genentech, Inc,
`Institution: Multi center
`
`Patient Group
`
`IHC 2+/3+
`
`'.'
`
`Study: H0648g, Phase 111
`HERCEPTIN (R) in Breast Cancer
`
`Table 14
`Time (Months) to Disease Progression in Study H0648g: Kaplan·Meier Statistics
`.
`(by FISH Availability)
`Chemotherapy Received on Day 1
`_ _ _ _ Ac _ _ _ _ _ _ _ . Pacl itaxel _ _ _ _ _ _ _ Total _ _ _ _
`Chemotherapy
`Hmeptin
`Pact itaxel
`. Herceptin
`Herceptin
`Alone
`+Chemotherapy
`Alone
`+ Pacl itaxel
`+ AC
`(N=234)
`(N=235)
`(N=96) .
`(N:92)
`(N=143)
`
`AC Alone
`(N=138)
`
`N
`No', of Events
`No. of Censored Obs.
`r. Censored
`Median
`95Y.C. I.
`25-75 Xile
`Min • Max
`P·value
`
`143
`97
`46
`32.2%
`7.8
`(7.3,9.4)
`4.8 • 12.7
`0.26* • 23.91*
`
`138
`'119
`19
`13.8%
`6.1
`. (4.9,7. 1)
`3.7 • 9.7
`0' 20* • 26' 7 4 *
`0.0002
`
`92
`63
`29
`
`(~
`
`3. 7 • 12.6
`0.00* • 21.38*
`
`96
`90
`6
`
`(~ 1.6 • 5.4
`
`0.03 • 13.29*
`0.0001
`
`235
`160
`75
`31.9%
`7.4
`(7.0,9.0)
`4.4 • 12.7
`0,00* • 23.91*
`
`234
`209
`25
`10.7%
`4.6
`(4.4,5.4)
`2.0 • 7.6
`0.03 • 26.74*
`0.0001
`
`Results are based on all enrolled patients.
`No~e: , Indicates that Keplan·Meier estimates are not available due to extensive censoring.
`* Indicates censored observation. p·values are computed using log·rank test.
`Source: Bi ostat I st I cs(aiyuwu) pgm(/inmuno/her2/h0648g/label2000/bi ostat/t_pd_2trt_ f i sh_avai l)
`Database Status: CLOSED (Clinical Data of 180CT99, FISH Data of 11FEB00)
`Label Amendment 2000: Generated 11 JU LOO 11: 06 Page 1 of 1
`
`EXHIBIT B
`
`13 of 14
`
`Celltrion, Inc., Exhibit 1008
`
`

`

`Genentech, Inc.
`Institution: Multicenter
`
`Patient Group
`
`HERCEPTrN
`
`(R)
`
`Study: H0650g
`in Breast Cancer
`
`Time (Months)
`
`Table 1
`to Disease Progression in Study H0650g: Kap!an·Meier Statistics
`4 mg/kg
`2 mg/kg
`(W=25)
`(N=33)
`
`Total
`(N=58}
`
`Received Prior Anthracycl ine N
`No. of Events
`No. of Censored Obs.
`% Censored
`Median
`95% C. J.
`25·75 %i le
`Min • Max
`
`33
`28
`5
`15.2%
`3.5
`(3.3,6.3)
`1.9 • 12.4
`0.16 • 20.39*
`
`25
`21
`4
`
`58
`49
`9
`
`16.0% ~
`
`3.5
`(1.9,5.6)
`1.8 . 7.1
`0. 72 • 13 . 82*
`
`(
`1.8 • 8.7
`0.16 • 20.39*
`
`Note: , Indicates that Kaplan·Meier estimates are not available due to extensive censoring.
`* Indicates censored observation.
`Source: Siostatistfcs(a!yuwu) pgm(/il!JllUno/her2/h0650g/explore00/biostat/t pd prevanc)
`CLOSED (Clinical Data of 140CT99, FISH Data of 11FES00} ....
`Database Status:
`H0650g Exploratory Analysis 2000: Generated 08AUGOO 15:07
`
`Page 1 of 1
`
`EXHIBIT C
`
`14 of 14
`
`Celltrion, Inc., Exhibit 1008
`
`