UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`
`PHIGENIX, INC.
`Petitioner
`
`v.
`
`IMMUNOGEN, INC.
`Patent Owner
`
`_____________________
`
`CASE: IPR2014-00676
`Patent 8,337,856
`_____________________
`
`
`
`
`
`DECLARATION OF LINDA T. VAHDAT, M.D.
`
`
`
`
`
`IMMUNOGEN 2103, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`TABLE OF CONTENTS
`
`I.
`Overview ........................................................................................................ 3
`II. My background and qualifications .............................................................. 12
`III.
`Person of ordinary skill in the art ................................................................ 14
`IV. The '856 patent and T-DM1 (Kadcyla®) ..................................................... 15
`V. HER2-positive breast cancer ....................................................................... 17
`VI. T-DM1 met a long-felt, unmet need for an immunoconjugate
`capable of providing targeted delivery of a cytotoxic agent to treat
`a solid tumor ................................................................................................ 19
`A.
`By March 2000, the need for an immunoconjugate capable
`of targeting delivery of cytotoxic agents to treat a solid
`tumor had gone unmet for decades ................................................... 20
`T-DM1 is a pioneering immunoconjugate that met the need
`for targeting delivery of cytotoxic agents to treat a solid
`tumor .................................................................................................. 30
`VII. T-DM1 was praised as groundbreaking in the field of clinical
`immunoconjugates ....................................................................................... 35
`VIII. Conclusion ................................................................................................... 39
`
`
`B.
`
`ii
`
`IMMUNOGEN 2103, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
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`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`I, Linda T. Vahdat, M.D., do hereby declare as follows:
`
`I.
`
`Overview
`1.
`
`I am a board certified oncologist and Professor of Medicine at Weill
`
`Cornell Medical College. This declaration is based on my personal knowledge as
`
`an oncologist and my opinions as an expert in the field of cancer research and
`
`treatment, including breast cancer. I understand that this declaration is being
`
`submitted together with a Patent Owner's Reply to Phigenix, Inc.'s Petition for
`
`inter partes review ("IPR") of claims 1-8 of U.S. Patent No. 8,337,856 ("the '856
`
`patent," Ex. 1001). I also understand that this declaration is being submitted
`
`together with a Declaration by Joyce O'Shaughnessy, M.D. (Ex. 2105). I have
`
`read Dr. O'Shaughnessy's Declaration and agree with the facts and opinions
`
`expressed therein.
`
`2.
`
`I have been retained as an expert witness on behalf of ImmunoGen,
`
`Inc. for this IPR. I am being compensated for my time in connection with this
`
`declaration at my standard consulting rate of $800 per hour. I have no personal or
`
`financial interest in the outcome of this proceeding. I am over the age of eighteen
`
`and otherwise competent to make this declaration.
`
`3.
`
`Based on the work I have done in this matter and my expertise in this
`
`field, I have concluded that:
`
`3
`
`IMMUNOGEN 2103, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`• T-DM1 filled a long-felt, unmet need for an immunoconjugate
`
`capable of targeting delivery of a cytotoxic agent to treat a solid
`
`tumor (as discussed in more detail in Section VI, below); and
`
`• T-DM1 received praise in the industry for this path-breaking
`
`achievement (as discussed in more detail in Section VII below).
`
`4.
`
`In preparing this declaration, I have reviewed the '856 patent (Ex.
`
`1001) as well as each of the other documents listed in the table below or cited
`
`herein, in light of general knowledge in the art.
`
`Exhibit #
`1001
`1008
`
`1012
`
`1015
`
`1018
`
`1020
`
`1028
`
`Description
`U.S. Patent No. 8,337,856 B2
`Herceptin® Label
`Chari, R.V.J., et al., "Immunoconjugates Containing Novel
`Maytansinoids: Promising Anticancer Drugs," Cancer Research
`52: 127-131 (1992)
`Chari, R.V.J., "Targeted delivery of chemotherapeutics: tumor
`activated prodrug therapy," Advanced Drug Delivery Reviews
`31: 89-104 (1998)
`Rosenblum, M.G., "Recombinant Immunotoxins Directed
`against the c-erb-2/HER2/neu Oncogene Product: In Vitro
`Cytotoxicity, Pharmacokinets, and in Vivo Efficacy Studies in
`Xenograft Models," Clinical Cancer Research 5: 865-874 (1999)
`Pegram M., "Inhibitory effects of combinations of HER-2/neu
`antibody and chemotherapeutic agents used for treatment of
`human breast cancers," Oncogene 18: 2241-2251 (1999)
`Trail, P.A., et al., "Monoclonal antibody drug conjugates in the
`treatment of cancer," Current Opinion in Immunology 11: 584-
`588 (1999), Exhibit H to Declaration of Mark X. Sliwkowski,
`Ph.D., dated on June 30, 2010, filed in U.S. Appl. No.
`11/949,351
`
`4
`
`IMMUNOGEN 2103, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`Exhibit #
`
`2006
`
`2010
`
`2011
`
`2012
`
`2015
`
`2016
`
`2025
`
`2029
`
`2030
`
`2031
`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`Walter Blättler, et al. "Immunoconjugates," Cancer
`Therapeutics: Experimental and Clinical Agents (Beverly A.
`Teicher ed., 1997)
`Tolcher, A., et al., "Randomized Phase II Study of BR96-
`Doxorubicin Conjugate in Patients With Metastatic Breast
`Cancer," Journal of Clinical Oncology 17: 478-484 (1999)
`Elias, D., et al., "Monoclonal Antibody KS1/4-Methotrexate
`Immunoconjugate Studies in Non-Small Cell Lung Carcinoma,"
`American Journal of Respiratory and Critical Care Medicine
`150: 1114-1122 (1994)
`Krop, I., et al., "Trastuzumab emtansine versus treatment of
`physician's choice for pretreated HER2-positive advanced breast
`cancer (TH3RESA): a randomised, open-label, phase 3 trial,"
`Lancet Oncology 15: 689-699 (2014)
`Cao, Y., et al., "Construction and Characterization of Novel,
`Completely Human Serine Protease Therapeutics Targeting
`Her2/neu," Molecular Cancer Therapeutics 12: 979-991 (2013)
`Cao, Y., and Rosenblum, M.G., "Design, Development, and
`Characterization of Recombinant Immunotoxins Targeting
`HER2/neu," in Antibody-Drug Conjugates and Immunotoxins:
`From Pre-Clinical Development to Therapeutic Applications,
`Chapter 18, pp. 319-348 (2013)
`Kadcyla™ Prescribing Information, pp. 1-21(2013)
`Pai-Scherf, L., et al., "Hepatotoxicity in Cancer Patients
`Receiving erb-38, a Recombinant Immunotoxin That Targets the
`erbB2 Receptor," Clinical Cancer Research 5: 2311-2315 (1999)
`Pai, L., et al., "Clinical Evaluation of Intraperitoneal
`Pseudomonas Exotoxin Immunoconjugate OVB3-PE in Patients
`With Ovarian Cancer," Journal of Clinical Oncology 9: 2095-
`2103 (1991)
`Gould, B., et al., "Phase I Study of an Anti-Breast Cancer
`Immunotoxin by Continuous Infusion: Report of a Targeted
`Toxic Effect Not Predicted by Animal Studies," Journal of the
`National Cancer Institute 81: 775-781 (1989)
`
`5
`
`IMMUNOGEN 2103, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`Exhibit #
`
`2060
`
`2072
`
`2073
`
`2100
`
`2102
`
`2105
`
`2107
`
`2108
`
`2109
`
`2115
`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`Burris, H., "Trastuzumab Emtansine: A Novel Antibody-Drug
`Conjugate for HER2-Positive Breast Cancer," Expert Opin. Biol.
`Ther. 11: 807-819 (2011)
`"Roche reports new T-DM1 results," available at
`http://www.european-biotechnology-news.com/news/news/2013-
`04/roche-reports-new-t-dm1-results.html (last accessed January
`20, 2014)
`"Anti-cancer drug T-DM1 benefits women with advanced breast
`cancer who have failed several previous treatments: results from
`TH3RESA trial," available at http://www.ecco-
`org.eu/Amsterdam2013/Global/News/ECC-2013-Press-Releases-
`EN/2013/09/Anticancer-drug-T-DM1-benefits-women-with-
`advanced-breast-cancer (last accessed January 20, 2014)
`Koppel, G., "Recent Advances with Monoclonal Antibody Drug
`Targeting for the Treatment of Human Cancer," Bioconjugate
`Chemistry 1: 13-23 (1990)
`Embelton, M., "Drug-targeting by monoclonal antibodies," Br. J.
`Cancer 55: 227-231 (1987)
`Declaration of Joyce Ann O'Shaughnessey, M.D.
`Priestman, T., "Quality of life after cytotoxic chemotherapy:
`discussion paper," Journal of the Royal Society of Medicine 77:
`492-495 (1984)
`DeVita, V., et al., "A History of Cancer Chemotherapy," Cancer
`Research 68: 8643-8653 (2008)
`Mathé, G., et al., "Experimental Medicine – Effect on Mouse
`Leukemia 1210 of a Combination by Means of Diazotization of
`Amethopterin and of y-Globulins from hamsters with this
`Leukemia by Means of Heterograft," Academie of Science
`Reports 246: 1626-1628 (1958)
`Kuan, C., et al., "Immunotoxins Containing Pseudomonas
`Exotoxin That Target LeY Damage Human Endothelial Cells in
`an Antibody-specific Mode: Relevance to Vascular Leak
`Syndrome," Clinical Cancer Research 1: 1589-1594 (1995)
`
`6
`
`IMMUNOGEN 2103, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`Exhibit #
`
`2116
`
`2117
`
`2118
`
`2120
`
`2121
`
`2162
`
`2178
`
`2179
`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`Pollack, A., " In Study, Drug Delays Worsening of Breast
`Cancer, With Fewer Side Effects," N.Y. TIMES (2012), available
`at http://www.nytimes.com/2012/06/03/health/research/in-study-
`drug-delays-worsening-of-breast-cancer-with-fewer-side-
`effects.html?ref=science&_r=0 (last visited Dec. 1, 2014)
`Slamon, D., et al., "Human Breast Cancer: Correlation of
`Relapse and Survival with Amplification of the HER-2/neu
`Oncogene," Science 235: 177-182 (1987)
`Herceptin® FDA Approval Letter, mailed Sept. 25, 1998
`Krop, I., et al., "A Phase II Study of Trastuzumab Emtansine in
`Patients With Human Epidermal Growth Factor Receptor 2–
`Positive Metastatic Breast Cancer Who Were Previously Treated
`With Trastuzumab, Lapatinib, an Anthracycline, a Taxane, and
`Capecitabine," Journal of Clinical Oncology 30: 3234-3241
`(2012)
`Verma, S., et al., "Trastuzumab Emtansine for HER2-Positive
`Advanced Breast Cancer," The New England Journal of
`Medicine 367: 1783-1791 (2012)
`Winer, L., et al., "Phase I Evaluation of an Anti-Breast
`Carcinoma Monoclonal Antibody 260F9-Recombinant Ricin A
`Chain Immunoconjugate," Cancer Research 49: 4062-4067
`(1989)
`FDA Clinical Review of BLA 98-0369, Herceptin®,
`Trastuzumab, approved Sept. 25, 1998, available at
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowD
`rugsareDevelopedandApproved/ApprovalApplications/Therapeut
`icBiologicApplications/ucm080591.htm (last visited Dec. 1,
`2014)
`LoRusso, P., et al., "Trastuzumab Emtansine: A Unique
`Antibody-Drug Conjugate in Development for Human Epidermal
`Growth Factor Receptor 2-Positive Cancer," Clin Cancer Res 17:
`6437-6447 (2011)
`
`7
`
`IMMUNOGEN 2103, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`Exhibit #
`
`2180
`
`2181
`
`2182
`
`2184
`
`2186
`
`2189
`
`2193
`
`2194
`
`2205
`
`2209
`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`FDA News Release, "FDA Expands Use of Herceptin for Early
`Stage Breast Cancer After Primary Therapy," released Nov. 16,
`2006, updated Dec. 12, 2006, available at
`http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncemen
`ts/2006/ucm108788.htm (last visited Dec. 1, 2014)
`Kadcyla® FDA Approval Letter, mailed Feb. 22, 2013
`Carey, M., "Etiology and Treatment of the Psychological Side
`Effects Associated with Cancer Chemotherapy: A Critical
`Review and Discussion," Psychological Bulletin 104: 307-325
`(1988)
`Palmer, B., et al., "Adjuvant chemotherapy for breast cancer:
`side effects and quality of life," British Medical Journal 281:
`1594-1597 (1980)
`Johnson, I., et al., "Monoclonal antibody drug conjugates for
`site-directed cancer chemotherapy: preclinical pharmacology and
`toxicology studies," Cancer Treatment Reviews 14: 193-196
`(1987)
`Welslau, M., et al., "Patient-Reported Outcomes From EMILIA,
`a Randomized Phase 3 Study of Trastuzumab Emtansine (T-
`DM1) Versus Capecitabine and Lapatinib in Human Epidermal
`Growth Factor Receptor 2–Positive Locally Advanced or
`Metastatic Breast Cancer," Cancer 120: 642-651 (2014)
`Spitler, L. E., et al., "Therapy of Patients with Malignant
`Melanoma Using a Monoclonal Antimelanoma Antibody-Ricin
`A Chain Immunotoxin." Cancer Res 47:1717-1723 (1987)
`Herceptin® FDA Approval Letter, mailed November 16, 2006
`American Cancer Society. Breast Cancer Facts & Figures 2013-
`2014
`Genentech Press Release entitled "FDA Approves Perjeta
`(Pertuzumab) for People With HER2-Positive Metastatic Breast
`Cancer," dated June 8, 2012, available at
`http://www.gene.com/media/press-releases/14007/2012-06-
`08/fda-approves-perjeta-pertuzumab-for-peop
`
`8
`
`IMMUNOGEN 2103, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
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`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`Perjeta® package insert, available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/1254
`09s051lbl.pdf
`Ixempra® package insert, available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/0220
`65s006lbl.pdf
`“FDA Approves First-Of-Its-Kind Breast Cancer Drug,” pp. 1-3
`(2013) available at
`http://www.huffingtonpost.com/2013/02/22/fda-approves-new-
`breast-cancer-drug-kadcyla_n_2742241.html (accessed
`December 5, 2014)
`Bookman, MA., et al., "Anti-Transferrin Receptor Immunotoxin
`(IT): Intraperitoneal (i.p.) Phase I Trial," Proceedings of the
`American Society for Clinical Oncology 9: 198(Abstract 722)
`(1990)
`Byers, V.S., et al., "Phase I Study of Monoclonal Antibody-Ricin
`A Chain Immunotoxin XomaZyme-791 in Patients with
`Metastatic Colon Cancer," Cancer Research 49: 6153-6160
`(1989)
`Elias, D., et al., "Phase I Clinical Comparative Study of
`Monoclonal Antibody KS1/4 and KS1/4-Methotrexate
`Immunoconjugate in Patients with Non-Small Cell Lung
`Carcinoma," Cancer Research 50: 4154-4159 (1990)
`Ford, C.H.J., et al., "Localisation and Toxicity Study of a
`Vindesine-Anti-CEA Conjugate in Patients with Advanced
`Cancer," Br. J. Cancer 47: 035-042 (1983)
`Gillespie, A.M., et al., "Phase I Open Study of the Effects of
`Ascending Doses of the Cytotoxic Immunoconjugate CMB-401
`(hCTM01-Calicheamicin)In Patients with Epithelial Ovarian
`Cancer," American Society of Clinical Oncology Meeting 17:
`Abstract 1686 (1998)
`Gonzalez, R., et al., "Single-Dose Murine Monoclonal Antibody
`Ricin A Chain Immunotoxin in the Treatment of Metastatic
`Melanoma: A Phase I Trial," Mol. Biother. 3: 192-196 (1991)
`
`Exhibit #
`
`2212
`
`2222
`
`2254
`
`2293
`
`2294
`
`2296
`
`2297
`
`2298
`
`2299
`
`9
`
`IMMUNOGEN 2103, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`Laske, D., et al., "Intraventricular Immunotoxin Therapy for
`Leptomeningeal Neoplasia," Neurosurgery 41: 1039-1051
`(1997)
`LoRusso, P.M., et al., "Phase I Study of Monoclonal Antibody –
`Ricin A Chain Immunoconjugate Xomazyme-791 in Patients
`with Metastatic Colon Cancer," Am J Clin Oncol(CCT) 18: 307-
`312 (1995)
`Melino, G., et al., "Drug Targeting For 7 Neuroblastoma Patients
`Using Human Polyclonal Antibodies," Protides Biol. Fluids 32:
`413-416 (1984)
`Azvolinsky, A., "ASCO: Unique Combination of Targeted
`Antibody Linked to Chemotherapy Shows Positive Results in
`HER2-Positive Breast Cancer Patients," available at
`http://www.cancernetwork.com/breast-cancer/asco-unique-
`combination-targeted-antibody-linked-chemotherapy-shows-
`positive-results-her2-positive (last visited Jan. 17, 2015)
`Oldham, R., et al., "Adriamycin Custom-Tailored
`Immunoconjugates in the Treatment of Human Malignancies,"
`Mol. Biother 1: 103-113 (1988)
`Oldham, R.K., et al., "Individually Specified Drug
`Immunoconjugates in Cancer Treatment," The International
`Journal of Biological Markers 4: 65-77 (1989)
`Oratz, R., et al., "Antimelanoma Monoclonal Antibody-Ricin A
`chain Immunoconjugated (XMMME-001-RTA) Plus
`Cyclophosphamide in the Treatment of Metastatic Malignant
`Melanoma: Results of a Phase II Trial," Journal of Biological
`Response Modifiers 9: 345-354 (1990)
`Orr, D., et al., "Phase I Trial of Mitomycin C Immunoconjugates
`Cocktails in Human Malignancies," Mol Biother 1: 229-240
`(1989)
`Pai, L., et al., "Treatment of Advanced Solid Tumors With
`Immunotoxin LMB-1: An Antibody Lined to Pseudomonas
`Exotoxin," Nature Medicine 2: 350-353 (1996)
`
`Exhibit #
`
`2300
`
`2301
`
`2302
`
`2303
`
`2304
`
`2305
`
`2306
`
`2307
`
`2308
`
`10
`
`IMMUNOGEN 2103, pg. 10
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`Salem, P. et al., "Treatment of Advanced Metastatic Melanima
`Using Single Dose Murine Monoclonal Antibody-Ricin A Chain
`Immunotoxin With Dose Escalation: A Phase I Study,"
`Proceedings of the American Association for Cancer Research
`Annual Meeting 30: 288 (Abstract 1147) (1988)
`Schneck, D., et al., "Disposition of a Murine Monoclonal
`Antibody Vinca Conjugate (KS1/4-DAVLB) in Patients With
`Adenocarcinomas," Clin Pharmacol Ther 47: 36-41 (1990)
`Schneck, D., et al., "Phase I Studies With a Murine Monoclonal
`Antibody Vinca Conjugate (KS1/4-DAVLB) in Patients with
`Adenocarcinoma," Antibody, Immunoconjugates, and
`Radiopharm 2: 93-100(1989)
`Selvaggi, K., et al., Phase I/II Study of Murine Monoclonal
`Antibody-Ricin A Chain (XOMAZYME-Mel) Immunoconjugate
`Plus Cyclosporine A in Patients With Metastatic Melanoma,"
`Journal of Immunotherapy 13: 201-207 (1993)
`Spitler, L., "Clinical Studies: Solid Tumors," in Immunotoxins
`Chapter 28, pp. 493-514 (1988)
`Takahashi, T., et al., "Clinical Application of Monoclonal
`Antibody-Drug Conjugates for Immunotargeting Chemotherapy
`of Colorectal Carcinoma," Cancer 61: 881-888 (1988)
`Tjandra, J.J., et al., "Phase I Clinical Trial of Drug-Monoclonal
`Antibody Conjugates in Patients With Advanced Colorectal
`Carcinoma: A Preliminary Report," Surgery 106: 533-545 (1989)
`Zalcberg, J.R., et al., "A Phase I/II Study of the Intralesional
`Injection of Ricin-Monoclonal Antibody Conjugates in Patients
`With Hepatic Metastases," European Journal of Cancer 30A:
`1227-1231 (1994)
`Pietersz, G., et al., "Pre-Clinical and Clinical Studies with N-
`Acetyl Melphalan Immunoconjugates and Tumor Necrosis
`Factor α," Antibody, Immunoconjugates, and
`Radiopharmaceuticals 2: 47-61 (1989)
`Durrant, L.G., et al., "Humoral Immune Responses to XMMCO-
`791-RTA Immunotoxin in Colorectal Cancer Patients," Clin Exp.
`Immunol. 75: 258-264 (1989)
`
`Exhibit #
`
`2309
`
`2310
`
`2311
`
`2312
`
`2313
`
`2314
`
`2315
`
`2316
`
`2327
`
`2328
`
`11
`
`IMMUNOGEN 2103, pg. 11
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Description
`Pietersz, G., et al., "Preclinical and Clinical Studies with a
`Variety of Immunoconjugates," Antibody, Immunoconjugates,
`and Radiopharmaceuticals 1: 79-103 (1988)
`
`Exhibit #
`
`2329
`
`5.
`
`In formulating my opinions, I have relied upon my experience,
`
`education, and knowledge in the relevant art. In formulating my opinions, I have
`
`also considered the viewpoint of a person of ordinary skill in the art ("POSA") as
`
`described in Section III, below.
`
`II. My background and qualifications
`6. My qualifications and credentials are fully set forth in my curriculum
`
`vitae, attached as Exhibit 2104. I am an expert in the field of cancer research and
`
`treatment. In particular, I have intimate knowledge of and experience with the
`
`techniques and therapies used in the field of breast cancer research and treatment.
`
`I have been an expert in this field since 1994. For at least the past 20 years, I have
`
`accumulated significant training and experience in the field of breast cancer
`
`treatment, and other related fields.
`
`7.
`
`I completed my undergraduate studies at Barnard College/Columbia
`
`University, graduating in 1982. I graduated with a Medical Doctor degree from
`
`Mount Sinai Medical School in New York City in 1987. Most recently, I
`
`completed a master's in business administration at the Sloan School of
`
`12
`
`IMMUNOGEN 2103, pg. 12
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`Management at the Massachusetts Institute of Technology in Cambridge,
`
`Massachusetts in June 2014.
`
`8. My internal medicine training was completed at the Mount Sinai
`
`School of Medicine and Hospital (1987-1990), and I completed a Fellowship in
`
`Hematology and Medical Oncology at Memorial Sloan Kettering Cancer Center
`
`(1991-1994), both in the City of New York. I was then recruited to Columbia
`
`University College of Physicians and Surgeons as an Assistant Professor of
`
`Medicine specializing in the treatment of metastatic and high-risk-for-relapse
`
`breast cancer, ultimately being promoted to lead the stem cell transplant group in
`
`breast cancer. In 2002, I was recruited to Weill Cornell Medical College to build a
`
`breast cancer research program being promoted to Associate Professor and
`
`ultimately to Professor of Medicine in 2010.
`
`9.
`
`I have published more than 100 papers in peer-reviewed national and
`
`international journals, including in the areas of breast cancer (mostly in metastatic
`
`disease), new breast cancer therapeutics, tumor dormancy, and chemotherapy-
`
`induced peripheral neuropathy. I am a peer reviewer for Clinical Cancer
`
`Research, Journal of Clinical Oncology, and Breast Cancer Research and
`
`Treatment. These are among the most widely read journals by the breast cancer
`
`constituency. I was also the Co-Chair of the American Society of Clinical
`
`Oncology (ASCO) Breast Cancer Symposium Meeting in 2010.
`
`13
`
`IMMUNOGEN 2103, pg. 13
`Phigenix v. Immunogen
`IPR2014-00676
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`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`10. Accordingly, I am an expert in the field of breast cancer treatment,
`
`and have been since 1994.
`
`III. Person of ordinary skill in the art
`I understand that a person of ordinary skill in the art ("POSA") is a
`11.
`
`hypothetical person or team of people who is presumed to be aware of all pertinent
`
`art, thinks in accordance with conventional wisdom in the art, and is a person of
`
`ordinary creativity. A POSA would know how to research the scientific literature
`
`regarding cancer, cancer therapeutics, immunoconjugates, or clinical trials of
`
`immunoconjugates. A POSA typically would have an M.D. degree and/or a Ph.D.
`
`degree in a Chemistry-, Pharmacology-, or Biology-related field. A POSA may be
`
`comprised of a multidisciplinary team, with each member drawing upon not only
`
`his or her own skills, but also taking advantage of certain specialized skills of
`
`others in the team, e.g., to solve a given problem. For example, a member of that
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`team may have knowledge and skill relating to the principles behind and use of
`
`immunoconjugates to treat cancer. That may include knowledge and skill relating
`
`to
`
`the processes and
`
`techniques used
`
`to
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`link
`
`the components of an
`
`immunoconjugate. And another team member may be a clinician experienced in
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`cancer research and treatment, including breast cancer research and treatment.
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`Each member of that team typically would have at least three years of experience.
`
`14
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`IMMUNOGEN 2103, pg. 14
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`IPR2014-00676
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`

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`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`12. From my viewpoint as an expert, I can describe what a POSA would
`
`have understood, known, and concluded in March of 2000 (and thereafter). My
`
`opinions herein are presented from the vantage point of a person of ordinary skill
`
`in the art.
`
`IV. The '856 patent and T-DM1 (Kadcyla®)
`I understand that the '856 patent issued on December 25, 2012, and
`13.
`
`resulted from U.S. Application No. 11/949,351, filed on December 3, 2007. I also
`
`understand that the U.S. Patent and Trademark Office ("USPTO") records state
`
`that the '856 patent is currently assigned to ImmunoGen, Inc.
`
`14. The face page of the '856 patent lists a series of patent applications. I
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`understand that the '856 patent is related to these patent applications. The earliest
`
`filing date of any of those applications is March 16, 2000. It is my understanding
`
`that the earliest date to which the '856 patent may claim priority is March 16,
`
`2000.
`
`15. The '856 patent specification is directed to "methods of treatment
`
`using anti-ErbB receptor antibody-maytansinoid conjugates, and articles of
`
`manufacture suitable for use in such methods." (Ex. 1001 at Abstract.) I have
`
`considered claim 8 of the '856 patent, and I understand that claim 8 is a dependent
`
`claim that includes the elements of the claims from which it depends (i.e., claims
`
`1, 2, and 7).
`
`15
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`IMMUNOGEN 2103, pg. 15
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`IPR2014-00676
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`

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`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`16. Claim 1, from which claims 2, 7, and 8 generally depend, recites an
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`immunoconjugate (IC) comprising huMAb4D5-8 (Herceptin®) conjugated to a
`
`maytansinoid. (Id. at 81:29-31.) Claim 2 depends from claim 1 and recites an
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`immunoconjugate comprising huMAb4D5-8 conjugated to the maytansinoid
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`DM1. (Id. at 81:32-53.) Claim 7 depends from claim 2 and recites that DM1 is
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`conjugated via a set of specific linkers. (Id. at 82:43-48.) And Claim 8, which
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`depends from claim 7, recites that the maytansinoid DM1 is conjugated to
`
`huMAb4D5-8
`
`via
`
`a
`
`succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-
`
`carboxylate ("SMCC") linker. (Id. at 82:49-51.)
`
`17. T-DM1 is marketed as Kadcyla®. (Ex. 2025.) As shown in the
`
`Kadcyla®
`
`label, T-DM1
`
`is a HER-2-targeting antibody-drug conjugate
`
`(immunoconjugate) that contains the antibody trastuzumab (which is marketed
`
`under the brand name Herceptin®; see Ex. 1008) covalently linked to the
`
`maytansinoid DM1 via the thioether linker SMCC (also known as "MCC"). (Ex.
`
`2025 at 14:7-8.) Thus, T-DM1 is an immunoconjugate that contains the same
`
`antibody, the same drug, and the same linker required by claim 8. In other words,
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`T-DM1 is coextensive with claim 8 of the '856 patent.
`
`18.
`
`I have prescribed T-DM1 for the treatment of breast cancer since it
`
`was approved by the FDA in 2013. My prescribing of T-DM1 has been based on
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`results of clinical trials published in peer-reviewed literature, which highlights its
`
`16
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`IMMUNOGEN 2103, pg. 16
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`IPR2014-00676
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`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`safety and clinical efficacy, as well as my own experience with patients, and not
`
`due to marketing efforts. The safety and clinical efficacy result from the
`
`combination of components in T-DM1, i.e., an immunoconjugate linking the
`
`Herceptin® antibody to the DM1 maytansinoid via the SMCC linker. Therefore, I
`
`prescribe T-DM1 to my patients due to the claimed features in the '856 patent.
`
`V. HER2-positive breast cancer
`19. Breast cancer is one of the most common forms of malignancies
`
`found in women. (Ex. 2178 at 6:1.) Human epidermal growth factor receptor 2
`
`(HER2) is overexpressed in approximately 15-30% of breast cancers. (Ex. 2205 at
`
`25:2:4 and Ex. 2178 at 6:1.) By 1987, it was recognized that this overexpression
`
`of HER2 correlated with poor prognosis. (Ex. 2117 at 178:1:21, 179:1:1 and 2,
`
`and 179:2:1 and Ex. 2178 at 7:7.) T-DM1 is approved for the treatment of HER2-
`
`positive metastatic breast cancer in patients who have previously received other
`
`breast cancer therapies. (Ex. 2025 at 1:1:5.)
`
`20. Before T-DM1 was approved,
`
`the U.S. Food and Drug
`
`Administration
`
`("FDA") approved
`
`the monoclonal antibody Herceptin®
`
`(trastuzumab) in 1998 for the treatment of metastatic HER2-postive breast cancer.
`
`17
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`IMMUNOGEN 2103, pg. 17
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`IPR2014-00676
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`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`(Ex. 1008 and Ex. 2118.) The initial approval was as a "first-line"1 therapy in
`
`combination with the chemotherapeutic paclitaxel or as a single agent therapy for
`
`patients previously treated with chemotherapy. (Ex. 1008 at 1:2:5 and Ex. 2118 at
`
`1:2.) In 2006, the FDA approved Herceptin® as part of a treatment regimen
`
`containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant
`
`treatment2 of patients with early-stage HER2-positive breast cancer (Ex. 2194 at
`
`1:1.) In 2008, Herceptin® gained further approval as an adjuvant treatment for
`
`early-stage HER2-positive breast cancer. (Ex. 2180 at 1:1.)
`
`21. Before the approval of T-DM1, HER2-positive breast cancer patients
`
`typically received pertuzumab3 (Perjeta®, first approved in 2012) and Herceptin®
`
`in combination with a taxane, such as paclitaxel, as a first-line therapy. (Ex. 2209.)
`
`If a patient's disease progressed despite this first-line treatment, then second-line
`
`HER2-directed therapies consisting of Herceptin® plus a chemotherapeutic agent
`
`1 "First-line" treatment refers to the first drug or set of drugs used to treat
`
`metastatic disease. "Second-line" treatment refers to the second drug or set of
`
`drugs used to treat metastatic disease.
`
`2 Adjuvant treatment is additional cancer treatment given after a primary
`
`treatment—typically surgery to remove tumor mass—designed to lower the risk
`
`that the cancer will recur.
`
`3 Pertuzumab is a humanized anti-HER2 antibody. (Ex. 2212 at 17:8)
`
`18
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`IMMUNOGEN 2103, pg. 18
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`IPR2014-00676
`
`

`
`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`or lapatinib (Tykerb®) plus the chemotherapeutic capecitabine (Xeloda®) were
`
`usually employed. (Ex. 2121 at 1784:1:1.) Upon failure of these second-line
`
`therapies, patients were
`
`treated other HER2-targeted
`
`therapies, generally
`
`Herceptin® in combination with other cytotoxic agents. The chemotherapeutic
`
`agent ixabepilone (Ixempra®) was also approved for use in patients who had
`
`previously received other therapies (anthracycline, taxane, and/or capecitabine),
`
`but it was rarely used. (Ex. 2222.)
`
`22. T-DM1 was approved by the FDA on February 22, 2013, for the
`
`treatment of patients who were previously treated with Herceptin® and a taxane.
`
`(Ex. 2181 at 1:3.) T-DM1 has proven to be safer and more efficacious than either
`
`(i) the combination of Herceptin® plus a chemotherapeutic agent (Ex. 2012 at
`
`695:1:2 and 697:2:2), or (ii) the combination of lapatinib and capecitabine (Ex.
`
`2121 at Abstract) in patients that have previously been treated with Herceptin®
`
`and a chemotherapeutic agent. And based on this increased safety and efficacy,
`
`most oncologists, including myself, now use T-DM1 instead of using (i)
`
`Herceptin® plus a chemotherapeutic or (ii) lapatinib plus capecitabine for the
`
`second and third-line treatment of metastatic breast cancer.
`
`VI. T-DM1 met a long-felt, unmet need for an immunoconjugate capable of
`providing targeted delivery of a cytotoxic agent to treat a solid tumor
`23. T-DM1 met a long-felt, unmet need for an immunoconjugate capable
`
`of providing targeted delivery of a cytotoxic (cell-killing) agent to treat a solid
`
`19
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`IMMUNOGEN 2103, pg. 19
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`

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`IPR2014-00676
`Declaration of Linda T. Vahdat, M.D. (Exhibit 2103)
`tumor. In doing so, T-DM1 played a major role in improving the negative view
`
`oncologists had about the usefulness of immunoconjugates in treating solid
`
`tumors. Although the concept of using antibodies to target delivery of cytotoxic
`
`agents to tumors was contemplated for decades, immunoconjugates that looked
`
`promising in animal models failed in the clinic time and time again. For example,
`
`Exhibit 2062 shows a timeline of publications of clinical trials testing the ability
`
`of immunoconjugates to treat solid tumors; ultimately, though, none of these
`
`immunoconjugates proved safe and effective
`
`in
`
`treating a solid
`
`tumor.
`
`Remarkably, as I explain below, T-DM1 has succeeded where all the others failed.
`
`I have been prescribing T-DM1 since it was approved by the FDA, and I have
`
`witnessed its success first hand. In my experience, and as the medical literature
`
`shows, T-DM1 treats some of the most refractory (or otherwise untreatable) breast
`
`cancer patients, and it does so with fewer side effects than traditional therapies.
`
`Thus, T-DM1 gives patients longer and better-quality lives.
`
`A. By March 2000, the need for an immunoconjug