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 JOYCE O'SHAUGHNESSY, M.D.
`
`
`
`
`
`IMMUNOGEN 2105, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`
`PHIGENIX, INC.
`Petitioner
`
`v.
`
`IMMUNOGEN, INC.
`Patent Owner
`
`_____________________
`
`CASE: IPR2014-00676
`Patent 8,337,856
`_____________________
`
`
`
`
`
`DECLARATION OF JOYCE O'SHAUGHNESSY, M.D.
`
`
`
`
`
`IMMUNOGEN 2105, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`TABLE OF CONTENTS
`
`I.
`Overview ........................................................................................................ 1
`II. My background and qualifications ................................................................ 6
`III.
`Person of ordinary skill in the art .................................................................. 8
`IV. The '856 patent and T-DM1 (Kadcyla®) ....................................................... 9
`T-DM1 is unexpectedly superior to Herceptin® in combination
`V.
`with a chemotherapeutic in Herceptin®-resistant patients ........................... 12
`VI. T-DM1 was praised throughout the field of breast cancer treatment .......... 19
`VII. Conclusion ................................................................................................... 23
`
`
`ii
`
`IMMUNOGEN 2105, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`I, Joyce O'Shaughnessy, M.D., do hereby declare as follows:
`
`I.
`
`Overview
`
`1.
`
`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 ImmunoGen, Inc.'s Patent Owner 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 Linda T. Vahdat, M.D. (Ex. 2103). I have read Dr.
`
`Vahdat'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 $500 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.
`
`I understand that the '856 patent issued on December 25, 2012, and
`
`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.
`
`1
`
`IMMUNOGEN 2105, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`The face page of the '856 patent lists a series of patent applications. I
`
`4.
`
`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 that March 16,
`
`2000 date.
`
`5.
`
`I am providing this declaration to establish that:
`
`•
`
`T-DM1 achieved unexpectedly superior results over prior
`
`Herceptin®-based treatments for metastatic HER2-positive
`
`breast cancer and received praise in the industry.
`
`6.
`
`In preparing this declaration, I have reviewed the '856 patent (Ex.
`
`1001). I have also considered each of the documents listed in the table below or
`
`cited herein, in light of general knowledge in the art.
`
`Exhibit #
`1001
`1008
`
`1012
`
`1018
`
`1020
`
`Description
`U.S. Patent No. 8,337,856 B2
`Herceptin® Label
`Chari, R., et al., "Immunoconjugates containing novel
`maytansinoids: promising anticancer drugs." Cancer Res., 52:
`127-131 (1992).
`Rosenblum, M., et al., "Recombinant immunotoxins directed
`against the c-erbB-2/HER2/neu oncogene product: in vitro
`cytotoxicity, pharmacokinetics, and in vivo efficacy studies in
`xenograft models." Clin. Cancer Res., 5: 865-874 (1999).
`Pegram, M., et al., "Inhibitory effects of combinations of HER-
`2/neu antibody and chemotherapeutic agents used for treatment
`of human breast cancers." Oncogene, 18: 2241-2251 (1999).
`
`2
`
`IMMUNOGEN 2105, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Exhibit #
`
`1029
`
`2012
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`Description
`Trail, P.A., et al., "Monoclonal antibody drug conjugates in the
`treatment of cancer," Current Opinion in Immunology 11: 584-
`588 (1999), Exhibit F to Declaration of Barbara Klencke, M.D.,
`filed on July 6, 2010, in U.S. Appl. No. 11/949,351
`
`Laino, C., "Targeted Breast Cancer Drug Shrinks Tumors: Study
`Shows T-DM1 Helps Patients Who Were Unsuccessfully
`Treated with Other Drugs," WebMD (2009), Exhibit I to
`Declaration of Barbara Klencke, M.D., filed on July 6, 2010, in
`U.S. App. No. 11/949,351
`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., 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)
`Engert, A., et al., "The Emerging Role of Ricin in A-Chain
`Immunotoxins in Leukemia and Lymphoma" in Clinical
`Applications of Immunotoxins by Frankel, A.E., (Ed.), pp. 13-
`33(1998)
`Roth, B., et al., "Clinical Cancer Advances 2012: Annual Report
`on Progress Against Cancer From the American Society of
`Clinical Oncology," Journal of Clinical Oncology 31: 131-161,
`2063 (2013)
`Gochenauer, G., "Roche/Genentech's "Magic Bullet" in HER2+
`Breast Cancer," available at
`http://www.kantarhealth.com/blog/gordon-
`gochenauer/2012/06/03/Roche_Genentech_Magic_Bullet_in_HE
`R2_Breast_Cancer (last visited Jan. 14, 2015) pp. 1-2 (2012)
`Miller, K., et al., "T-DM1: Golden Age in HER2+ Breast
`Cancer?" pp. 1-6 available at
`http://www.medscape.com/viewarticle/765248 (last visited Jan.
`14, 2015)
`
`3
`
`IMMUNOGEN 2105, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Exhibit #
`2025
`
`2027
`
`2048
`
`2049
`
`2050
`
`2051
`
`2052
`
`2056
`
`2103
`
`2116
`
`2119
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`Description
`Kadcyla™ Prescribing Information, pp. 1-21(2013)
`Nandini, D., et al., "T-DM1: A Giant Step Forwards in HER2
`Therapeutics," Cancer Therapy 9: 45-54 (2013)
`Christianson, T., et al., "NH2-terminally Truncated HER-2/neu
`Protein: Relationship with Shedding of the Extracellular Domain
`and with Prognostic Factors in Breast Cancer," Cancer Research
`58: 5123-5129 (1998)
`Sliwkowski, J., et al., "Nonclinical Studies Addressing the
`Mechanism of Action of Trastuzumab (Herceptin)," Seminars in
`Oncology 26: 60-70 (1999)
`Zabrecky, J., et al., "The Extracellular Domain of p185/neu Is
`Released from the Surface of Human Breast Carcinoma Cells,
`SK-BR-3," Journal of Biochemistry 266: 1716-1720 (1991)
`Kwong, K., et al., "A Novel Splice Variant of HER2 with
`Increased Transformation Activity," Molecular Carcinogenesis
`23: 62-68 (1998)
`Koski, R., U.S. Patent No. 5,783,404 (filed Apr. 13, 1995, issued
`July 21, 1998)
`Mountain, A., and Adair, J.A., "Engineering Antibodies for
`Therapy," Engineering Antibodies for Therapy, Biotechnology
`and Genetic Engineering Review 10: 1-142 (1992)
`Declaration of Dr. Linda T. Vahdat
`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?_r=0 (last visited Jan. 14, 2015)
`Lisa Raedler, Kadcyla (Ado-Trastuzumab Emtansine): First
`Antibody-Drug Conjugate Approved for the Treatment of HER2-
`Positive Metastatic Breast Cancer, AMERICAN HEALTH & DRUG
`BENEFITS, available at http://www.ahdbonline.com/select-drug-
`updates/1433-article-1433 (last visited Jan. 14, 2015)
`
`4
`
`IMMUNOGEN 2105, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Exhibit #
`
`2120
`
`2121
`
`2122
`
`2123
`
`2129
`
`2130
`
`2151
`
`2184
`
`2189
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`Description
`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)
`Barok, M., et al., "Trastuzumab emtansine: mechanisms of
`action and drug resistance," Breast Cancer Research 16: 209-220
`(2014)
`Carlson, R., "Metastatic Breast Cancer: T-DM1 Conjugate
`Superior to Standard Treatment with Capecitabine-Lapatinib,"
`Oncology Times 34: 26 and 28 (2012)
`Szöllösi, J., et al., "ERBB-2 (HER-2/neu) Gene Copy Number,
`p185HER-2 Overexpression, and Intratumor Heterogeneity in
`Human Breast Cancer," Cancer Research 55: 5400-5407 (1995)
`Smyth, M., et al., "Immunochemotherapy of Human Colon
`Carcinoma Xenografts in Nude Mice Using Combinations of
`Idarubicin-Monoclonal Antibody Conjugates," Immunology and
`Cell Biology 71: 167-179 (1993)
`Ewer, M., et al., "Cardiotoxicity in Patients Receiving
`Trastuzumab (Herceptin): Primary Toxicity, Synergistic or
`Sequential Stress, or Surveillance Artifact?," Semin Oncol 26:
`96-101 (1999)
`Palmer, B., et al., "Adjuvant chemotherapy for breast cancer:
`side effects and quality of life," British Medical Journal 281:
`1594-1597 (1980)
`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)
`
`5
`
`IMMUNOGEN 2105, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Exhibit #
`
`2192
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`Description
`Jacobs, T., et al., "Specificity of HercepTest in Determining
`HER-2/neu Status of Breast Cancers Using the United States
`Food and Drug Administration–Approved Scoring System,"
`Journal of Clinical Oncology 17: 1983-1987 (1999)
`
`7.
`
`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
`8. My qualifications and credentials are fully set forth in my curriculum
`
`vitae, attached as Exhibit 2106. 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 1990. For the past 25 years, I have
`
`accumulated significant training and experience in the field of breast cancer
`
`treatment, and other related fields.
`
`9.
`
`I received a Bachelor's Degree in Biology from Holy Cross College
`
`in Worcester, Massachusetts in 1978. I received a Medical Degree from Yale
`
`University Medical School 1982.
`
`10. From 1976 to 1978, I was a Research Assistant at the Worcester
`
`Foundation for Experimental Biology. From 1982 to 1985, I was an Intern and
`
`6
`
`IMMUNOGEN 2105, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`Resident of Internal Medicine at Massachusetts General Hospital. From 1985 to
`
`1987, I was a Medical Oncology Fellow at the National Cancer Institute. From
`
`1987 to 1988, I was a Senior Investigator in the Biologics Evaluation Section at
`
`the National Cancer Institute. From 1988 to 1990, I was the Special Assistant to
`
`the Director at the National Cancer Institute. From 1990 to 1995, I was a Senior
`
`Investigator in the Medical Breast Cancer Section in the Division of Cancer
`
`Treatment at the National Cancer Institute. From 1995 to 1997, I was an
`
`oncologist at the Kentuckiana Medical Oncology Associates in Louisville,
`
`Kentucky. From 2000 to the present, I have been Director of the Breast Cancer
`
`Research and Prevention Program at the Baylor—Charles A. Sammons Cancer
`
`Center in Dallas, Texas.
`
`11.
`
`In 1982, I became Board Certified by the National Board of Medical
`
`Examiners. In 1985, I became Board Certified by the American Board of Internal
`
`Medicine. And in 1987, I received a Medical Oncology Board Certification. I am
`
`licensed to practice medicine in Texas.
`
`12. Since 1997, I have been a Medical Oncologist at Texas Oncology.
`
`Since 2000, I have been a Chair of the Breast Cancer Research program at US
`
`Oncology. Since 2010, I have been a Medical Director at US Oncology Research.
`
`7
`
`IMMUNOGEN 2105, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`I also have particular experience with T-DM1 (Kadcyla®)—which, as
`
`13.
`
`described in ¶21, I understand is an embodiment of the '856 patent. I was a
`
`participating clinical investigator in clinical trials that were evaluating T-DM1.
`
`14.
`
`I have published more than 150 papers in peer-reviewed national and
`
`international journals, including in the areas of novel breast cancer treatments and
`
`antibody-based therapy for metastatic breast cancer. I am a member of the
`
`editorial board of Clinical Breast Cancer.
`
`15.
`
`I am a member of the American Association for Cancer Research, the
`
`American Society of Clinical Oncology, and the Texas Medical Association. I
`
`have received several awards since 1977 and have been appointed to numerous
`
`advisory boards, such as the American Society of Clinical Oncology (ASCO)
`
`Nominating Committee,
`
`the ASCO Breast Cancer Symposium Program
`
`Committee, the Susan G. Komen Foundation scientific advisory committee, and
`
`the National Cancer Institute Breast Cancer Progress Review Group since 1982.
`
`16. Accordingly, I am an expert in the field of breast cancer treatment,
`
`and have been since at least 1988.
`
`III. Person of ordinary skill in the art
`I understand that a person of ordinary skill in the art ("POSA") is a
`17.
`
`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
`
`8
`
`IMMUNOGEN 2105, pg. 10
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`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
`
`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
`
`link
`
`the components of an
`
`immunoconjugate. And another team member may be a clinician experienced in
`
`cancer research and treatment, including breast cancer research and treatment.
`
`Each member of that team typically would have at least three years of experience.
`
`18. 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 POSA.
`
`IV. The '856 patent and T-DM1 (Kadcyla®)
`I have read and considered the specification of the '856 patent
`19.
`
`specification, which describes "methods of treatment using anti-ErbB receptor
`
`antibody-maytansinoid conjugates, and articles of manufacture suitable for use in
`
`9
`
`IMMUNOGEN 2105, pg. 11
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`such methods." (Ex. 1001 at Abstract.) In particular, 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).
`
`20. Claim 1, from which claims 2-8 generally depend, recites an
`
`immunoconjugate comprising huMAb4D5-8 (Herceptin®) conjugated
`
`to a
`
`maytansinoid. (Id. at 81:29-31.) Claim 2 depends from claim 1 and recites an
`
`immunoconjugate comprising huMAb4D5-8 conjugated to the maytansinoid
`
`DM1. (Id. at 81:32-53.) Claim 7 depends from claim 2 and specifies that DM1 is
`
`conjugated via any one of a set of specific linkers. And Claim 8, which 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.)
`
`21. As shown in the Kadcyla® label, the "T" in T-DM1 stands for
`
`trastuzmuab (which is marketed under the brand name Herceptin®), and the
`
`"DM1" refers to the same DM1 maytansinoid recited in claim 2. (Ex. 2025 at
`
`14:7-8 and 15:Figure.) T-DM1 also uses the same SMCC linker recited in claim 8
`
`to conjugate Herceptin® to DM1. (Id. at 14:7.) Thus, T-DM1 is coextensive with
`
`claim 8 of the '856 patent.
`
`10
`
`IMMUNOGEN 2105, pg. 12
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`22. T-DM1is indicated for the treatment of HER2-positive breast cancer
`
`in patients whose disease has progressed after previously receiving first-line
`
`treatment of Herceptin® (trastuzumab) and a taxane. (Ex. 2025 at 1.)
`
`23. Since its approval by the FDA in 2013, I have prescribed T-DM1for
`
`the treatment of HER2-positive breast cancer, which followed my administering
`
`T-DM1 to patients in several clinical trials prior to 2013. I have witnessed the
`
`extraordinary results of T-DM1 first-hand. T-DM1 treats some of the most
`
`refractory patients, extending their lives sometimes significantly. (See ¶¶24-35,
`
`below.) Importantly, it does so with fewer toxic side effects than Herceptin® in
`
`combination with a chemotherapeutic—allowing terribly sick patients to have a
`
`better quality of life than when administered alternative second-line and third-line
`
`therapies. (See ¶39.) Notably, women treated with T-DM1 also do not suffer
`
`alopecia (hair loss), which is often the most emotionally difficult side effect of
`
`traditional chemotherapy regimens. (Ex. 2120 at 3238:2:4; Ex. 2184 at Abstract
`
`and 1595:1:7.) And based on this increased safety and efficacy, oncologists,
`
`including myself, now use T-DM1 instead of using Herceptin® plus a
`
`chemotherapeutic or lapatinib plus capecitabine for the second and third-line
`
`treatment of metastatic breast cancer. Thus, I have prescribed T-DM1 based on its
`
`clinical efficacy and safety, as well as my own experience with patients, and not
`
`due to marketing efforts.
`
`11
`
`IMMUNOGEN 2105, pg. 13
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`V. T-DM1 is unexpectedly superior to Herceptin® in combination with a
`chemotherapeutic in Herceptin®-resistant patients
`24. T-DM1 is superior to the combination of Herceptin® and a
`
`chemotherapeutic, such as a taxane, as later-line therapy as evidenced by its ability
`
`to treat Herceptin®-resistant patients. A phase III clinical study published by Krop
`
`et al. demonstrates that T-DM1 is superior to the combination of Herceptin® and
`
`an unconjugated chemotherapeutic in patients whose disease had previously
`
`progressed after treatment with a combination of Herceptin® plus a taxane (i.e.,
`
`Herceptin-resistant patients). (Ex. 2012 at 690:1:3.)
`
`25. Persons of ordinary skill in this field would not have expected T-
`
`DM1 to be superior to Herceptin® in combination with an unconjugated
`
`chemotherapeutic because of two considerations: (1) the mechanisms of resistance
`
`to Herceptin® would have been expected to cause resistance to T-DM1 and (2) the
`
`heterogeneous expression of HER2 on tumor cells would have led one to expect
`
`that T-DM1 would be less effective than Herceptin in combination with an
`
`unconjugated chemotherapeutic.
`
`26. First, by March 2000, at least two lines of evidence would have
`
`suggested to a person of ordinary skill in the art that resistance to Herceptin® in
`
`some patients could be due to factors that prevented Herceptin® from interacting
`
`with HER2 on cancer cells. As explained in more detail below, one would have
`
`expected patients with the shed extracellular domain of HER2 in their blood or
`
`12
`
`IMMUNOGEN 2105, pg. 14
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`expressing a variant of HER2 could develop resistance to both Herceptin® and T-
`
`DM1. (See ¶¶27-28.)
`
`27. By March 2000, it was known that the extracellular domain of
`
`HER2—the domain that binds to Herceptin®—was shed of the surface of breast
`
`cancer cells. (Ex. 2048 at 5123: 2:2; Ex. 2049 at 61:2:2.) And it had been shown
`
`that the shed extracellular domain "is competitive with [full-length HER2] for
`
`binding to [HER2]-specific monoclonal antibodies." (Ex. 2050 at 1718:1:3-4 and
`
`1719:2:3.) These data would have suggested to those in the field that the presence
`
`of the soluble extracellular domain of HER2 in a patient's blood could allow
`
`HER2-posititve tumors to escape killing by Herceptin® by neutralizing its effect.
`
`(Ex. 2048 at 5123:2:2.) T-DM1 relies on its Herceptin® component to bind to
`
`HER2. (Ex. 2121 at 1784:1:2.) So, one would expect that factors such as soluble
`
`HER2 that prevented Herceptin® from interacting with cell-bound HER2 would
`
`also prevent T-DM1 from targeting HER2-positive cancer cells. As such, tumors
`
`resistant to Herceptin® would also be expected to be resistant to T-DM1.Thus, one
`
`would have expected that resistance to Herceptin® resulting from shed HER2
`
`would also have resulted in resistance to T-DM1 in some patients. Consequently,
`
`T-DM1 would not be expected to be active in some Herceptin®-resistant patients.
`
`28.
`
`In addition, in March 2000, researchers in the field believed that a
`
`naturally-occurring variant of the HER2 protein caused Herceptin® resistance.
`
`13
`
`IMMUNOGEN 2105, pg. 15
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`This variant, which was found in human breast cancer cell lines, lacks a portion of
`
`the extracellular domain of HER2 located within Domain IV of HER2. (Ex. 2051
`
`at Fig. 1; Ex. 2052 at 7:49-51.) The mouse monoclonal antibody 4D5 (Herceptin®
`
`is the humanized1 version of 4D5) was known to recognize a portion of the HER2
`
`extracellular domain also within Domain IV. (Ex. 2049 at 61:2:2; Ex. 2052 at
`
`7:49-51.) Thus, a person of ordinary skill would have expected Herceptin® to
`
`bind the same region based on the studies with 4D5. From this information, one
`
`would have expected that Herceptin® resistance could arise as a result of breast
`
`cancer cells expressing the variant describe above and due to Herceptin®'s
`
`inability to bind to such a variant. More specifically, cells expressing the truncated
`
`variant of HER2 would have been expected to be refractory to treatment with
`
`Herceptin® due to the missing portion of Domain IV. And such a deletion would
`
`be believed to alter HER2 in a way that would prevent Herceptin®, and
`
`consequently T-DM1, from binding to HER2.
`
`29. Additionally, metastatic breast cancers are comprised of a very
`
`heterogeneous population of cells that differ from each other substantially with
`
`
`1 Humanized antibodies are non-human antibodies that have been modified to
`
`replace "as many as possible of the nonhuman residues of the antibody with
`
`those from a human antibody." (Ex. 2056 at 12: 3.)
`
`14
`
`IMMUNOGEN 2105, pg. 16
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`respect to the expression level of HER2. (Ex. 2129 at 5400:2:3.) Even within a
`
`single patient's breast cancer, some cancer cells can express a high level of HER2
`
`protein, whereas other cancer cells from the same tumor mass can express much
`
`lower levels of HER2 or no HER2 at all. In fact, breast cancers are classified as
`
`staining 3+, 2+, 1+, or 0 for HER2 expression. (Ex. 2192 at Abstract.) Tumors
`
`classified as 3+ or 2+ stain strongly positive or moderately positive, respectively,
`
`for HER2 using immunohistochemistry assays. (Id. at 1984:1:4 and 2:3.) And
`
`those 3+ tumors need only exhibit HER2 staining in 10% or more of the tumor
`
`cells to be considered HER2-positive and a candidate for Herceptin®-based
`
`therapy. (Id.) Therefore, in some HER2-positive patients, almost 90% of the
`
`cancer cells in a tumor mass may have low levels of HER2 expression or no
`
`HER2 expression at all. This large variability in HER2 levels has important
`
`implications for treating breast cancers because Herceptin® is able to effectively
`
`treat only those tumor cells that express HER2. In fact, tumor cell heterogeneity,
`
`like that seen with expression of HER2, has been called "a principle cause of
`
`treatment failure" and considered "a formidable barrier" to achieving effective
`
`tumor cell kill with immunoconjugates. (Ex. 2130 at Abstract.)
`
`30.
`
`In an effort to circumvent this problem, oncologists traditionally
`
`treated HER2-positive breast cancer patients with a chemotherapeutic agent (such
`
`as paclitaxel) in combination with Herceptin®, so that the chemotherapeutic agent
`
`15
`
`IMMUNOGEN 2105, pg. 17
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`could kill tumor cells that do not express HER2, and which are therefore not
`
`susceptible to Herceptin®. (Ex. 1008; Ex. 2151 at 96:2:3.) Thus, administering a
`
`chemotherapeutic agent in combination with Herceptin allows for treatment and
`
`killing of the tumor cells that express HER2 and the tumor cells in that same
`
`patient that do not express HER2. In fact, Pegram et al. have suggested that the
`
`"additive … antiproliferative effects of [Herceptin®] plus cytotoxic drugs [such as
`
`taxanes] are due to a mechanism of action involving each agent acting
`
`independently." (Ex. 1020 at 2248:1:2.) Further, given this knowledge of tumor
`
`heterogeneity, researchers predicted that the major role of immunoconjugates in
`
`treating solid tumors would be, at best, "in combination-chemotherapy regimens."
`
`(Ex. 1029 at 48:2:3.)
`
`31. For T-DM1, however, the cytotoxic agent (DM1) is linked directly to
`
`Herceptin®, so that DM1 is delivered specifically and only to cells expressing
`
`HER2. (Ex. 2121 at 1784:1:2; Ex. 2189 at 648:1:1.) Thus, T-DM1's mechanism of
`
`action is distinct from the known mechanisms of action for Herceptin® and free
`
`chemotherapeutics. (See, e.g., Ex. 1020-08:1:2.) Consequently, those in the field
`
`would have expected that linking a cytotoxic agent, such as DM1, to Herceptin®
`
`would prevent the cytotoxic agent from reaching and killing tumor cells that do
`
`not express HER2 because, upon conjugation, the cytotoxic agent would only be
`
`delivered to cells targeted by the immunoconjugate's antibody portion. (See, e.g.,
`
`16
`
`IMMUNOGEN 2105, pg. 18
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`Ex. 2189, 648:1:1 (stating that T-DM1 combines "the direct delivery of the
`
`cytotoxic agent DM1 to HER2-overexpressing cells combined with the specific
`
`antitumor activity of the trastuzumab portion of T-DM1").) Therefore, in view of
`
`the heterogeneity of HER2 levels on cancer cells, one would have expected that
`
`the combination of Herceptin® and a unconjugated chemotherapeutic agent, such
`
`as a taxane, would act on and kill a greater percentage of tumor cells than would
`
`T-DM1. And because T-DM1 would be expected to act on fewer tumor cells—i.e.,
`
`only those expressing HER2—one would have expected T-DM1 to be less
`
`effective than Herceptin® plus a chemotherapeutic agent because its use would
`
`lead to the omission of the complementary effect of the chemotherapeutic killing
`
`cells not expressing HER2 and both the Herceptin® and the chemotherapeutic
`
`agent killing HER2-overexpressing cells.
`
`32.
`
`In sum, given the above, those in the field would have expected that
`
`T-DM1 would demonstrate less efficacy than the combination of Herceptin and a
`
`chemotherapeutic in patients whose disease had previously progressed after
`
`treatment with Herceptin® and a taxane.
`
`33. Krop et al. studied patients with HER2-positive, unresectable locally-
`
`advanced or recurrent breast cancer or metastatic breast cancer. (Ex. 2012 at
`
`690:1:4-2:1.) Patients were required to have previously received Herceptin® and a
`
`taxane. (Id.) Patients also had to have documented disease progression during the
`
`17
`
`IMMUNOGEN 2105, pg. 19
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`Herceptin®-based therapy. (Id.) Patients were randomly assigned to receive either
`
`T-DM1 or a physician's choice of treatment. The vast majority of physician's
`
`chose to use Herceptin® plus a chemotherapeutic. (Id. at 690:2:4 and 691:1:1-2.)
`
`This study tested the ability of T-DM1 to treat cancers that had progressed despite
`
`treatment with Herceptin® plus a microtubule-inhibiting chemotherapeutic and
`
`also provided a clinical comparison of T-DM1 to the combination of Herceptin®
`
`with a free chemotherapeutic in these treatment-resistant patients.
`
`34. The results of
`
`the clinical
`
`trial demonstrated a significant
`
`improvement in the median progression-free survival in patients treated with T-
`
`DM1. (Id. at 695:1:2.) This outcome shows that T-DM1 is effective in treating
`
`cancers that have progressed despite treatment with Herceptin® and a microtubule-
`
`inhibiting chemotherapeutic. Moreover, median progression-free survival was 6.2
`
`months in patients treated with T-DM1 and only 3.2 months in patients treated
`
`with Herceptin® plus a chemotherapeutic. (Id. at 695:1:2 and Fig. 2B.) This result
`
`shows that T-DM1 has superior efficacy to the combination of Herceptin® with a
`
`chemotherapeutic in patients whose tumors are resistant to multiple HER2-
`
`directed therapies, including Herceptin®-based therapies.
`
`35. Consequently, given the mechanisms of Herceptin®-resistance known
`
`by March 2000 (see ¶¶25-28), practitioners would not have expected that T-DM1
`
`would be efficacious in patients whose disease had previously progressed on
`
`18
`
`IMMUNOGEN 2105, pg. 20
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Inter Partes Review of USPN 8,337,856
`Declaration of Joyce O'Shaughnessy, M.D. (Exhibit 2105)
`treatment with Herceptin® in combination with a taxane. Moreover, those in the
`
`field would not have expected T-DM1 to be more effective than Herceptin® in
`
`combination with a chemotherapeutic because linking DM1 to Herceptin® would
`
`have been expected to reduce DM1's ability to act on cells that do not express high
`
`levels of HER2 (see ¶¶29-31). So, it would have been unexpected that T-DM1
`
`would be active, let alone superior to, Herceptin® in combination with a
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
