Case No. IPR2017-01122
`Declaration of Dr. Susan Tannenbaum
`
`Filed on behalf of Patent Owner Genentech, Inc. by:
`
`David L. Cavanaugh (Reg. No. 36,476)
`Rebecca A. Whitfield (Reg. No. 73,756)
`Robert J. Gunther, Jr. (Pro Hac Vice)
`Lisa J. Pirozzolo (Pro Hac Vice)
`Kevin S. Prussia (Pro Hac Vice)
`Andrew J. Danford (Pro Hac Vice)
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
`
`Adam R. Brausa
`(Reg. No. 60,287)
`Daralyn J. Durie
`(Pro Hac Vice)
`DURIE TANGRI LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________________________________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`
`____________________________________________
`
`Case IPR2017-01122
`Patent No. 7,892,549
`
`____________________________________________
`
`EXPERT DECLARATION OF DR. SUSAN TANNENBAUM
`
`Genentech 2062
`Celltrion v. Genentech
`IPR2017-01122
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`Case No. IPR2017-01122
`Declaration of Dr. Susan Tannenbaum
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`TABLE OF CONTENTS
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`Page
`
`I.
`
`INTRODUCTION AND BACKGROUND .................................................. 1
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`A. Qualifications And Experience ........................................................... 2
`
`B.
`
`C.
`
`Compensation ..................................................................................... 5
`
`Prior Expert Testimony ....................................................................... 5
`
`II.
`
`LEGAL PRINCIPLES ON OBVIOUSNESS ................................................ 6
`
`III. BACKGROUND OF THE TECHNOLOGY ................................................ 8
`
`A.
`
`Types of Cancer and Cancer Treatment .............................................. 8
`
`1.
`
`2.
`
`Types of Cancer ........................................................................ 8
`
`History of Cancer Treatments ................................................. 12
`
`B.
`
`Breast Cancer Treatments in the 1990s ............................................. 14
`
`1.
`
`2.
`
`3.
`
`Anthracyclines ........................................................................ 16
`
`Taxoids ................................................................................... 21
`
`Platinum-Based Drugs ............................................................ 24
`
`C. Development of Cancer Treatments in the 1990s Was Highly
`Unpredictable.................................................................................... 25
`
`1.
`
`2.
`
`Preclinical trials ...................................................................... 26
`
`Clinical trials .......................................................................... 32
`
`D. HER2-Positive Cancer Research and Treatment ............................... 40
`
`1.
`
`HER2-Positive Cancer ............................................................ 40
`
`2. Monoclonal Antibodies as a Possible Treatment ..................... 42
`
`3.
`
`Research into HER2-Positive Breast Cancer Monoclonal
`Antibody Treatment Prior to the Date of the Invention ........... 45
`
`IV. THE CLAIMS UNDER CONSIDERATION AND THEIR
`INTERPRETATION .................................................................................. 49
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`A.
`
`The ’549 Patent ................................................................................. 49
`
`B.
`
`C.
`
`D.
`
`Summary Of Contested Claims ......................................................... 54
`
`The Person Of Ordinary Skill In The Art .......................................... 58
`
`Claim Construction of “In an Amount Effective to Extend the
`Time to Disease Progression in Said Human Patient” and “An
`Effective Amount” ............................................................................ 58
`
`V.
`
`SUMMARY OF THE PRIOR ART ............................................................ 66
`
`A. Asserted Prior Art ............................................................................. 66
`
`1.
`
`2.
`
`3.
`
`4.
`
`Baselga ’96 ............................................................................. 66
`
`Seidman ’96 ............................................................................ 69
`
`1995 Taxol PDR ..................................................................... 71
`
`Pegram ’95.............................................................................. 72
`
`B. Other Prior Art Discussed by Petitioner ............................................ 73
`
`1.
`
`2.
`
`Baselga Abstracts .................................................................... 73
`
`Seidman ’95 ............................................................................ 76
`
`VI. OPINIONS REGARDING THE ASSERTED PRIOR ART ....................... 76
`
`A.
`
`Baselga ’96, Combined with Seidman ’96, the 1995 Taxol
`PDR, and Pegram ’95 Do Not Suggest Administering the
`Combination of rhuMAB HER2 and Paclitaxel to a Human
`Patient ............................................................................................... 77
`
`1.
`
`2.
`
`3.
`
`Baselga ’96 Does Not Teach Administering the Claimed
`Combination in a Human Patient ............................................ 77
`
`Neither Seidman ’96, the 1995 Taxol PDR, nor Pegram ’95 Fill
`In the Teachings Missing from Baselga ’96 ............................ 80
`
`Reading Baselga ’96 with Seidman ’96, the 1995 Taxol PDR,
`and Pegram ’95 Would Not Suggest the Claimed Combination
`in a Human Patient Given Significant Missing Foundation
`Information ............................................................................. 82
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`4.
`
`Application of Dr. Earhart’s “Four Principles” Does Not
`Support Combining rhuMAb HER2 with Paclitaxel ............... 89
`
`B.
`
`Baselga ’96, Combined with Seidman ’96, the 1995 Taxol
`PDR, and Pegram ’95 Do Not Suggest that the Claimed
`Combinations would Result in Claimed Clinical Efficiency.............. 94
`
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`Case No. IPR2017-01122
`Declaration of Dr. Susan Tannenbaum
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`I.
`
`INTRODUCTION AND BACKGROUND
`
`1.
`
`I, Dr. Susan Tannenbaum, have been retained by counsel for
`
`Genentech, Inc. (“Patent Owner”) as an expert in this proceeding.
`
`2.
`
`I understand that, in an October 4, 2017 decision, the Patent Trial and
`
`Appeal Board (the “Board”) instituted inter partes review as to claims 1-11 and 14-
`
`18 of U.S. Patent No. 7,892,549 (the “’549 patent”). I further understand that the
`
`references relied upon by the Board in instituting inter partes review (“IPR”)
`
`include (1) Jose Baselga, et al., Phase II Study of Weekly Intravenous Recombinant
`
`Humanized Anti-p185HER2 Monoclonal Antibody in Patients with HER2/neu-
`
`Overexpressing Metastatic Breast Cancer, 14(3) JOURNAL OF CLINICAL ONCOLOGY
`
`737-44 (1996) (“Baselga ’96”) (Ex. 1020); (2) A.D. Seidman et al., Over-
`
`Expression and Clinical Taxane Sensitivity: A Multivariate Analysis in Patients
`
`with Metastatic Breast Cancer (MBC), 15 PROC. AM. SOC. CLINICAL ONCOLOGY
`
`104, abs. 80 (March. 1996) (“Seidman ’96”) (Ex. 1011); (3) Pegram et al., phase II
`
`Study of Intravenous Recombinant Humanized Anti-p185 HER-2 Monoclonal
`
`Antibody (rhuMAB HER-2) Plus Cisplatin in Patients with HER-2/NEU
`
`Overexpressing Metastatic Breast Cancer, 14 Proc. Am. Soc. Clincial Oncology
`
`106, abs (“Pegram ’95”) (Ex. 1022); and (4) Taxol® (Paclitaxel) for Injection
`
`Concentrate, PHYSICIANS’ DESK REFERENCE, 682-685 (49th ed. 1995) (“1995 Taxol
`
`PDR”) (Ex. 1012). (Paper 9, Decision Granting Institution at 27-28.)
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`3.
`
`I have been asked to review the claims of the ’549 patent and the
`
`references relied upon by the Board in instituting IPR, and evaluate whether the
`
`cited references render the claims of the ’549 patent unpatentable. As part of my
`
`review I have been asked to evaluate the prior art and scientific accuracy of the
`
`observations that the Board made in the decision instituting inter partes review. I
`
`also was asked to evaluate certain statements that Dr. Robert Howard Earhart made
`
`in a declaration (Ex. 1002).
`
`4.
`
`A list of materials I have reviewed in the preparation of this
`
`Declaration is attached as Exhibit B. I have also relied upon my scientific
`
`knowledge as of December 1997 when the ’549 patent was filed.
`
`A. Qualifications And Experience
`
`5. My background is summarized below and in my curriculum vitae,
`
`which includes a list of my publications and patents and is attached as Exhibit A.
`
`6.
`
`I graduated from Cornell University in 1974 with a major in biology
`
`and then spent the next four years (1974-1978) at the State University of New
`
`York at Downstate, where I received my Medical Doctor degree. From 1978-
`
`1982, I did my Residency and Chief Residency in Internal Medicine at Bronx
`
`Municipal Hospital Center/Albert Einstein College of Medicine, after which I was
`
`board certified in Internal Medicine. I then trained in Hematology-Oncology at the
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`University of Pennsylvania, from 1982-1986, after which I was board certified in
`
`Hematology and Oncology.
`
`7.
`
`For the next nine years (from 1986-1995), I engaged in laboratory
`
`research and clinical care of patients at the Clinical Center at the National Institute
`
`of Health. During this time, I had the opportunity to work with patients receiving
`
`treatments for cancer and blood disorders, including treatment with novel
`
`biologics. In particular, I was involved with caring for patients on clinical trials in
`
`which novel monoclonal antibodies were utilized. One such trial involved treating
`
`patients with HTLV-1 induced leukemia with anti-Tac antibodies. These
`
`antibodies recognized the IL2-receptor on the leukemia cell surface conjugated
`
`with radioactive yttrium -90 and preferentially bound them. An unexpected toxicity
`
`was significant effects on the bone marrow. This significantly limited the anti-Tac
`
`antibodies’ clinical usefulness despite targeting the cancer cell specifically. At that
`
`time at the NIH, there was active diagnostic and therapeutic drug and device
`
`development ongoing. In my role as a hematology consultant, I often saw these
`
`patients with toxicities, helping to understand some of the off-target side effects of
`
`these drugs.
`
`8. With a desire to return to a greater focus on clinical care, I spent the
`
`next year taking care of people on a Navajo reservation in Shiprock, New Mexico.
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`I then worked for a private practice at Wilshire Oncology, in the San Bernardino
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`Valley in California, from 1997 through 2003.
`
`9.
`
`At Wilshire Oncology, which was part of the UCLA network, 70% of
`
`my clinical practice was focused on women with breast cancer. During this time I
`
`was also part of early clinical trials involving trastuzumab, both in the metastatic
`
`and later in the adjuvant setting. When I came to Wilshire Oncology, the practice
`
`was treating patients on the pivotal metastatic trastuzumab trial with patients both
`
`on anthracycline or paclitaxel with or without trastuzumab, and I was involved
`
`with these patients’ care. I also actively accrued patients to the adjuvant
`
`trastuzumab BCIRG 006 study utilizing docetaxel and carboplatin with or without
`
`trastuzumab, for people with HER2 overexpressing breast cancers.
`
`10.
`
`In 2003, I became the primary breast medical oncologist at the
`
`University of Connecticut Health Center, now known as UCONN Health. In 2012,
`
`I became the Medical Director of the Clinical and Translational Breast Program.
`
`In these roles, my practice involved both academic and clinical components. I
`
`taught classes in the UCONN Health Medical School concerning breast and lung
`
`cancer, writing the curriculum and engaging other clinicians in the teaching. I also
`
`ran the breast cancer research conferences, along with a basic science colleague.
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`As to research, I was actively engaged in basic and translational research projects
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`looking at novel diagnostics, new treatments and survivorship concerns for breast
`
`cancer patients, and have been the Principal Investigator on many breast cancer
`
`clinical trials in the metastatic, adjuvant as well as neoadjuvant setting.
`
`11.
`
`In 2016, I became the Division Chair of Hematology-Oncology and
`
`the Clinical Director of the Cancer Center. My clinical responsibilities remain
`
`with added responsibilities of managing operations of our Cancer Center as well as
`
`developing our mission, recruiting faculty, and setting standards for the Division of
`
`Hematology-Oncology.
`
`12.
`
`I continue my clinical care and clinical research as well as
`
`administrative responsibilities in this setting. I attend the San Antonio Breast
`
`Cancer Symposium yearly, often presenting work in that venue.
`
`B. Compensation
`
`13.
`
`I am being compensated at my normal consulting rate for my work,
`
`which is $500 per hour. My compensation is not dependent on and in no way
`
`affects the substance of my statements in this Declaration.
`
`C.
`
`14.
`
`Prior Expert Testimony
`
`I have not provided expert testimony within the last four years.
`
`Concurrently with this declaration, I am submitting declarations in Hospira, Inc. v.
`
`Genentech, Inc., IPR2017-00731, Hospira, Inc. v. Genentech, Inc., IPR2017-
`
`00737, and Celltrion, Inc. v. Genentech, Inc., IPR2017-001121.
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`II. LEGAL PRINCIPLES ON OBVIOUSNESS
`
`15.
`
`I have been informed and understand that in order to invalidate a
`
`patent claim as obvious in the context of an inter partes review, it must be shown
`
`by a preponderance of the evidence that the claim would have been obvious to a
`
`person of ordinary skill at the time the invention was made. The prior art does not
`
`need to render obvious every possible embodiment within the scope of the claim:
`
`the prior art renders the claim obvious if the combined teachings disclose an
`
`embodiment that is within the scope of the claim.
`
`16.
`
`I have been informed and understand that factors relevant to the
`
`determination of obviousness include the scope and content of the prior art, the
`
`level of ordinary skill in the art at the time of the invention, differences between
`
`the claimed invention and the prior art and “secondary considerations” or objective
`
`evidence of non-obviousness.
`
`17.
`
`I have been informed and understand that obviousness can be
`
`established by combining or modifying the teachings of the prior art to produce the
`
`claimed invention where there is some teaching, suggestion or motivation to do so;
`
`and that a reasonable expectation of success in achieving the subject matter of the
`
`claim at issue must also be shown. Further, I have been informed and understand
`
`that the teaching, suggestion or motivation test is flexible and that an explicit
`
`suggestion to combine the prior art is not necessary—the motivation to combine
`
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`may be implicit and may be found in the knowledge of one of ordinary skill in the
`
`art, from the nature of the problem to be solved, market demand or common sense.
`
`18.
`
`I have been informed and understand that a patent claim composed of
`
`several limitations is not obvious merely because each limitation was
`
`independently known in the prior art. Hindsight reasoning is not an appropriate
`
`basis for combining references to form an obviousness combination. I also have
`
`been informed and understand that it can be important to identify a reason that
`
`would have prompted a person of ordinary skill in the relevant field to combine the
`
`limitations in the way the claimed new invention does.
`
`19.
`
`In undertaking an obviousness analysis, I have been informed and
`
`understand that I may take into account the inferences and creative steps that a
`
`person of ordinary skill would have employed in reviewing the prior art at the time
`
`of the invention. If the claimed invention combines elements known in the prior
`
`art and the combination yields results that would have been predictable to a person
`
`of ordinary skill at the time of the invention, then this evidence would make it
`
`more likely that the claim was obvious.
`
`20.
`
`I have also been informed and understand that obviousness may be
`
`established if the combination of prior art elements was obvious to try, even if no
`
`one attempted the combination. For a combination to be obvious to try, however, a
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`solution must be among a finite number of identified, predictable solutions. Where
`
`the art is uncertain or unpredictable, a person of ordinary skill in the art will not
`
`have a reasonable expectation of success.
`
`21.
`
`I have been informed and understand that an obviousness analysis
`
`must take into account any “secondary considerations” or, as they are sometimes
`
`called, objective indicia of non-obviousness. These secondary considerations can
`
`include the invention’s commercial success, long-felt but unresolved needs,
`
`licenses showing industry respect, the failure of others, skepticism by experts,
`
`praise by others, teaching away by others, recognition of a problem and copying of
`
`the invention by competitors. Such secondary considerations, when present, offer
`
`objective information as to the state of the art at the time of the invention and
`
`provide a check to hindsight analysis.
`
`III. BACKGROUND OF THE TECHNOLOGY
`
`22. Because the ’549 patent is directed to treatment of metastatic breast
`
`cancer, I provide the following background regarding cancer, treatments, and the
`
`technology at issue.
`
`A. Types of Cancer and Cancer Treatment
`
`1.
`
`Types of Cancer
`
`23. The term “cancer” refers to a collection of related diseases, all of
`
`which are characterized by the uncontrolled growth of cells in the body. Cancer
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`cells divide without stopping (i.e., their growth is unregulated) and spread to
`
`surrounding tissues either by direct extension (i.e., the cancer expands directly into
`
`neighboring tissues or structures), or by way of blood vessels or the lymphatic
`
`system.
`
`24. Cancer can grow almost anywhere in the human body. Some cancers
`
`form masses, called tumors. A solid tumor is a mass of tissue that does not include
`
`any liquid or cysts. Major types of solid tumors include sarcomas (tumors in a
`
`blood vessel, bone, fat tissue, ligament, lymph vessel, muscle, or tendon), and
`
`carcinomas (tumors that form in epithelial cells). Alternatively, cancers of the
`
`blood (i.e., leukemias) generally do not form solid tumors.
`
`25. The “biology” of each cancer, i.e., how it grows and spreads, is
`
`dictated by the genes the cancer cells express and the cells’ interactions with the
`
`surrounding environment. Some cancers will stay where they were formed, slowly
`
`growing, while others spread as they grow. When a cancer spreads from the part
`
`of the body where it started (the primary site) to other parts of the body, it is called
`
`metastatic cancer.
`
`26. There are many different types of cancer, usually named for the
`
`organs or tissues in which the cancer initially arises, even if the cancer spreads to
`
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`other parts of the body. For example, “breast cancer” is cancer that first arises in
`
`the breast, and in most cases forms solid tumors.
`
`27. Breast cancers were first categorized by the glandular portion of the
`
`breast from which they arose (e.g., ducts, lobules, etc.), but are now also
`
`categorized by the different receptors that are expressed on the surface of the
`
`cancer cells. These receptors affect the biology of the cancer cells and how the
`
`cancer cells spread.
`
`28. For example, the estrogen receptor is found on normal breast cells
`
`and, about 70% of the time, is also found on cancerous breast cells. When
`
`estrogen receptors are found on cancerous breast cells, the cancer is called
`
`“estrogen-receptor-positive” breast cancer. The presence of this receptor not only
`
`speaks in general to a better biology (one that is less deadly) but also enables a
`
`more personalized treatment directed to this receptor (discussed more below).
`
`(See, e.g., Ex. 2122, Gary M. Clark, et al., Steroid Receptors and Other Prognostic
`
`Factors in Primary Breast Cancer, SEMINARS IN ONCOLOGY 15(2), Supp. 1 20-25,
`
`20 (1988) (discussing estrogen-receptor-positive cancer).)
`
`29.
`
`In addition to the estrogen receptor, another receptor of central
`
`importance to classifying the behavior of breast cancer cells is the epidermal
`
`growth factor receptor called “ERBB2” or “HER2/neu.” This receptor was
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`discovered in the 1980s and 1990s, and it is one of a family of receptors that
`
`promotes the growth and spread of cancer cells. Normal breast cells (and all cells
`
`in the body) normally contain two copies of the HER2-producing gene, one on
`
`each of a pair of chromosomes. In about 25-30% of breast cancers, however, more
`
`than two copies are found. This is called “HER2-positive” breast cancer, and these
`
`cancer cells have enhanced growth compared to other breast cancers. As described
`
`in more detail below (see infra Section III.D.1), in the 1990s, prior to the work that
`
`led to the ’549 patent, HER2-positive breast cancer was more aggressive and
`
`associated with a worse prognosis than HER2-negative breast cancer.
`
`30. The following graphic depicts a normal cell versus that of a HER2-
`
`positive cell. While a normal cell has two HER2 genes, which form a small
`
`number of HER2 receptors at the cell surface (as shown below, on the left), a
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`HER2-positive cell has several additional copies of the HER2 gene, resulting in
`
`many more HER2 receptors at the cell surface. These additional HER2 receptors
`
`enhance cell growth.
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`
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`(See JADPRO, Narratives on Collaboration, available at
`
`http://www.advancedpractitioner.com/narratives/her2/)
`
`2. History of Cancer Treatments
`
`31. As of the 1990s, clinicians had available a number of treatments for
`
`cancer patients including surgery, radiation, chemotherapy, and hormone therapy.
`
`32. The first main treatment developed for cancer was surgery to remove
`
`cancerous cells and tumors. For example, treatment for breast cancer up until the
`
`mid-twentieth century generally involved radical mastectomy, i.e., surgical
`
`removal of the breast, underlying chest muscle, and lymph nodes.
`
`33. Clinicians later learned that radiation treatment (i.e., using high-
`
`energy waves directed to the cancer) could kill cells and shrink tumors. In the case
`
`of breast cancer, in the second half of the twentieth century, clinicians found that
`
`more conservative surgery combined with radiation treatment had similar
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`outcomes to radical mastectomy. This then became the standard local treatment
`
`for breast cancer.
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`34. Local treatments of surgery and radiation were often not enough to
`
`cure cancer, as some cells might escape, grow, and spread, causing cancer
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`recurrence. Systemic treatments were therefore needed.
`
`35. To address this need, scientists developed chemotherapies to stop or
`
`slow the growth and spread of cancer cells. Chemotherapy is a systemic therapy,
`
`in which chemical agents are used to stop the growth of cancer cells throughout the
`
`body, either by killing those cells or by stopping them from dividing. Generally,
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`chemotherapeutic agents are indiscriminate: they attack cancer cells, but also affect
`
`healthy cells. As a result, in using chemotherapy, clinicians must balance the
`
`benefits of keeping the cancer cells from spreading with the potential side effects
`
`to healthy cells and the body generally.
`
`36. Since the first reports of chemotherapy causing tumor shrinkage in the
`
`1940s, a number of chemotherapeutic agents have been identified, researched, and
`
`used to treat cancer. (See Ex. 2023, Silvia Marsoni and Robert Wittes, Clinical
`
`Development of Anticancer Agents—A National Cancer Institute Perspective, 68
`
`CANCER TREATMENT REPORTS 77 (1984) (hereinafter “Marsoni 1984”);; see also
`
`Ex. 2051, Trisha Gura, Systems for Identifying New Drugs Are Often Faulty,
`
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`278(5340) SCIENCE, 1041-1042, at 1041 (Nov. 1997) (hereinafter “Gura 1997”)
`
`(stating that 39 chemotherapies were approved from 1955-1995).)
`
`37. As some of the mechanisms of growth for certain cancers become
`
`more known, scientists developed other types of treatment, such as hormone
`
`therapy. For example, in the late 1970s, estrogen-receptor-positive and
`
`progesterone-receptor-positive breast cancers were treated with antiestrogen
`
`therapies to keep estrogen or progesterone from helping the cancer grow. This was
`
`accomplished by either lowering estrogen levels or stopping the estrogen from
`
`acting on breast cancer cells by inhibiting the binding of estrogen to its receptor on
`
`breast cancer cells.
`
`B.
`
`Breast Cancer Treatments in the 1990s
`
`38. As of 1997, doctors had a variety of tools to treat breast cancer,
`
`including surgery (generally involving radical mastectomy or lumpectomy, i.e.,
`
`removal of the cancerous tumor and surrounding tissue), radiation therapy,
`
`chemotherapy, and targeted hormone therapy (to the extent the cancer is sensitive
`
`to it).
`
`39.
`
`If the cancer was localized to the breast, common treatment included
`
`surgery followed by radiation and/or chemotherapy and (where appropriate)
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`antiestrogen therapy, a type of hormone therapy. This treatment following surgery
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`is referred to as “adjuvant therapy” (i.e., therapy applied after initial surgical or
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`Case No. IPR2017-01122
`Declaration of Dr. Susan Tannenbaum
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`radiation treatment for cancer, usually to suppress secondary tumor formation).
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`Although this treatment regime provided a cure for many patients with cancer
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`localized in the breast, cancer would recur and spread in some patients.
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`40.
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`If the cancer was metastatic, i.e., the cancer had spread to other tissues
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`and/or parts of the body, treatment generally involved antiestrogen therapy first (in
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`estrogen receptor positive disease) and some form of chemotherapy to shrink the
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`tumors and prevent the spread of cancer to other areas. There was (and still today
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`is) no cure for metastatic breast cancer, but treatments extend life expectancy and
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`provide higher quality of life.
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`41. After a “first-line” therapy stopped working to prevent the spread of
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`cancerous cells in a metastatic breast cancer patient, such patient was often
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`prescribed a “second-line” of therapy. Second and third line treatments generally
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`were not as effective as, and/or had more significant side effects than, first-line
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`treatments. However, because first-line therapy had already failed patients
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`receiving these therapies, their options were fewer; moreover, this set of patients
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`was closer to having no therapeutically effective options left. All of these
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`therapies required the doctor and patient to balance efficacy of the treatment
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`regime with side effects caused by the treatment and the resulting decreased
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`quality of life.
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`Case No. IPR2017-01122
`Declaration of Dr. Susan Tannenbaum
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`42.
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`In the 1990s there was a wide variety of different types of
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`chemotherapeutic agents either available for treatment or in development.
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`According to Petitioner’s expert Dr. Earhart, the number of chemotherapeutic
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`agents for breast cancer was in the “double figures.” (Ex. 2050, Earhart Dep.
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`117:11-12.) In my practice in the 1990s, I regularly treated my breast cancer
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`patients with a variety of chemotherapies, including, for example, anthracyclines
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`(Adriamycin and Epirubicin), cytoxan, methotrexate, and 5flurouracil (often as a
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`combination referred to as “CMF”), Taxol, Taxotere, cisplatinum, Navelbine,
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`Gemzar, and Xeloda.
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`1.
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`Anthracyclines
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`43. One of the drugs often used in first-line metastatic breast cancer,
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`doxorubicin (trade name Adriamycin), is a type of anthracycline.
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`44. Anthracyclines are extracted from Streptomyces bacteria, and have
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`several mechanisms of action (i.e., ways of disrupting and killing cancer cells).
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`These mechanisms of action include, for example, (1) intercalation (i.e., insertion
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`of molecules) between adjacent DNA pairs, which deforms the DNA, (2) inhibition
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`of the enzyme topoisomerase II, which blocks DNA transcription and replication,
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`and (3) free radical formation, which damages the DNA, proteins, and cell
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`membranes by causing a cascade of oxidation and reduction reactions. (Ex. 2055,
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`Hortobagyi, Anthracyclines in the Treatment of Cancer, 54 Drugs Suppl. 4:1-7, at
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`1-2 (Oct. 1997) (hereinafter “Hortobagyi 1997”); Ex. 2030, Doroshow,
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`Anthracyclines and Anthracenediones, in CANCER CHEMOTHERAPY &
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`BIOTHERAPY: PRINCIPLES AND PRACTICE 409-429, at 410 (1996) (hereinafter
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`“Doroshow 1996”).)
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`45. These different mechanisms of action allow anthracyclines to be
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`effective in treating many different types of cancer; indeed, as of 1997
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`anthracyclines had the widest spectrum of antitumor activity, making them one of
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`the most widely-used chemotherapies as of 1997. (Ex. 2055, Hortobagyi 1997 at
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`4; Ex. 2102, Raymond B. Weiss, The Anthracyclines: Will We Ever Find a Better
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`Doxorubicin?, 19(6) SEMINARS IN ONCOLOGY 670–86, at 670 (1992).) As to breast
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`cancer in particular, anthracyclines were known to be “especially active” against
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`breast cancer, and they formed the basis for standard treatment of metastatic breast
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`cancer. (Ex. 2030, Doroshow 1996 at 409; Ex. 2055, Hortobagyi 1997 at 3; Ex.
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`2050, Earhart Dep. 127:21-128:5 (doxorubicin is “especially active” against breast
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`cancer).)
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`46. Anthracyclines’ wide use was attributable to the fact that they are
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`active over a wide range of doses and administration schedules, and at the time did
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`not have any known antagonistic interactions with other commonly used anticancer
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`agents. (Ex. 2030, Doroshow 1996 at 409; see also Ex. 2055, Hortobagyi 1997 at
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`Case No. IPR2017-01122
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`3 (“In patients with breast cancer, both doxorubicin and epirubicin are used in the
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`treatment of advanced disease and as the basis of adjuvant regimens in some
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`patients with early disease.”).)
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`47. For purposes of treatment, it was well-known that higher doses of
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`anthracyclines resulted in higher response rates. (See Ex. 2055, Hortobagyi 1997
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`at 3-4 (noting that “response rates [of anthracyclines] appear to increase with
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`increasing doses”).) However, like any chemotherapy, it was also known that
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`higher doses could increase negative side effects, and researchers and clinicians
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`knew that these side effects must be monitored and taken into account.
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`48. The main side effect of anthracyclines was cardiotoxicity. However,
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`given anthracyclines’ wide use in both the research and clinical setting, it was also
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`well-known at the time how to manage the cardiotoxicity risk. (See generally Ex.
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`2030, Doroshow 1996.)
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`49. For example, clinicians knew that cardiotoxicity could be reduced by
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`adopting an administration schedule that minimized the peak concentrations of
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`anthracycline in the blood. (Ex. 2055, Hortobagyi 1997 at Abstract; Ex. 2030,
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`Doroshow 1996 at 425 (“It is now clear that the risk of cardiac toxicity from
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`doxorubicin is a function of peak drug level not AUC [total body exposure to a
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`drug].”).) Dexrazoxane could also be administered along with anthracyclines to
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`Case No. IPR2017-01122
`Declaration of Dr. Susan Tannenbaum
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`provide cardioprotection. (Ex. 2055, Hortobagyi Drugs 1997 at Abstract; Ex.
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`2103, Marco Venturini, et al., Multicenter Randomized Controlled Clinical Trial to
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`Evaluate Cardioprotection of Dexrazoxane Versus No Cardioprotection in Women
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`Receiving Epirubicin Chemotherapy for Advanced Breast Cancer, 14(12) JOURNAL
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`OF CLI