`Timeline
`
`Date
`
`1975
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`1976
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`1976
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`1981
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`1984
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`1984
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`1984
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`1985
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`1985
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`1987
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`Event
`
`Georges Köhler and César Milstein, scientists at the Medical Research Council,
`Laboratory of Molecular Biology (Cambridge, UK), discovered the potential of using
`antibodies in vitro to fight disease.
`
`The research of Michael Bishop and Harold Varmus at the University of California
`San Francisco showed that disturbances in one or more members of a family of
`genes can lead to the transformation of a normal cell into a cancer cell.
`
`Genentech was founded by venture capitalist Robert A. Swanson and biochemist
`Dr. Herbert W. Boyer.
`
`Genentech scientists John McGrath and Art Levinson cloned and sequenced a
`portion of the human HER2 gene for the first time.
`
`Robert Weinberg and his team of scientists at the Massachusetts Institute of
`Technology discovered an unusual mutant rat gene encoding a tyrosine kinase
`that produced cancer features in transfected cells and named it "neu."
`
`Georges Köhler and César Milstein win the Nobel Prize in Medicine, "for theories
`concerning the specificity in development and control of the immune system and
`the discovery of the principle for production of monoclonal antibodies."
`
`Genentech scientists Axel Ullrich and Peter Seeberg, in collaboration with Mike
`Waterfield at the Imperial Cancer Research Fund and Joseph Schlesinger at the
`Weizmann Institute, published the complete human EGFR sequence in Nature.
`
`Following work that began in the early 1980s, a Genentech team of scientists,
`including Axel Ullrich and Art Levinson, clone the first fulllength human HER2 gene.
`This achievement is described in a paper published in Science.
`
`Stu Aaronson at the National Institute of Health showed that the HER2/neu gene
`is frequently amplified in human breast tumors.
`
`Michael Shepard, Axel Ullrich and their teams at Genentech developed mouse 4D5,
`the parent of Herceptin, simultaneous with the discovery by Dr. Dennis Slamon at
`UCLA, and colleagues at the University of Texas Health Science Center, that linked
`HER2 overexpression with a more aggressive type of breast cancer found in
`approximately 25 percent of patients. Further work by Shepard's group
`demonstrated that the 4D5 could suppress the growth of HERoverexpressing
`tumor cells, and also enhance their sensitivity to killing by the host immune
`system. Further proof of concept was the demonstration by the Genentech and
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`1989
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`1990
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`1992
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`1993
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`1995
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`UCLA teams that radiolabeled 4D5 could localize to HER2overexpressing tumors in
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`patients.
`
`Michael Bishop and Harold Varmus were awarded the Nobel Prize in Medicine for
`their discovery that normal cells contain genes capable of becoming cancer genes.
`
`Len Presta, Paul Carter and Michael Shepard of Genentech create Herceptin by
`humanizing the 4D5 mouse antibody directed at HER2.
`
`Genentech filed an Investigational New Drug Application (IND) with the U.S. Food
`and Drug Administration (FDA) and Phase I clinical trials were initiated.
`
`Genentech initiated two Phase II clinical trials that evaluated the investigational
`antiHER2 antibody as a single agent and in combination with chemotherapy in the
`relapsed setting.
`
`Genentech began enrollment of the Phase III pivotal trials for patients with HER2
`overexpressing metastatic breast cancer.
`
`Pivotal trial 648, doubleblind, placebocontrolled study of the investigational
`antiHER2 antibody plus chemotherapy to include 450 women with newly
`diagnosed metastatic breast cancer
`
`Trial 649, study of the investigational antiHER2 antibody as a single agent to
`include 200 women whose metastatic disease had failed to respond to one or
`two rounds of chemotherapy
`
`Trial 650, study of the investigational antiHER2 antibody to include 200
`women who had newly diagnosed metastatic breast cancer but did not want
`chemotherapy
`
`Genentech worked closely with breast cancer patient advocates to design an
`expanded access program to ensure the investigational agent is available to
`patients with no other therapeutic alternatives.
`
`Genentech advanced the construction of a new manufacturing facility that would
`produce the antiHER2 antibody.
`
`1996
`
`Critical efforts are undertaken to enroll patients into the trials, including:
`
`Genentech clinicians and outside investigators spearheaded an amendment to
`the study protocol of pivotal trial 648 to include paclitaxel chemotherapy as
`an alternative to doxorubicin chemotherapy and traveled across the country
`to inform investigators to spur interest in the trial;
`
`Genentech and patient advocates worked together to publicize the trials to
`the breast cancer community.
`
`March 1996
`
`Researchers at Memorial Sloan Kettering coauthored a paper titled, "Phase II
`study of weekly intravenous recombinant humanized antip185HER2 monoclonal
`antibody in patients with HER2neuoverexpressing metastatic breast cancer,"
`which showed that the antibody was clinically active in women with HER2neu
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`which showed that the antibody was clinically active in women with HER2neu
`overexpressing metastatic breast cancer who had received prior therapy. The
`
`study provided evidence that targeting growth factor receptors caused regression
`of human cancer.
`
`December 1996 Genentech initiated a partnership with diagnostics company DAKO to develop a
`commercial test to identify patients who overexpress the HER2 gene.
`
`March 1997
`
`Genentech completed enrollment of the Phase III pivotal trials for the antiHER2
`antibody (now known as Herceptin® (Trastuzumab)).
`
`May 1998
`
`Genentech submitted a biologic license application (BLA) for Herceptin, and DAKO
`submitted a premarket approval (PMA) application to the FDA for approval of the
`diagnostic HercepTest. The FDA designated Herceptin as a "Fast Track" product
`for the treatment of metastatic breast cancer.
`
`Herceptin treatment can result in heart problems, including those without
`symptoms (reduced heart function) and those with symptoms (congestive
`heart failure).
`
`May 1998
`
`Results from a Phase III investigational clinical trial of Herceptin were presented at
`the American Society of Clinical Oncology (ASCO) annual meeting. Results showed
`that Herceptin, in combination with chemotherapy, increased time to disease
`progression and response rates.
`
`July 1998
`
`September
`1998
`
`Herceptin treatment can result in heart problems, including those without
`symptoms (reduced heart function) and those with symptoms (congestive
`heart failure).
`
`Genentech and Roche signed a licensing agreement giving Roche exclusive
`marketing rights for Herceptin outside of the United States.
`
`Herceptin received FDA approval for use in women with metastatic breast cancer
`who have tumors that overexpress the HER2 protein. It is indicated for treatment
`of patients both as firstline therapy in combination with paclitaxel
`chemotherapy and as a single agent for those who have received one or
`more chemotherapy regimens. Dako's HercepTest is approved simultaneously to
`aid in the identification of patients for Herceptin treatment.
`
`Herceptin was the first therapeutic antibody targeted to a specific (HER2) cancer
`related molecular marker to receive FDA approval.
`
`Herceptin treatment can result in heart problems, including those without
`symptoms (reduced heart function) and those with symptoms (congestive heart
`failure). The risk and seriousness of these heart problems were highest in people
`who received both Herceptin and a certain type of chemotherapy (anthracycline).
`Some patients have had serious infusion reactions and lung problems; fatal infusion
`reactions have been reported. In most cases, these reactions occurred during or
`within 24 hours of receiving Herceptin.
`
`May 2000
`
`Genentech issued a letter to healthcare providers about reports of serious adverse
`events, including hypersensitivity, infusion and pulmonary reactions.
`
`Some patients have had serious infusion reactions and lung problems; fatal
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`IMMUNOGEN 2208, pg. 3
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`infusion reactions have been reported. In most cases, these reactions
`
`occurred during or within 24 hours of receiving Herceptin.
`
`August 2000
`
`European Commission approved Herceptin for the treatment of HER2positive
`metastatic breast cancer.
`
`December 2000 Enrollment of two Phase III clinical trials evaluating the potential use of Herceptin
`for the adjuvant treatment of earlystage HER2positive breast cancer was
`initiated. Adjuvant therapy is given to women with earlystage (localized) breast
`cancer who have had initial treatment — surgery with or without radiation therapy
`— with the goal of reducing the risk of cancer recurrence and/or the occurrence of
`metastatic disease. The studies are sponsored by the National Cancer Institute
`(NCI), part of the National Institutes of Health, and conducted by a network of
`researchers led by the National Surgical Adjuvant Breast and Bowel Project
`(NSABP) and the North Central Cancer Treatment Group (NCCTG).
`
`March 2001
`
`Further data from a pivotal Phase III clinical trial were published in the New
`England Journal of Medicine (NEJM) that showed a significant increase in survival
`for women with HER2positive metastatic breast cancer who received Herceptin
`and chemotherapy over chemotherapy alone.
`
`Herceptin treatment can result in heart problems, including those without
`symptoms (reduced heart function) and those with symptoms (congestive
`heart failure). The risk and seriousness of these heart problems were
`highest in people who received both Herceptin and a certain type of
`chemotherapy (anthracycline).
`
`March 2001
`
`HERA, the third adjuvant trial of Herceptin, began enrollment.
`
`December 2001 Genentech received FDA approval to include, in the product label, data that
`showed an improved median overall survival for women with HER2positive
`metastatic breast cancer treated initially with Herceptin and chemotherapy,
`compared to chemotherapy alone (median 25.1 months compared to 20.3 months).
`
`Worsening of low white blood cell counts associated with chemotherapy has also
`occurred. Herceptin can cause low amniotic fluid levels and harm to the fetus
`when taken by a pregnant woman. The most common side effects associated with
`Herceptin were fever, nausea, vomiting, infusion reactions, diarrhea, infections,
`increased cough, headache, fatigue, shortness of breath, rash, low white and red
`blood cells, and muscle pain.
`
`December 2001 BCIRG 006, the fourth adjuvant trial of Herceptin, began enrollment.
`
`August 2002
`
`May 2005
`
`Genentech received FDA approval to include information about a breast cancer
`genedetection test method called FISH (fluorescence in situ hybridization) in the
`Herceptin product labeling.
`
`Results from a joint analysis of the Phase III NSABP and NCCTG clinical trials
`evaluating the addition of Herceptin to standard adjuvant therapy for earlystage
`HER2positive breast cancer were presented at the ASCO annual meeting.
`According to this 3year planned joint analysis, Herceptin in combination with
`chemotherapy significantly reduced the risk of cancer recurrence.
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`IMMUNOGEN 2208, pg. 4
`Phigenix v. Immunogen
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`Some patients have had serious infusion reactions and lung problems; fatal
`
`infusion reactions have been reported. In most cases, these reactions
`occurred during or within 24 hours of receiving Herceptin.
`
`August 2005
`
`Genentech issued a letter to healthcare providers informing them of updated
`cardiotoxicity information related to the use of Herceptin, obtained from the Phase
`III NSABP study (B31).
`
`Herceptin treatment can result in heart problems, including those without
`symptoms (reduced heart function) and those with symptoms (congestive
`heart failure). The risk and seriousness of these heart problems were
`highest in people who received both Herceptin and a certain type of
`chemotherapy (anthracycline). In one study with Herceptin and certain types
`of chemotherapy, an inadequate blood supply to the heart occurred.
`
`February 2006
`
`Based on results from the joint analysis of the NSABP and NCCTG trials, Genentech
`filed a supplemental Biologics License Application (sBLA) with the FDA for Herceptin
`for the adjuvant treatment of earlystage HER2positive breast cancer.
`
`November 2006 The FDA approved Herceptin as part of a treatment regimen containing
`doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment
`of patients with earlystage HER2positive, nodepositive breast cancer
`based on the joint analysis of the NSABP and NCCTG studies.
`
`Herceptin can cause low amniotic fluid levels and harm to the fetus when taken by
`a pregnant woman. Patients should talk to their doctor if they are pregnant or
`become pregnant while taking Herceptin.
`
`December 2006 Genentech submitted an sBLA with the FDA based on the global HERA study to
`potentially expand Herceptin's use in the adjuvant treatment of earlystage HER2
`positive breast cancer.
`
`June 2007
`
`January 2008
`
`Genentech submitted two sBLAs to the FDA based on the global BCIRG 006 trial to
`potentially expand Herceptin's use in the adjuvant treatment of earlystage HER2
`positive breast cancer.
`
`Based on the HERA oneyear data, the FDA approved Herceptin as a single agent
`for the adjuvant treatment of earlystage HER2positive nodepositive
`breast cancer or nodenegative (ER/PRnegative or with one highrisk
`feature) following multimodality, anthracyclinebased therapy. Herceptin
`also may be administered as a single agent in an everythreeweek dosing
`schedule for one year.
`
`Patients receiving their first dose of Herceptin may have chills and fever as well as
`nausea, vomiting, pain, headache, dizziness, shortness of breath, low blood
`pressure, rash, and weakness.
`
`May 2008
`
`Based on the results of the BCIRG 006 study, the FDA approved two new
`Herceptincontaining regimens for the adjuvant treatment of earlystage HER2
`positive nodepositive or nodenegative (ER/PRnegative or with one highrisk
`feature) breast cancer.
`
`The first regimen is in combination with docetaxel and carboplatin, (also
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`IMMUNOGEN 2208, pg. 5
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`known as TCH for Taxotere®, carboplatin, and Herceptin) which does
`
`not contain an anthracycline (doxorubicin) component.
`
`The second is part of a treatment regimen containing anthracycline
`(doxorubicin), cyclophosphamide, and docetaxel (ACTH).
`
`In comparison to ACTH, TCH provided a similarly effective treatment option.
`
`Worsening of low white blood cell counts associated with chemotherapy has also
`occurred.
`
`October 2008
`
`More than 420,000 women with HER2positive breast cancer have been treated
`with Herceptin worldwide.
`
`October 2010
`
`The FDA approved Herceptin in combination with cisplatin and capecitabine or 5
`fluorouracil, for the treatment of patients with HER2overexpressing metastatic
`gastric or gastroesophageal junction adenocarcinoma, who have not received prior
`treatment for metastatic disease.
`
`Important Safety Information and Serious Side Effects
`
`Herceptin treatment can result in heart problems, including those without
`symptoms (such as reduced heart function) and those with symptoms (such
`as congestive heart failure). One patient died in an adjuvant (early) breast
`cancer trial from significantly weakened heart muscle. The risk and
`seriousness of these heart problems were highest in people who received
`both Herceptin and a certain type of chemotherapy (anthracycline).
`
`Before taking the first dose of Herceptin and during treatment, a patient’s doctor
`should check to see if there are any health conditions that may increase the
`patient’s chance of having serious heart problems. This includes a review of the
`patient’s health history and tests to see how well the heart muscle is working.
`These tests may include an echocardiogram or a MUGA scan. Some early breast
`cancer patients may also need to have a test done after they have finished taking
`Herceptin to see how well their heart muscle is working.
`
`Some patients have had serious infusion reactions and lung problems; fatal
`infusion reactions have been reported. These reactions usually occur during or
`within 24 hours of receiving Herceptin.
`
`IMMUNOGEN 2208, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`
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`The patient’s doctor may need to completely stop Herceptin treatment if the
`patient has a severe allergic reaction, swelling, lung problems, inflammation of
`the lung, or severe shortness of breath.
`
`Herceptin can cause harm to the fetus (unborn baby), in some cases death to
`the fetus, when taken by a pregnant woman. Women who could become
`pregnant need to use effective birth control methods during Herceptin treatment
`and for at least 6 months after treatment with Herceptin. Nursing mothers treated
`with Herceptin should discontinue nursing or discontinue Herceptin.
`
`Worsening of low white blood cell counts associated with chemotherapy has also
`occurred.
`
`Patients must have a HER2 test to determine if their breast or stomach cancer is
`HER2 positive before using Herceptin, as benefit has only been shown in patients
`that are HER2 positive.
`
`The most common side effects associated with Herceptin in patients with breast
`cancer are fever, nausea, vomiting, infusion reactions, diarrhea, infections,
`increased cough, headache, fatigue, shortness of breath, rash, low white and red
`blood cells, and muscle pain.
`
`The most common side effects associated with Herceptin in patients with stomach
`cancer are low white blood cell counts, diarrhea, fatigue, low red blood cell counts,
`inflammation of the lining of the mouth, weight loss, upper respiratory tract
`infections, fever, low platelet counts, swelling of mucus membranes, swelling of
`the nose and throat, and a change in taste.
`
`Because everyone is different, it is not possible to predict what side effects any
`one person will have. Patients with questions or concerns about side effects
`should talk to their doctor.
`
`Patients should read the Herceptin Full Prescribing Information including Boxed
`WARNINGS, at www.herceptin.com.