Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 1 of 761 PageID #: 24486
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`C.A. No. 18-924-CFC
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`Plaintiffs,
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`Defendant.
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`GENENTECH, INC. and CITY OF HOPE,
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`
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`v.
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`AMGEN, INC.,
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`EXHIBITS 115-229 TO THE DECLARATION OF NORA Q.E. PASSAMANECK
`
`VOLUME 3 OF 3
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`
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`PUBLIC VERSION FILED: July 19, 2019
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`

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`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 2 of 761 PageID #: 24487
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`MCCARTER & ENGLISH LLP
`
`
`/s/ Michael P. Kelly
`Michael P. Kelly (#2295)
`Daniel M. Silver (#4758)
`Alexandra M. Joyce (#6423)
`Renaissance Centre
`405 N. King Street, 8th Floor
`Wilmington, Delaware 19801
`Tel.: (302) 984-6300
`Fax: (302) 984-6399
`mkelly@mccarter.com
`dsilver@mccarter.com
`ajoyce@mccarter.com
`
`Attorneys for Plaintiffs Genentech,
`Inc. and City of Hope
`
`Date: July 10, 2019
`
`Of Counsel:
`
`William F. Lee
`Lisa J. Pirozzolo
`Emily R. Whelan
`Kevin Prussia
`Andrew J. Danford
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`60 State Street
`Boston, MA 02109
`(627) 526-6000
`william.lee@wilmerhale.com
`lisa.pirozzolo@wilmerhale.com
`emily.whelan@wilmerhale.com
`kevin.prussia@wilmerhale.com
`andrew.danford@wilmerhale.com
`
`Robert J. Gunther Jr.
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`7 World Trade Center
`250 Greenwich Street
`New York, NY 10007
`(212) 230-8800
`robert.gunther@wilmerhale.com
`
`Daralyn J. Durie
`Adam R. Brausa
`DURIE TANGRI LLP
`217 Leidesdorff St.
`San Francisco, CA 94111
`(415) 362-6666
`ddurie@durietangri.com
`abrausa@durietangri.com
`
`
`2
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`

`

`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 3 of 761 PageID #: 24488
`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 3 of 761 PageID #: 24488
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`EXHIBIT 115
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`EXHIBIT 115
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`

`

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`Héré‘rEBtifl ikwwlrbfiée $3€fi§n§8fv3i£zwqfilfedlbdil¥§ffg
`Page 5 of 761 Pageleflg‘ifizfgdo
`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 5 of 761 PageID #: 24490
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`Some breast cancer cells make too many copies of (overexpress) a particular gene known as HER2. The HER2 gene
`makes a protein known as a HER2 receptor. HER2 receptors are like ears, or antennae, on the surface of all cells. These
`
`HER2 receptors receive signals that stimulate the cell to grow and multiply. But breast cancer cells with too many HER2
`receptors can pick up too many growth signals. This causes them to start growing and multiplying too much and too fast.
`
`Breast cancer cells that overexpress the HER2 gene are said to be HER2-positive.
`
`Herceptin works by attaching itself to the HER2 receptors on the surface of breast cancer cells and blocking them from
`receiving growth signals. By blocking the signals, Herceptin can slow or stop the growth of the breast cancer.—
`— In addition to blocking HER2 receptors, Herceptin can also help fight breast
`cancer by alerting the immune system to destroy cancer cells onto which it is attached.
`
`This video animation illustrates how Herceptin attaches itself to the HER2 receptors on the surface of breast cancer cells
`
`and blocks them from receiving growth signals.
`
`
`How Herceptin Works: the Mechanism of Action from Breastcancerorg on Vimeo.
`
`This video was created by Genentech BioOncology.
`
`Back to top
`
`Is Herceptin right for you?
`
`Herceptin is used to treat breast cancers that are HER2-positive.
`
`Four different tests can be used to figure out if the cancer is HER2-positive and if it will likely respond to Herceptin:
`
`IHC (lmmunoHistoChemistry)
`
`IHC is the most commonly used test to see if a tumor has too much of the HER2 receptor protein on the surface of the
`cancer cells.
`
`

`

`Héré‘tEBtifl fiWwE'cf—tée eeeaaeimmmwmg Page 6 of 761 Pageiopfig‘ifiziéfo
`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 6 of 761 PageID #: 24491
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`The IHC test gives a score of 0 to 3+ that measures the amount of HER2 receptor protein on the surface of cells in a breast
`
`cancer tissue sample. lfthe score is; 0 to 1+, it’s called “HER2 negative.” If the score is 2+, it's called "borderline." A score of
`3+ is called ”HER2 positive.”
`
`If the IHC test results are borderline, it’s likely that a FISH test will be done on a sample of the cancer tissue to determine if
`the cancer is HER2-positive.
`
`FISH (Fluorescence In Situ Hybridization)
`
`The FISH test also looks to see if the cancer is HER2-positive. This test is the most accurate, but it is more expensive and
`
`takes longer to return results. This is why an IHC test is usually the first test done to see if a cancer is HER2-positive. The
`FISH test shows how many copies of the HER2 gene are in tumor cells. The more copies of the gene, the more HER2
`receptors the cells have.
`
`With the FISH test, you get a score of either "positive" or "negative" (some hospitals call a negative test "zero"). If the
`
`cancer is FISH positive, it will probably respond well to Herceptin.
`
`SPoT-Light HER2 CISH (Subtraction Probe Technology Chromogenic In Situ Hybridization)
`
`The SpoT—Light HER2 CISH test looks for how many copies of the HER2 gene are in the tumor cells of a breast cancer
`tissue sample. The SPOT-Light test is less complicated than the FISH or IHC tests.
`
`With the SPoT—Light test, you get a score of either "positive" or "negative." lfthe cancer is SPoT-Light HER2-positive, it will
`
`probably respond well to Herceptin.
`
`Inform HER2 Dual ISH (In Situ Hybridization)
`
`The Inform HER2 Dual ISH test uses a special stain that makes HER2 proteins change color. The test can be used on
`
`tissue samples that have been stored in wax or other chemicals. The Inform HER2 Dual ISH test offers more precise results
`than the IHC HER2 test. It is also less expensive and doesn’t need the special microscope of the FISH HER2 test.
`
`With the Inform HER2 Dual ISH test, you get a score of either “HER2 positive" or “HER2 negative."
`
`Learn more in Breast Cancer Tests.
`
`Back to top
`
`What to expect when taking Herceptin
`
`— which means it is delivered directly into your bloodstream through
`an IV or a port. The first dose of Herceptin takes about 90 minutes. After that, it only takes about 30 minutes to get other
`
`doses of Herceptin. Your Herceptin treatment schedule will depend on whether you are receiving it with other medicines.
`You can talk to your doctor about your treatment schedule options.
`
`If you’ve been diagnosed with early-stage HER2-positive breast cancer, you’ll likely receive Herceptin together with a
`
`chemotherapy regimen. You will receive it for a specific amount of time.
`
`If you’ve been diagnosed with metastatic HER2-positive breast cancer, you will keep being treated with Herceptin as
`long as you are getting benefits from the medicine and aren’t having troubling side effects.
`
`

`

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`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 8 of 761 PageID #: 24493
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`
`

`

`Héré‘rEBtifl igr-Wfidgfi‘lfbg—lée $3€fi§nfififvsiifiv9§ltedibdil¥§ffe
`Page 9 of 761 Pageiopfig‘ifiziézlo
`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 9 of 761 PageID #: 24494
`
`.
`
`in combination with Taxol as the first treatment for metastatic disease
`
`- as a single treatment for people who have been treated with one or more chemotherapy regimens for metastatic disease
`
`Side effects
`
`Like Herceptin, Herceptin Hylecta can cause side effects, some of them severe. Common Herceptin Hylecta side effects
`include:
`
`' Emil—e
`
`- ioint pain
`
`- diarrhea
`
`- iniection site reaction
`
`0 upper respiratory tract infection
`
`' w
`
`- muscle pain
`
`‘ W
`
`- headache
`
`° swelling
`
`- flushing
`
`. fever
`
`- cough
`
`- pain in extremities
`
`- chills
`
`- infection
`
`- insomnia
`
`
`Like Herceptin, less common but more severe side effects of Herceptin Hylecta include weakening of the heart muscle and
`
`other heart problems, as well as serious lung problems.
`
`Also like Herceptin, women who are pregnant or planning to get pregnant should not be treated with Herceptin Hylecta.
`
`Herceptin Hylecta can harm the developing fetus. If there is any chance you can become pregnant, you must use effective
`
`birth control while you’re being treated with Herceptin Hylecta and for at least 7 months after your last dose. Visit Treatment
`
`for Breast Cancer During Pregnancy for more information.
`
`Learn more about Herceptin Hylecta.
`
`Back to top
`
`Herceptin biosimilars
`
`_ “biologic" drug. This means that it is made from living organisms, in this case a protein
`from a mouse cell. A monoclonal antibody is a type of protein made in the lab that can bind to substances in the body,
`
`including cancer cells. Each monoclonal antibody is made so that it binds only to one substance. Herceptin binds to the
`HER2 receptor proteins in cancer cells.
`
`

`

`3?I=?HKCF "7I;JKLNLE;<#1 6C>? 2@@?=KJ$ 3GM CK 8GIDJ$ ;F> 4GI?
`5;A? . G@ (’
`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 10 of 761 PageID #: 24495
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`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 11 of 761 PageID #: 24496
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`

`

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`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 12 of 761 PageID #: 24497
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`

`

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`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 13 of 761 PageID #: 24498
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`Last modified on April 10, 2019 at 8:50 AM
`BTTa TbcP _jVX]P T] Tb_Pk^[
`
`

`

`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 14 of 761 PageID #: 24499
`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 14 of 761 PageID #: 24499
`
`EXHIBIT 116
`
`EXHIBIT 116
`
`

`

`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 15 of 761 PageID #: 24500
`Page 15 of 761 PageID #:
`24500
`Case 1'18-C-V--00924CFC. Document.33.41....EileclQZIlQJéngu
`Site >
`
`
`Full Prescribing Information
`Hercept in
`tra 'tIIJYIIJr'I uh
`
`
`Resources
`
`a Safety First!
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`Roll over lo read limit:-
`
` Learn more about the
`
`proposed mechanism of
`action >
`
`Related Links
`Resources
`Download the full
`Prescribing Information
`
`HERZ + Status
`Proposed
`Mechanism of
`Action
`Adjuvant Breast
`Cancer
`Clinical Study
`Results
`Sid e Effects
`Dosing and
`Administration
`Metastatic Breast
`Cancer
`Metastatic
`Gastric/G E]
`Cancer
`
`Proposed Mechanism of Action
`Herceptin MOA
`Herceptin (trastuzumab) is a monoclonal antibody specifically designed to target HERZ.
`HERZ protein exists on normal cells and HER2+ tumor cells.
`
`lRD TLJZUMAB
`
`Herceptin prevents HERZ shedding.I
`
`HER? SHEDDING
`
`B ,CKS HERE SHEDDING
`
`”at;
`
`Indications and Important Safety Information:
`Adjuvant Breast Cancer
`llerceptin is indicated for adjuvant treatment of I IERzioverexpressing l'IOdeflJOSlllVe or nodeinegative (LR'PRinegative or With one highirisk featureV) breast
`cancer:
`As part ofa treatment regimen containing doxorubicin, cyclophosphamide and either paclitaxel or docetaxel
`With docetaxel and carboplatin
`As a single agent followmg multiimodality anthracyclinerbased therapy
`Select patients for therapy based on an FDA approved companion diagnostic for Herceptin
`'* ngl'Isl’lSk is defined as ER ‘PR positive With one ofthe following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.
`Metastatic Breast Cancer
`
`https ://vwvw. hercepti n. com/hop/treatment/moa
`
`1/3
`
`

`

`Case 1:18-cv-00924-CFC Document 314 Filed 07/19/19 Page 16 of 761 PageID #: 24501
`Case 1:18-cv-0909n24e‘ ,aggmp,ggt,i,memg,to§,1,4 File 97/19/19 Page 16 of 761 PagelD #: 24501
`bination
`coverexpressing
`
`As a single agent for treatment of HERZcoverexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic
`disease
`Select patients for therapy based on an FDAcapproved companion diagnostic for Ilerceptin
`Metastatic Gastric Cancer
`llerceptin is indicated, in combination With cisplatin and capecitabine or Scfluorouracil, for the treatment of patients With IIERZ overexpressing metastatic
`gastric or gastroesophagealjunction adenocarcinoma, Who have not received prior treatment for metastatic disease.
`Select patients for therapy based on an FDAcapproved companion diagnostic for Ilerceptin
`
`BOXED WARNINGS and Additional Important Safety Information
`Cardiomyopathy
`Herceptin administration can result in sub—clinical and clinical cardiac failure. The incidence and severity was highest in patients
`receiving Herceptin with anthracycline—containing chemotherapy regimens
`Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in
`patients receiving adj uvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in
`left ventricular function
`
`Infiusion Reactions; Pulmonary Toxicity
`
`Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur du
`within 24 hours of Herceptin administration. Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor
`patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis. or acute
`respiratory distress syndrome
`
`Embryo—Fetal Toxicity
`Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary
`hypoplasia. skeletal abnormalities. and neonatal death. Advise patients of these risks and the need for effective contraception
`
`Cardiomyopathy
`Herceptin administration can result in sub—clinical and clinical cardiac failure. The incidence and severity was highest in patients
`receiving Herceptin with anthracycline—containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who
`developed CHF died of cardiomyopathy
`Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death
`Herceptin can also cause asymptomatic decline in LVEF
`Discontinue Herceptin treatment in patients receiving adjuvant breast cancer therapy and withhold Herceptin in patients with
`metastatic disease for clinically significant decrease in left ventricular function
`
`Cardiac Monitoring
`Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after
`completion of Herceptin
`Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan
`Monitor frequently for decreased left ventricular function during and after Herce ptin treatment
`Monitor more frequently if Herceptin is Withheld for significant left ventricular cardiac dysfunction
`Infiusion Reactions
`Herceptin administration can result in serious and fatal infusion reactions
`Symptoms usually occur during or within 24 hours of Herceptin administration
`Interrupt Herceptin infusion for dyspnea or clinically significant hypotension
`Monitor patients until symptoms completely resolve
`Discontinue Herceptin for infusion reactions manifesting as anaphylaxis. angioedema, interstitial pneumonitis, or acute respiratory
`distress syndrome. Strongly consider permanent discontinuation in all patients with severe infusion reactions
`Infusion reactions consist ofa symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at
`tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia
`
`Embryo—Fetal Toxicity
`Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary
`hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception
`Verify the pregnancy status of females of reproductive potential prior to the initiation of Herce ptin
`Advise pregnant Women and females of reproductive potential that exposure to Herceptin during pregnancy or Within 7 months prior to conception can
`result in fetal harm
`Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months folloWing the last dose of Herceptin
`Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Herceptin treatment and any potential adverse
`effects on the breastfed child from Herceptin or from the underlying maternal condition
`Encourage Women Who receive Herceptin during pregnancy or Within 7 months prior to conception to enroll in the MotHER Pregnancy Registry by
`contacting l 800 690 6720 or visiting http: ’ ’www.motherpregnancyregistry.com,
`lf Herceptin is administered during pregnancy, or ifa patient becomes pregnant While receiving Herceptin or within 7 months followmg the last dose of
`Herceptin, health care providers and patients should immediately report Herceptin exposure to Genentech at l 888 835 2555
`
`Pulmonary Toxicity
`Herceptin administration can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary
`infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary
`fibrosis. Such events can occur as sequelae of infusion reactions
`Patients with symptomatic intrinsic lung disease or With extensive tumor involvement ofthe lungs, resulting in dyspnea at rest, appear to have more
`severe toxicity
`Discontinue Herceptin in patients experiencing pulmonary toxicity
`
`Exacerbation of Chemotherapy—Induced Neutropenia
`In randomized, controlled clinical trials, the percpatient incidences of NCIchC Grade 374 neutropenia and offebrile