EC")
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`EDITION
`
`2004
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`ISBN: 1'56363—471—6
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`NOVARTIS EXHIBIT 2036
`Par v. Novartis, IPR 2016-01479
`Page 1 of 7
`
`

`

`
`1B12/ELI LILLY
`
`PHYSICIANS’ DESK REF
`
`Your health care provider may take sample
`urine during treatment to check your respon:'°
`You .
`Also, your health care provider may ask
`9
`low-up tests of bone mineral density,
`How should I store FORTEO?
`‘
`I Keep your FORTEO en in the
`refuge“, a
`46°F (2“ to 8°C).
`p
`:
`- Do not freeze the en. Do not
`use FORTE "'
`been frozen.
`P
`0 You can use your FORTEO pen for u
`P t0"i
`the first injection from the pen.
`- Throw away the pen properly (See the U '
`silver 28 days of use. even if it is not (:0
`i
`..
`0 Recap the pen after each use (see the 1:21;:
`protect from physical damage.
`General information about usin F0
`RTEO “f! ._
`tlvely
`a
`Medicines are sometimes prescribed for fund"
`not mentioned in Medication Guides. D0 no;
`for a condition for which it was not prescribed.-
`FORTEO to other people, even if they haw th
`lion you have.
`he
`This Medication Guide summarizes the most .
`,
`formation about FORTEO. If you would like "I
`tion, talk with your doctor, nurse, or mama
`ask your pharmacist or health care provider f0 1'
`about FORTEO that is written for health cal-g
`|
`You can also call Lilly toll free at 1.866.4Fo~".'-..
`436.7836).
`v
`.
`Ingredients
`In addition to the active ingredient ter‘lparg '
`ingredients are glacial acetic acid. sodium h
`drone), mannitol, Metacresol, and Water for In
`dition, hydrochloric acid solution 10% vi
`droxide solution 10% may have been ad :
`product pH.
`This Medication Guide has been approved
`and Drug Administration. '
`Literature issued November 2002
`Manufactured by Lilly FrancerSAS.
`F-67640 Fegersheim, France
`for Eli Lilly and Company
`.
`Indianapolis, IN 46285, USA
`J
`r
`I
`www.1illy.com
`_
`PA 0241 FSAMP
`Copyright © 2002, Eli Lilly and Camp's - ;
`reserved. I
`_
`Shown in Product Identification Gzzlds._
`
`.
`
`GEMZAR"
`[jém-zar]
`(Gemcitabine Hcl)
`FOR INJECTION
`
`DESCRIPTION
`Gesz (gemcitabine HCl) is a nucleosid
`"
`exhibits antitumor activity. Gemcitabine._
`2’ ,2'-difluorocytidine monohydrochloride (li‘ '
`The structural formula is as follows:
`.1 .
`NHz ' Ha
`
`I
`
`stN
`
`H0
`
`it?o
`
`.
`
`I
`
`I
`
`.
`
`
`
`Forteo—Cont.
`
`Overdose managEment—There is no specific antidote for
`teriparatide. Treatment of suspected overdose should in-
`clude discontinuation of FORTEO, monitoring of serum cal-
`cium and phosphorus, and implemenmfion of appropriate
`supportive measures, such as hydration.
`DOSAGE AND ADMINISTRATION
`FORTEO should be administered as a subcutaneous injec-
`tion into the thigh or abdominal wall. The recommended
`dosage is 20 meg once a day.
`'
`FORTEO should be administered initially under circum~
`stances in which the patient can sit or lie down if symptoms
`oforthostatic hypotension occur (see PRECAUTIONS, Infor-
`mation for the Patient),
`FORTEO is a clear and colorless liquid. Do not use if solid
`particles appear or if the solution is cloudy or colored, The
`FORTEO pen should not be used past the stated expiration
`date.
`No data are available on the safety or eflicacy ofintravenous
`or intramuscular injection of FORTEO.
`The safety and emcacy of FORTEO have not been evaluated
`beyond 2 years of treatment. Consequently, use of the drug
`for more than 2 years is not recommended.
`INSTRUCTIONS FOR PEN USE
`Patients and caregivers who administer FORTEO should
`receive appropriate training and instruction on the proper
`use of the FORTEO pen from a qualified health'profes-
`sional. It is important to read, understand, and follow the
`instructions in the FORTEO pen User Manual for priming
`the pen and dosing. Failure to do so may result in inaccu-
`rate dosing. Each FORTEO pen can be used for up to 28
`days alter the first injection. After the 28»day use period,
`discard tho FORTEO pen, even if it still contains some un-
`used solution. Never share a FORTEO pen.
`STORAGE
`The FORTEO pen should be stored under refrigeration at 2°
`to 8‘0 (36" to 46°F) at all times. Recap the pen when not in
`use to protect the cartridge from physical damage and light.
`During the useperiod, time out ofthe refrigerator should be
`minimized; the dose may be delivered immediately follow-
`ing removal from the refrigerator.
`’
`Do not freeze. Do not use FORTEO if it has been frozen.
`HOW SUPPLIED
`The FORTEO pen is available in the following package size;
`One 3 mL prefilled pen
`delivery device
`NDC 0002-8971-01 (M58971)
`Literature issued November 2002
`Manufactured by Lilly France S.A.S.
`F~67640 Fegereheim, France
`for Eli Lilly and Company
`.
`Indianapolis, IN 46285, USA
`www.1illy.com
`Copyright © 2002, Eli Lilly and Company. All rights
`reserved.
`Medication Guide
`FOFITEO'”
`Generic name: tcriparnfide erNA origin) injection ,
`Read this information carefully before you start taking
`FORTEO lfor-TAY»o) to learn about the benefits and risks of
`FUR’I‘EO. Before beginning therapy, read the FORTEO pen
`User Manual for information on how to use the pen to inject
`your medicine. Read the information you get with FORTEO
`each time you get a refill, in case something has changed.
`Talk with your health care provider if'there is something
`you do not understand or if you want to learn more about
`FORTEO.
`.
`-
`What Is the most important information I should know
`about FORTEO?
`As part ofdrug testing, teriparatide, the active ingredient in
`FORTEO, was given to rats for a significant part of their
`lifetime. In these studies, teriparotide caused some rats to
`develop osteasarcoma, a bone cancer. Osteosarcoma in hu-
`mans is a serious but very rare cancer. Osteosarcoma occurs
`in about 4 out of every million older adults each year. I! is
`not known if humans treated with FORTEO also have a
`higher chance at getting osteosarcoma.
`FORTEO is approved for use in both men and postmeno-
`pausal (after the ffchange of life") women with osteoporosis
`who are at high risk for having broken bones (fractures)
`from osteoporosis.
`Before starting treatment, talk with your doctor about the
`possible benefits and risks of FORTEO so you can decide if
`it is right for you.
`,
`What is Osteoporosis?
`Osteoporosis is a disease in which the bones become thin .
`and weak, increasing the chance of having a broken bone.
`Osteoporosis usually causes no symptoms until a fracture
`happens. The most common fractures are in the spine (back-
`bone). They can shorten height, even Without causing pain.
`Over time, the spine can become curved or deformed and
`the body bent over. Fractures from osteoporosis can also
`happen in almost any bone in the body, for example, the
`wrist, rib. or hip. Once you have had a fracture, the chance
`for more fractures greatly increases.
`The following risk factors increase your chance of getting
`fractures from osteoporosis:
`0 past broken bones from osteoporosis
`0 very low bone mineral density (BMD)
`' frequent falls
`
`-
`
`U limited movement, such as using a wheelchair
`- medical conditions likely to cause bone loss, such as
`some kinds of arthritis
`- medicines that may cause bone loss, for example: sei-
`zure medicines [such as phenytoin), blood thinners
`r (such as heparin). steroids (such as prednisone), or high
`doses of vitamins A or D.
`What is FORTEO?
`FORTEO is a prescription medicine used to treat osteoporo~
`sis by forming new bone. FORTEO is the brand name for
`teriparatide, which is the same as the active part of a nat-
`ural hormone called parathyroid hormone or “PTH.”
`FORTEO forms new bone, increases bone mineral density
`and bone strength, and as a result, reduces the chance of
`getting a fracture. In a study of postmenopausal (alter the
`“change oflife”) women with osteoporosis, FORTEO reduced
`the number of fractures of the spine and other bones. The
`effect on fractures has not been studied in men.
`FORTEO is approved for use in both men and postmeno-
`pausal women with osteoporosis who are at high risk for
`having fractures. FORTEO can be used by people who have
`had a fracture related to osteoporosis, or who have multiple
`risk factors for fracture (See “What is osteoporosis?”), or
`who cannot use other osteoporosis treatments.
`Who should not use FORTEO?
`Do not use FORTE0 it you:
`‘ have Paget’s disease of the bone
`0 have unexplained high levels of alkaline phosphatase
`in your blood, which means you might have Paget’s dis-
`ease. If you are not sure, ask your doctor.
`c are a child or growing adult
`' have ever been diagnosed with bone cancer or other
`cancers that have spread (metastasized) to your bones
`0 have had radiation therapy involving your bones
`t have certain bone diseases. If you have a bone disease,
`tell your doctor.
`.
`0 have too much calcium in your blood (hypercalcernia)
`' are pregnant or nursing.
`I have had an allergic reaction to FORTEO or one of its
`,
`ingredients (See the ingredients section at the and of
`this Medication Guide)
`- have trouble injecting yourself and do not have some-
`, one who can help you.
`V
`FORTEO should not be used to prevent osteoporosis or to
`treat patients who are not considered to be at high risk for
`fracture.
`Tell your health care provider and pharmacist about all the
`medicines you are taking when you start
`taking
`FORTEO, and if you start taking a new medicine alter you
`start FORTEO treatment. Tell them about all medicines you
`get with prescriptions and without prescriptions, as well as
`herbal or natural remedies. Your doctor and pharmacist
`need this information to help keep you from taking a com-
`bination of products that may harm you.
`How should I take FOHTE07
`.
`- Take FORTEO once a day for as long as your doctor
`prescribes it for you. Use of FORTEO for more than 2
`years is not recommended. Your health care profes-
`sional (doctor, nurse, or pharmacist) should teach you
`how to use the FORTEO pen (prefilled delivery device).
`(See the User Manual for written instructions on how
`to use the FORTEO pen.)
`- Some patients get dizzy or get a fast heartbeat after the
`first few (loses. For the first few doses, inject FORTEO
`where you can sit or lie down right away if you get
`dizzy:
`- Inject FORTEO once each day in your thigh or abdo-
`men (lower stomach area).
`0 You can take FORTEO with or without food or drink.
`I You can take FORTEO at any time of the day, To help
`you remember to take FORTEO, take it at about the
`same time each day
`0 Do not use FORTEO ifit has solid particles in it, or ifit
`is cloudy or colored. It should be clear and colorless.
`U Do not use FORTEO after the expiration date printed
`on the pen and pen packaging.
`I
`' Throw away any FORTEO pen that you started using
`more than 28 days earlier, even if it still has medicine
`in it (See the User Manual).
`1
`'
`- Inject FORTEO shortly after you take the pen out of
`the refrigerator. Recap the pen and put it back into the
`refrigerator right alter use (See the User Manual).
`0 If you forget or are unable to take FORTEO at your
`usual time, take it as soon‘ as possible on that day. Do
`not take more than one injection in the some day.
`6 Talk with your health care provider about other ways
`you can help your osteoporosis, such as exercise, diet,
`supplements, and reducing or stopping your use of to-
`bacco and alcohol. If your health care provider recum-
`mcnds calcium and vitamin D supplements, you can
`take them at the same time as FORTEO.
`‘
`What are the possible side etfects of FORTEQ7
`Most side effects are mild and include dizziness and leg
`cramps. If you become lightheaded or have fast heartbeats
`alter your injection, sit or lie down until you feel better. If
`you do not feel better, call your health.care.provider before
`continuing treatment,
`Contact your health care provider if you have continuing
`nausea, vomiting, constipation, low energy, or muscle weak-
`ness. These may be signs there is too much calcium in your
`blood.
`‘
`These are not all the possible side effects of FORTEO. For
`more information, ask your health care provider or pharma-
`cist.
`
`Information will be superseded by supplements and snbsuquanl editions
`
`_ u
`
`‘
`
`The empirical formula for gemcitabine H _
`0 HCl. It has a molecular weight of .29
`Gemcitabine HG] is a white to olf-WhIl?e 5
`water, slightly soluble in methanol. and
`ble in ethanol and polar organic solvent-
`The clinical formulation is supplied in _3 5 '
`travenous use only. Vials of Gemzar 60“
`or 1 g of gemcitabine HCl (expresse‘i
`lated‘with mannitol (200 mg or 1 E_ .
`sodium acetate (12.5 mg or 62.5 mg, r3“
`ile lyophilized powder. Hydrochloric 86‘,
`droxide may have been added for PH 5 .u-
`CLINICAL PHARMACOLOGY -
`Gcmcitabine exhibits cell phase spec‘ficg ’
`cells undergoing DNA synthesis (5
`as '
`the progression of cells through the 1
`r1
`Gemcitabine is metabolized‘intracellll 3?) ‘_
`oases-to the active diphosphate (d
`(dFdCTP) nucleusides. The cytot
`attributed to a combination of m .d
`phate and the triphosphatc nucleus!
`hibition of DNA synthesis. First:
`inhibits ribonuclsotidé rcductaSE. Wt
`catalyzing the reactibns that Z§nefihimt p:
`triphosphates for DNA synthesis.
`a
`by the diphosphate nucleoside cause: u _
`centrations of deoxynuclcotidesy m. it“ I
`gemcitabine triphosphate commie?” in ,_.
`ration into DNA. The reduction In‘ : dip.
`nation of :1ch (by the action of themph
`the incorporation of gemcimblne
`
`NOVARTIS EXHIBIT 2036
`Par v. Novartis, IPR 2016-01479
`Page 2 of 7
`
`

`

`
`
`. ORMATION
`
`ELI LILLY/1813
`
`I
`
`'
`
`“er the gemcitahine nucleotide is incor-
`only one additional nucleotide is added to
`‘
`" I strands. Alter this addition; there is inhi-
`" 'NA synthesis. DNA polymerase epsilon is
`'
`the gemcitabinc nucleotide and repair the
`l'
`- “d5 (masked chain termination). In CEM
`' face]le gemcitabine induces intemucleoso- '
`"l
`[imam], one of the characteristics of pro-
`l..q mtho
`n'strated dose-dependent synergistic ac-
`" “in m uitro. No efi‘ect of cisplatin on gem-
`r hate accumulation or DNA double-strand
`Wed, 1;; viuo, gemcitabine showed activity
`,7 with cigplatin against the LX-l and CALU-6
`'
`. ggmi’csy but minimal activity was seen with
`.or NOLH520 xenografts. Gcmcitabine was
`cisplatin in the Lewis lung murine xeno-
`" “1 exposure to gomcitabine 4 hours before
`fled the greatest interaction.
`' whimtics—Gemcitsbinc disposition was
`'v Henri; who received a single 1000 mg/m2/30
`_'I of wdiolabeled drug. Within one (1) week,
`a dose was recovered, almost entirely in the
`1
`'- bine (<10%) and the inactive uracil metabo-
`"‘ zudifluorouridine (dFdU), accounted for
`-
`ted (1090. The metabolite dFdU is also found
`_ d cimbine plasma protein binding is negligi-
`. kinetics of gezncitabine were examined in 353
`.11 2/3 men, with various solid tumors. Pharma- f
`stars were derived using data from patients
`'
`'fyjng durations of therapy given weekly with
`5 Weeks and using both short infusions (<70
`long infusions (70 to 285 minutes). The total
`or from 500 to 3600 mg/mz.
`.. hrmacokinetics are linear and are described
`_ ment model. Population pharmacokinctic
`mbined single and multiple dose studies
`.1! a volume of distribution of gemcitabine was
`.._. ucnced by duration of infusion and gender.
`afiected by age and gender. Difl‘erences in ei-
`.. ': volume of distribution based on patient
`4»: or the duration of infusion result in changes
`- u plasma concentrations. Table 1 shows
`- ace and half-life of gemcitabine following i
`...r for typical patienuz by age and gender.
`w. 1: Gcmcitsbino Clearance and
`.
`.
`n -Lilo for the "Typical" Patient
`earance Clearance Half-Life“
`
`i
`
`.
`
`to 638 minutes, depending on age and gender, reflecting a
`greatly increased volume of distribution with longer infu-
`sions. The lower clearance in women and the elderly results
`in higher concentrations of gemcitabine for any given dose.
`The volume of distribution: was increased with infusion
`length. Volume of dishibution of gemoitabine was 50 L/m2
`following infusions lasting <70 minutes, indicating that
`gemcitabine, after short infusions, is not extensively distrib-
`uted into tissues. For long infusions, the volume of distribu-
`tion rose to 370 Uni", reflecting slow equilibration of gem-
`citabine within the tissue compartment.
`The maximum plasma concentrations of chlU (inactive me—
`tabolite) were achieved up to 30 minutes after discontinua-
`tion of the infusions and the metabolite is excreted in urine
`without undergoing further biotransformation. The metab-
`olite did not accumulate with weekly dosing, but its elimi-
`nation is dependent on renal excretion, and could accumu-
`late with decreased renal function.
`Tlie effects of significant renal or hepatic insufliciency on
`the disposition of gemcitabine have not been assessed.
`The active metabolite, gemcitabine triphosphate, can be ex-
`tracted from peripheral blood mononuclear cells. The half-
`life ofthe terminal phase for gemcitabine triphosphate from
`mononuclear cells ranges from 1.7 to 19.4 hours.
`Drug Interactions—When gemcitabine (1250 mg/m2 on
`Days I and 8) and cisplatin (75 ,mg/rnz. on Day 1) was ad-
`ministered in NSCLC patients, the clearance ofgemcitabine
`on Day 1 was 128 L/hr/mz and on Day 8 was 107 LIhr/mz.
`The clearance of cis latin in the same study was reported to
`be 3.94 mL/minlm with a corresponding half-life of 134
`hours (see Drug Interactions under PRECAUTIONS).
`CLINICAL STUDIES
`Non-Small Cell Lung Cancer (NSCLC)——-Data from 2 ran-
`domized clinical studies (657 patients) support the use‘cf
`Gemzar in combination with cisplatin for the first-line
`treatment of patients with locally advanced or metastatic
`NSCLC.
`Gemzar plus cisplatin versus cisplatin: This study was
`conducted in Europe, the US, Canada in 522 patients with
`inoperable Stage IILA, 11113, or IV NSCLC who had not re-
`ceived prior chemotherapy. Gemzar 1000 mg/m2 was admin-
`istered on Days 1, 8, and 15 of a 28<day cycle with cisplaiin
`100 mg/m2 administered on Day 1 of each cycle. Single-
`agent cisplatin 100 mg/‘m2 was administered on Day 1 of
`each 28—day cycle. The primary endpoint was survival. Pa-
`tient demographics are shown in Table 2. An imbalance
`with regard to histology was observed with 48% of patients
`on the cisplntin arm and 37% of patients on the Gcmzor
`plus cisplstin arm having adenocarcinoma.
`The Kaplan-Meier survival, curve is shown in Figure 1. Me-
`dian survival, time on the Gemzar plus cisplatin arm was
`9.0 months compared to 7.6 months on the single-agent cis—
`platin arm (Logrank p=0.008, two-sidedbMedian time to
`disease progression was 5.2 months on the Gemzar plus cis-
`platin arm compared to 3.7 months on the cisplatin arm
`(Logrank p=0.009, two-sided). The objective response rate
`on the Gemzar plus cisplatin arm was 26% compared to 10%
`with cisplatin (Fisher's Exact p<0.0001, two—sided). No dif-
`ference between treatment anus with regard to duration of
`response wasubserved.
`‘
`
`Gemzar >pll1sigj§platln versus etoposide plus cisplatin: A
`second, multi-center, study in Stage IIIB or IV NSCLC ran-
`
`Half-Life“
`Women
`
`49
`57
`73
`94
`
`atients receiving a short infusion (<70 min).
`
`1l~life for short infusions ranged from 32 to
`d the value for long infusions varied from 245
`
`
`
`
`
`I"
`
`Consul! 2 004 Full" supplements and [inure editions for revisions
`
`
`
`
`stle 2 Randomized Trial: of Combination Theiapv with Gemzar plus Cisplstin in NSCLC
`28-day Schedule"
`21-day Schedule”
`Gemzar/
`Gemzar/
`Cisplatin/
`‘ Cisplatin
`
`Cis‘platin Etoposide
`Cisplatin
`69
`66
`260 '
`262
`64
`61
`182
`186
`5
`5
`78
`76
`63
`5B
`60
`35 to 79
`83 to 76
`35 to 75
`N/A
`52%
`49%
`52%
`49%
`
`V
`
`150.003
`7.0
`6.0, 9.7
`p=0,009
`4.1
`‘ 2.4, 4.5
`14%
`p<o.ooor‘
`
`
`
`lo-
`ageemlar plus cisplatin: Gemzar 1000 mg/m2 on Da 3 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 every
`' g e-agent cisplatin' cioplatin 100 mglm on Day 1 every 28 days.
`‘
`s oisplatin: Ge
`lfl!‘ 1260 rug/1n2 on Days I and B and cisplntin 100 mglm2 on Day 1 every 21
`' e plus
`'splatln isplatin 100 mym2 on Day 1 and l.V. etoposide 100 mg/m2 on Days ‘1; 2,
`every 2] da s.
`We Status.
`ya
`We
`'In.
`Taspmse was calculated using the two-sided Fisher’s exact test for difference in binomial proportions. All
`. Calculated using the Logrank test for difference in overall time to an event.
`
`domized 135 patients to Gemzar 1250 nag/m2 on Days 1 and
`8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to
`etoposide 2100 mg/m2 IV. on Days 1, 2, and 3 and cisplatin
`100 mglm on Day 1 on a 21-day cycle (Table 2).
`There was no signifith difl'erence in survival between the
`two treatment arms (Logrank p=0.18, two-sided). The me-
`dian survival was 8.7 months for the Gemzar plus cisplatin
`arm versus 7.0 months for the etoposide plus cisplatin arm.
`Median time to disease progression for the Gemzar plus cis»
`platin arm was 5.0 months compared 'to 4.1 months on the
`etoposide plus cisplatin arm (Logrank p=0.015, two-sided).
`The objective response rate for the Gemzar plus cisplatin
`arm was 33% compared to 14% on the etoposide plus cis<
`platinarm (Fisher’s Exact p=0.01, two‘sided).
`ualit of Life ( 0L): QOL was a secondary endpoint in
`ran cause at
`ies. In the Gemzar plus cisplatin verv
`sus cisplatin study,- QOL.was measured using the FACT-L,
`which assessed physical, social, emotional and functional
`well-being, and lung cancer symptoms. In the study of
`Gemzar plus cisplatin versus etoposide plus cisplatin, QOL
`was measured using the EORTC QLQ-C30 and LC 13, which
`assessed physical and psychological functioning and symp-
`toms related to both lung cancer and its treatment. In both
`studies no significant difl‘erences were observed in QOL be-
`tween the Gemzar plus cisplatin arm and the comparator
`arm.
`7
`
`Flgure 1
`Kaplan-Mcicr Survival Curve in
`'
`Gemzar plus Cisplatln versus Cisplstln NSCI.C Study (N=512)
`
`Sui-mull
`prahlhlllly
`
`W Mutual
`nun 1 Ch; at: months
`39%
`7n monllu
`as as
`Cls
`V IELSmlsm: will:
`Loan-cc
`tum
`womvon
`0.1m
`
`v
`
`_ Gnmdilllino’Clsplalln
`(N=260)
`
`/
`
`Survival limo (ms-uh.)
`
`I
`._
`[See table 2 at left]
`Pancreatic Cancer—Data from 2 clinical trials evaluated
`the use of Gemzar in patients with locally advanced or
`metastatic pancreatic cancer. The first trial compared
`Gemzar to 5«Fluorouracil (fr-FU) in patients who had ’re-
`ceived no prior chemotherapy. A second trial studied the use
`of Gcmzar in pancreatic cancer patients previously treated
`with 5-FU or a E-FU-containing regimen. In both studies,
`the first cycle of Gemzar was administered intravenously at
`a dose of 1000 mg/n'i2 over 30 minutes once weekly for up to
`7 weeks (or until toxicity necessitated holding a dose) fol-
`lowed by a week of rest from treatment with Gemzar. Sub-
`sequent cycles consisted ofinjections once weekly for 3 con-
`secutive weeks out of every 4 weeks.
`The primary eflicacy parameter in these studies was “clini-
`cal benefit response,” which is a measure of clinical im-
`provement based on analgesic consumption, pain intensity,
`pei‘fui‘nimlce status, and Weight change. Definitions for im-
`provement in these variables were formulated prospectively
`during the design of the 2 trials. A patient was considered a
`clinical benefit responder if either:
`i)
`the patient showed a 250% reduction in pain intensity
`(Memorial Pain Assessment Card) or analgesic con-
`sumption, or a 20-point or greater improvement in per-
`formance status (Kamofsky Performance Scale) for a pe-
`riod of at least 4 consecutive weeks, without showing
`any sustained worscning in any of the other parameters.
`Sustained worsening was defined as 4 consecutive weeks
`with either any increase in pain intensity or analgesic
`consumption or a 20-point decrease in performance sta-
`tus occurring during'the first 12 weeks of therapy.
`0R:
`ii) the patient was stable on all of the aforementioned pa-
`rameters, and showed a marked, sustained weight gain
`(>7% increase maintained for 24 weeks) not due to fluid
`accumulation.
`‘
`The first study was a multi-oenter (17 sites in US and Can-
`ada), prospective, single-blinded, two-arm, randomized,
`comparison of Gemzar and 5-FU in patients with locally ad-
`vanced or metastatic pancreatic cancer who had received no
`prior treatment with chemotherapy. 5-FU was administered
`intravenously at a weekly dose of 600 mg/m2 for 30 minutes.
`The results from this randomized trial are shown in Table 3.
`Patients treated with Gemzar had statistically significant
`increases in clinical benefit response, survival, and time to
`disease progression compared to 5AFU. The Kaplan-Meier
`curve for survival is shown in Figure 2. No confirmed objec-
`tive tumor responses were observed with either treatment.
`[See table 3 at top of next page]
`Continued on next page
`
`information was
`ldenli-Code® symbol. This product
`‘
`prepared in June 2002. Currentinfovmation on these and other
`products cl Eli Lilly and company may be obtained by direct
`inquiry to Lilly Research Laboratories. Lillv Corporate Center.
`'lndlanasolis, Indiana 46285. (800) 545-5979.
`
`NOVARTIS EXHIBIT 2036
`Par v. Novartis, IPR 2016-01479
`Page 3 of 7
`
`

`

`# 1
`
`814IEL| LILLY
`
`PHYSICIANS’ DESK RE
`Table 3: Gemzar Versus 5-FU m Pancreatic Oancer
`Gemzar
`5-FU
`
`Number of patients
`63
`68
`Male
`34
`~ 34
`29
`Female
`29
`61 years
`62 years
`36 to 77
`Median age
`37 to 79
`Range
`71.4%
`
`
`
`
`
`
`I
`76.2%
`Stage IV disease
`
`69.8%Baseline KPSII 570 68.3%
`
`4.8%
`22.2%
`Clinical benefit response
`(N=3)
`(N°=14)
`
`Survival
`4.2 months
`5.7 months
`Median
`(N=19) 29%
`(N=30) 46%
`6-month probability”
`(N = 4) 5%
`(N = 14) 24%
`9-month probability"
`(N = 2) 2%
`- (N = 9) 18%
`1-year probability"
`0.4 to 15.1I months
`0.2 to 18.6 months
`Range
`'
`3.1 to 6.1 months
`4.7 to 6.9 months
`95% C1. of the median
`
`2.1 months
`V 0.9 months
`Time to Disease Progression l
`Median
`0.1 to 12.0+ months
`Range
`0.1+ to 9.4 months
`0.9 to 1.1 months
`1.9 to 3.4-‘months
`of the median
`95%
`" Kamof'sky Performance Status
`b Kaplan-Meier estimates
`“ N=number of patients.
`+ No progression at last visit; remains alive.
`The p-vnlue for clinical benefit response was calculated using the two-sided test for diflerence in binomial D ,,
`other p-values were calculated using the Logrank test for diiference in overall time to an event.
`'
`
`hazard to the fetus.
` __,_____1T’__
`
`Discontin'.f-
`-n
`All
`Pat‘
`Grades
`Gradecl
`Grades GradeS
`
`Grade 3 LGrade 4
`Laboratory<1
`Hematologic
`Anemia
`leukopenia
`Neutropenia
`Thrombocy‘lopenia
`Hepatic
`ALT ‘
`AST
`Alkaline Phosphatase
`Bilirubin
`Rena]
`Proteinuria
`Hematuria
`BUN
`Creatinine
`Non-laboratorye
`Nausea and Vomiting ,
`Pain
`Fever
`Rash
`Dyspnea
`Constipation
`Diarrhea
`Hemorrhage
`Infection
`Alopecia
`Stomatitis
`Sonmolence
`Paresthesias
`——.—-
`Grade based on criteria from the Wor d Health Organization (WHO).
`‘ N=699-974; all patients with laboratory or non-laboratory data.
`" N=l El -241; all pancreatic cancer patients with laboratory or non-laboratory data.
`c N=979.
`d Regardless of causality.
`‘ Table includes nonrloboratury data with incidence for all patients 210%. For approximately 60% 0f the I'
`laboratory events were graded only if assessed to be possibly drug-related.
`mza
`Hi
`‘ PregmncyiPi-egnoncy Category 13- Ge
`harm when administered to a prelim“
`lforlfl"l
`bins, is embryotoxic causing fetal m9
`gas of 1'
`ate, incomplete ossification) at do
`d 1‘“uil "I
`mice éabout 1/200 the recommend?
`mg/m basis). Gemeitabine is fetowmc “9
`bscrnle 0
`motions (fused pulmonary artery, 8
`doses of 0.1 mg/kyday in rabbits (
`mended human dose on 3 mgr/m2 1335‘”
`characterized by decreased feml viabilitYa
`There 9
`sizes, and developmental delays-
`
`G mzal‘- I
`Gemzal‘ in pregnant women. If
`9
`pregnancy, or if the patient becomes Paid
`Gemzar, the patient should be 8P9“
`
`‘Gemzar cont
`Clinical benefit response was achieved by 14 patients
`treated with Gemzar and 3 patients treated with 5—FU. One
`patient on the Gemz’ar arm showed improvement in all 3
`primary parameters (pain intensity, analgesic consumption,
`and performance status). Eleven patients on the Gemzar
`arm and 2 patients on the 5-FU arm showed improvement
`in analgesic consumption and/or pain intensity with stable
`performance status/two patients on the Gemsor arm
`showed improvement in analgesic consumption or pain in-
`tensity with improvement in performance status. One pa-
`tient on the 5-FU arm was stable ’with regard to pain inten—
`city and analgesic consumption ‘ with improvement in
`perfoniiance status. No patient on either arm achieved a
`clinical benefit response based 0'1: Weight gain.
`
`Figure 2
`Ka Ian-Meier Survival Curve
`
`
`
`FractionSun/iving
`
`I”
`n
`scrum. I“... "mum;
`
`The second trial was a multi-center (17 US and Canadian
`centers), open-label study of Gemzar in 63 patients with ad—
`vanced pancreatic cancer previously treated with 5-FU or a ‘
`67EUrcontaining regimen. The study showed a clinical ben-
`efit response rate of 27% and median survival of 3.9 months.
`Other Clinical Studies—When Gemzar was administered
`more frequently than once weekly or with infusions longer
`than 60 minutes, increased toxicity was observed. Results of
`a Phase 1 study of Geinzar to assess the maximum tolerated
`dose (MTD) on a daily x 5 schedule showed that patients
`developed significant hypotension and severe flu-like symp-
`toms that were intolerable at doses above 10 mg/m2. The
`incidence‘and severity of these. events were dose-related.
`Other Phase 1 studies doing a twice—weekly schedule
`reached MTDs of only 65 mglro2 (30-minute infusion) and
`150 mg/m2 (57minute bolus).’ The dose-limiting toxicities
`were thrombocytopenia and flu-lilie symptoms, particularly
`asthenin. In a Phase 1 study to assess the maximum toler-
`ated infusion time, cllnically significant toxicity, defined as
`myelbsup ression, was
`seen with weekly doses of
`300 mg/m at or above a