EXHIBIT 2017
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`EXHIBIT 2016
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`Cephalon Exhibit 2016
`Fresenius v. Cephalon
`
`|PR2016-00111
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`6
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`

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`N e w s & a N a ly s i s
`
`Bendamustine
`
`cross-resistance with other alkylating
`agents and fludarabine4,5.
`
`Drug properties
`Bendamustine causes DNA damage that
`is thought to lead to cell death via several
`pathways, including apoptosis and mitotic
`catastrophe4,6. A recent study suggests that
`bendamustine has mechanistic features that
`differentiate it from other alkylating agents,
`which might contribute to its efficacy in
`patients with disease refractory to these drugs4.
`
`Clinical data
`The safety and efficacy of bendamustine
`were evaluated in an open-label,
`randomized, controlled comparative
`trial involving 301 previously untreated
`patients with Binet Stage B or C (Rai Stages
`I–IV) CLL requiring treatment6. Need-
`to-treat criteria included haematopoietic
`insufficiency, B-symptoms, rapidly
`progressive disease or risk of complications
`from bulky lymphadenopathy6.
`Patients were randomly assigned to
`receive either bendamustine hydrochloride
`(100 mg per m2, administered intravenously
`over a period of 30 minutes on days 1 and 2)
`or chlorambucil (0.8 mg per kg administered
`orally on days 1 and 15 of each 28-day
`cycle)6. The efficacy end points of objective
`response rate and progression-free survival
`were calculated using a pre-specified
`algorithm based on the National Cancer
`Institute’s working group criteria for CLL6.
`Patients receiving bendamustine
`showed a higher overall response rate
`(59%, with a complete response rate of
`8%) than patients receiving chlorambucil
`(26% overall response rate, with a
`complete response rate of <1%)6.
`For patients receiving bendamustine,
`median progression-free survival was
`18 months, compared with 6 months
`for patients receiving chlorambucil6.
`
`Indications
`Bendamustine is approved by the FDA
`for the treatment of patients with CLL6.
`Efficacy relative to first-line therapies other
`than chlorambucil has not been established6. ▶
`
`fresh from the pipeline
`Bendamustine
`
`Michael J. Keating, Christian Bach, Uma Yasothan and
`Peter Kirkpatrick
`
`performed for unrelated reasons rather than
`because of signs or symptoms of the disease,
`and approximately a third of patients never
`need treatment1. Standard management of
`most patients has therefore traditionally
`involved a period of watchful waiting to see
`if the disease progresses1. However, there is
`currently a focus on modifying this strategy
`as understanding of potential prognostic
`factors improves1.
`For those patients with CLL who are
`treated, therapy is generally palliative1.
`Regimens based on DNA alkylating agents
`such as chlorambucil have been used for
`decades1,2. In the 1980s, purine analogues
`such as fludarabine were shown to be
`better at achieving complete remissions
`than alkylator-based regimens1,2. Since
`then, considerable efforts have focused on
`developing combination regimes that are
`built on fludarabine, with some including
`newer biological therapies such as the
`B-cell-targeted monoclonal antibody,
`rituximab (Rituxan; Biogen–Idec/
`Genentech)1,2. Identification of agents with
`activity against resistant or treatment-
`refractory CLL has also remained a high
`priority.
`
`Basis of discovery
`Alkylating agents that exert cytotoxic
`effects through covalent modification of
`DNA bases were first introduced as cancer
`therapies more than half a century ago3.
`Several such agents, including chlorambucil
`and cyclophosphamide (FIG. 1a,b), are
`still commonly used, particularly in
`haematological cancers.
`In the 1960s, bendamustine (FIG. 1c)
`was designed with the aim of creating a
`bifunctional anticancer agent possessing
`an alkylating group and also potential
`antimetabolite properties associated with a
`benzimidazole ring4. It was found to have
`clinical activity against various cancers,
`including non-Hodgkin’s lymphoma,
`CLL and multiple myeloma, and was first
`marketed in Germany in the early 1970s4.
`Interest in the drug for the treatment of CLL
`has recently been stimulated by clinical trials
`indicating strong efficacy and apparent low
`
`In March 2008, bendamustine
`hydro­chlo­ride (Treanda; Cephalo­n),
`a DNA alkylating anticancer agent,
`was appro­ved by the US FDA fo­r the
`treatment o­f chro­nic lympho­cytic
`leukaemia.
`
`Chronic lymphocytic leukaemia (CLL),
`which results from the production of
`long-lived abnormal lymphocytes, is the
`most common type of leukaemia in North
`America and Europe1. It mainly affects the
`elderly, and has a highly variable course, with
`survival ranging from months to decades1.
`Most patients with CLL are now
`identified through blood tests that have been
`
`Cl
`
`Cl
`
`N
`
`COOH
`
`Chlorambucil
`
`Cl
`
`Cl
`
`O
`
`N
`
`O
`P
`HN
`
`Cyclophosphamide
`
`COOH
`
`HCl
`
`NN
`
`CH3
`
`Cl
`
`Cl
`
`N
`
`a
`
`b
`
`c
`
`Bendamustine hydrochloride
`
`1H-benzimidazole-2-butanoic acid, 5-[bis(2-
`chloroethyl)amino]-1-methyl-, monohydrochloride
`C16H21Cl2N3O2 • HCl; Mr = 394.7
`
`Figure 1 | DNA alkylating anticancer drugs.
`a | Chlo­rambucil. b | Cyclo­pho­sphamide.
`Nature Reviews | Drug Discovery
`c | Bendamustine hydro­chlo­ride. All three
`co­mpo­unds have a 2-chlo­ro­ethylamine
`alkylating gro­up.
`
`NATuRE REVIEwS | Drug Discovery
`
` VoLuME 7 | juNE 2008 | 473
`
`© 2008 Nature Publishing Group
`
`CEPHALON, INC. -- EXHIBIT 2016 0001
`
`

`
`N e w s & a N a ly s i s
`
`AnAlysis | ChronIC lymphoCytIC leukaemIa
`
`▶
`
`Analysing issues in the treatment of
`chronic lymphocytic leukaemia is Michael
`j. Keating, M.B., B.S., Professor of Medicine,
`Department of Leukemia, MD Anderson
`Cancer Center, Houston, Texas, uSA.
`
`For more than 30 years, the only treatment
`available for chronic lymphocytic leukaemia
`(CLL) was the alkylating agents chlorambucil
`and cyclophosphamide. These drugs were
`‘grandfathered’ in as initial therapy for
`CLL, and transient control was achieved in
`approximately half the patients. Fludarabine
`was then found to be very effective in patients
`resistant to alkylating agents7, and it was able
`to achieve complete remissions, leading to
`its approval for refractory CLL. Fludarabine
`has also been compared with chlorambucil in
`clinical trials as a first-line treatment, but not
`submitted for approval in this setting.
`The monoclonal antibody alemtuzumab
`(Campath; Genzyme/Bayer) was initially
`approved for CLL for the treatment of
`fludarabine-refractory patients where there
`was no other available option. Recently,
`alemtuzumab has also been compared
`with chlorambucil, demonstrating a higher
`response rate and longer progression-free
`survival (PFS) in a randomized comparative
`trial8, and it is now approved by the FDA as
`a single agent for first-line therapy.
`
`Bendamustine, which has laboratory
`evidence to support its activity as a ‘better’
`alkylating agent4, was approved by the FDA
`in March this year on the basis of a similar
`study comparing it with chlorambucil, in
`which it showed a higher response rate and
`PFS than chlorambucil6. There is extensive
`experience with bendamustine in Germany
`and more recently in the rest of Europe, and
`it has been shown to have activity not only in
`CLL, but also in a variety of lymphomas alone
`or combined with rituximab. The chemical
`structure of bendamustine suggests that it
`might be a hybrid drug with some purine
`analogue qualities, although this has not
`been validated.
`while it is refreshing to have new agents
`with superior activity to chlorambucil in
`front-line CLL settings available for use
`in practice, the era of chlorambucil is largely
`past. It is clear that fludarabine has superior
`activity to chlorambucil from the point of view
`of response rate and PFS. However, whether
`any agent results in improved survival has not
`been resolved with fludarabine, alemtuzumab
`or bendamustine. Combinations of purines
`and alkylators have been demonstrated to be
`superior to single agents, and combinations
`of rituximab with fludarabine or fludarabine
`and cyclophosphamide have led to a dramatic
`improvement in complete responses and
`
` Bo­x 1 | market for chronic lymphocytic leukaemia
`Analysing the market for therapies for chronic lymphocytic leukaemia are Christian Bach and Uma
`yasothan, ims health, london, UK.
`Chronic lymphocytic leukaemia (Cll) is a slow progressive disease of abnormal white blood cells
`that occurs predominantly in the elderly. it is estimated that there were ~15,000 new Cll cases
`diagnosed in the United states in 2007, with more than 75% of those diagnosed over 50 years old
`and about 4,500 deaths annually11,12. At present, there are ~25,000 Cll patients identified as being
`on active treatment in the United states13.
`At early stages of the disease, an aggressive chemotherapy approach is often not necessary
`and a ‘wait and watch’ strategy is typically adopted. for first-line and refractory patients who are
`treated, a range of options are available, including traditional cytotoxic drugs such as chlorambucil,
`cyclophosphamide and fludarabine. more recently, the monoclonal antibodies rituximab (rituxan;
`Biogen–idec/Genentech) and alemtuzumab (Campath; Genzyme/Bayer) have been evaluated for
`Cll alone or in combination with fludarabine-based regimens. in general, monoclonal antibodies
`such as rituximab have gained wide recognition as useful agents in haematological malignancies.
`Bendamustine hydrochloride (treanda; Cephalon) belongs to the family of drugs known as
`alkylating agents, and was approved by the Us fDA for the treatment of patients with Cll in
`march 2008. the drug has been designated as an orphan drug in the United states, conferring
`prolonged market exclusivity. Cephalon in-licensed the drug from Astellas pharma and will be
`promoting it in the United states. in europe, the agent is available under the name of ribomustin,
`and is indicated as a single agent or in combination with other anticancer agents for indolent non-
`hodgkin’s lymphoma, multiple myeloma and Cll. Analysts estimate the initial market potential
`for bendamustine for Cll in the United states to be $100 million with front line-therapy, which
`would increase if the drug is subsequently also used in refractory cases and in other combination
`regimens, for which clinical trials are ongoing.
`
`PFS9,10, although rituximab has not yet been
`approved for CLL. Long-term studies of
`such regimens are suggesting that there is
`an improvement in survival compared with
`historical experience.
`The challenge now in CLL is to establish
`the best way to introduce these new drugs
`into clinical practice. For bendamustine,
`several questions remain, and the lack of peer-
`reviewed clinical trial data so far is a concern
`for the academic community. Although it
`seems clear that bendamustine is a better
`alkylating agent, it is not yet established
`whether it will be a major advance when
`incorporated into combination strategies. For
`CLL, it is anticipated that bendamustine will
`be combined with purine analogues and/or
`monoclonal antibodies, and there is no reason
`why bendamustine should not establish itself
`as a significant new agent in lymphoprolifera-
`tive disorders.
`Michael J. Keating is at the Department
`of Leukemia, MD Anderson Cancer Center,
`PO Box 301402, Houston, Texas 77025, USA.
`
`Uma Yasothan and Christian Bach are at IMS Health,
`7 Harewood Avenue, London NW1 6JB, UK.
`Peter Kirkpatrick is at Nature Reviews Drug Discovery.
`e-mails: mkeating@mdanderson.org; UYasothan@
`de.imshealth.com; p.kirkpatrick@nature.com
`
`doi:10.1038/nrd2596
`
`1. Dighiero, G. & Hamblin, T. J. Chronic lymphocytic
`leukaemia. Lancet 371, 1017–1029 (2008).
`2. Lin, T. S. et al. Changing the way we think about chronic
`lymphocytic leukemia. J. Clin. Oncol. 23, 4009–4012
`(2005).
`3. Chabber, B. A. & Roberts, T. G. Jr. Chemotherapy and
`the war on cancer. Nature Rev. Cancer 5, 65–72 (2005).
`4. Leoni, L. M. et al. Bendamustine (Treanda) displays a
`distinct pattern of cytotoxicity and unique mechanistic
`features compared with other alkylating agents.
`Clin. Cancer Res. 14, 309–317 (2008).
`5. Bergmann, M. A. et al. Efficacy of bendamustine in
`patients with relapsed or refractory chronic lymphocytic
`leukemia: results of a phase I/II study of the German CLL
`Study Group. Haematologica 90, 1357–1364 (2005).
`6. Food and Drug Administration. FDA labelling
`information [online], <http://www.fda.gov/cder/foi/
`label/2008/022249lbl.pdf> (2008).
`7. Keating, M. J. et al. Fludarabine: a new agent with
`major activity against chronic lymphocytic leukemia.
`Blood 74, 19–25 (1989).
`8. Hillmen, P. et al. Alemtuzumab compared with
`chlorambucil as first-line therapy for chronic
`lymphocytic leukemia. J. Clin. Oncol. 25, 5616–5623
`(2007).
`9. Byrd, J. C. et al. Randomized phase 2 study of
`fludarabine with concurrent versus sequential
`treatment with rituximab in symptomatic, untreated
`patients with B-cell chronic lymphocytic leukemia:
`results from Cancer and Leukemia Group B 9712
`(CALGB 9712). Blood 101, 6–14 (2003).
`10. Tam, C. et al. Long-term results of the fludarabine,
`cyclophosphamide and rituximab regimen as an initial
`therapy of chronic lymphocytic leukemia. Blood (in the
`press).
`11. Morton, L. M. et al. Lymphoma incidence patterns
`by WHO subtype in the United States, 1992–2001.
`Blood 107, 265–276. (2006)
`12. National Cancer Institute. Cancer statistics [online],
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`13. IMS Oncology Analyzer (2008).
`
`474 | juNE 2008 | VoLuME 7
`
` www.nature.com/reviews/drugdisc
`
`© 2008 Nature Publishing Group
`
`CEPHALON, INC. -- EXHIBIT 2016 0002