“LT—um:193M..:-\.mu-uu‘#n—'H—-=-bt.-{i4::u2f.-’.:-7¢.":h aziwhflwz311-w:L-T-—‘J€;==Tb,-w.:,u:“gr":-'=m=,,L\A,-.W:ALE:D=1 swagg--
`
`- :w:
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application of: Jerome B. Zeldis
`
`Group Art Unit: 1629
`
`ScrialNo.: 12/621,502
`
`Confirmation No: 2588
`
`Filed: November 19, 2009
`
`Examiner: Anderson, James D.
`
`For: METHODS USING 3~(4—AMINo—l -ox0~1 ,3- Attorney Docket No: 95 t6-904-999
`tJlHYDRO-lSOl‘NDOL-2-YL)-PIPERIDINIB-2,6-
`DlONF. FOR TREATMENT OF MANTLE CELL
`LYMPIIOMAS
`
`DECLARATION BY LEI ZHANG, M.D. UNDER 37 C.F.R. 1.132
`
`Commissioner for Patents
`P.0. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`I, Lei Zhang, M.D., declare and state that:
`
`l,
`
`I received my MD. degree from the Capital Medical University in Beijing, China,
`
`and a MS. degree in biochemistry at Medical College of Virginia, Virginia Commonwealth
`
`University, Richmond, Virginia.
`
`2.
`
`Following completion of my medical degree, 1 was trained as a staff physician in
`
`internal medicine, including the diagnosis and treatment of hematologic malignancies.
`
`I later
`
`worked at several major pharmaceutical companies in their clinical deveioptnent and regulatory
`
`submission divisions, with an emphasis on oncology drugs. [joined Celgcne Corporation,
`
`Summit, New Jersey in 2008.
`
`I am presently a Executive Director and Clinical Research
`
`Physician of C elgene Corporation, and I am responsible for its oncology clinical research and
`
`development in the lymphoma program.
`
`i have been the lead physician in Celgene
`
`Cm-poration’s global regulatory submission team in Mantle Cell Lymphoma (“MCL”)
`
`registration program.
`
`1 have overseen the clinical and scientific activities in key global
`
`registration studies of lenalidomide in MCL treatment. A copy of my curriculum Vitae is
`
`enclosed herewith.
`
`Apotex EX. 1008, p. 1
`
`Apotex Ex. 1008, p. 1
`
`

`

`..
`
`,_._.w m ’__.s_.t_._-_-..-_m..-..-.-.-.s_-.._-._l_--.- I.P.f'.fv’.7€.'.:£fl‘mkmwm
`
`.n .mw..;...-.m .....an-_-.m.s...=.w_e~=.-.mmu_—_-mhmn , >n..,2::- . u: 4...“... -_-.
`
`'5
`
`-.....:.:..-.,:.,-“u ----i-
`
`3.
`
`I am familiar with the disclosure and claims ofthe above-identified patent
`
`application (“the ‘502 application”).
`
`I understand that the pending claims are directed to, inter
`
`aha, methods of treating MCI. with about 5 mg to 25 mg per day of3-(4-amino-1-oxo-l ,3-
`
`dihydro-isoindol-2—yl)«piperidine—2,6-dionc (Le, lcnalidomide) or its salt or hydrate. The
`
`compound lenalidomidc is administered for a period of time followed by a period of rest.
`
`I also
`
`understand that in an Office Action issued on September 19, 2013 by the Patent Office, the
`
`pending, claims are rejected under 35 U.S.C. § 103(a) as allegedly being unpatentable over Zeldis
`
`(US. Publication No. 2004f0029332 A1) in View of secondary references Damaj e: at.
`
`(Leukemia, 2003, vol. 17, pages 1914-i9t 5; “Damaj”), Wilson et at. (British J. ofHaemarology,
`
`2002, vol. 119, pages t28~l30; “W ilson“ , and Kaufmann at al. (Blood, 2004, vol. £04, no. 8,
`
`pages 2269~2271; “Kaufmann”).
`
`4.
`
`I have reviewed the cited references including Damaj, Wilson and Kaufmann. It
`
`is my opinion that one of ordinary skill in the art would not have concluded based on the
`
`disclosure of these references that the compound thalidomide would be therapeutically effective
`
`in treating MCL. Damaj reported two individual MCL patients treated with thalidomide. Wilson
`
`reported the case of a single MCL patient. To determine whether an agent is therapeutically
`
`effective in treating a certain disease, one of ordinary skill in the art would have needed a
`
`statistically significant amount of evidence, including preclinical safety and toxicity information.
`
`The evidence presented in Damaj and Wilson is limited to three individual patients and is clearly
`
`insufficient. While Kaufmann evaluated a combination strategy using thalidomide and rituximab
`
`in to patients and reported that 13 patients achieved objective responses, only 3 of these patients
`
`were previously treated with rituxirnab, an agent that was known to inhibit MCL at the time of
`
`Kaufmann’s study. As such, it cannot be ascertained whether the response observed in the 13
`
`patients was induced by rituximab, thalidomide, or their combination. Therefore, it is my
`
`opinion that one of ordinary skill in the art would not have concluded that thalidomide is
`
`therapeutically effective in treating MCL based on these three references. Additionally, 1 am not
`
`aware of any large-scale clinical study of thalidomide in treating MCL that was conducted
`
`following the publication of these references.
`
`5.
`
`There is a significant unmet need in therapeutic options for MCI. patients, in
`
`particular those with relapsed, refractory, or relapsed and refractory MCL.
`
`In spite of improved
`
`Apotex EX. 1008, p. 2
`
`Apotex Ex. 1008, p. 2
`
`

`

`treatment options for MCL patients. MCL continues to have the poorest prognosis among non-
`
`Hodgkin's lymphoma (NHL) subtypes. With each successive relapse. MCL patients experience
`
`chemo—resistance and shorter duration of response. The overall survival for relapsed or
`
`refractory MCL is estimated to be only 1-2 years. Prior to June 2013, bortezomib (Velcade Q)
`
`was the only drug approved by the US. Food and Drug Administration (“FDA") for patients
`
`with relapsed or refractory MC L. Once the patients relapse after or fail the bortezomib
`
`treatment. no clear treatment option is available.
`
`6.
`
`l was the lead clinician in the Phase II study oflenalidomide in MCL treatment.
`
`I
`
`am familiar with both the compound lenalidomide and its therapeutic effects in MCL patients.
`
`All patients enrolled in this study were heavily pretreated for MCL (median number of prior
`
`treatments is 4) and 93% of the patients had stage Ill—[V MC L.
`
`In addition, all patients had
`
`received prior treatment with bortezomib. Lenalidomide, when administered as described in the
`
`claims, achieved an overall response rate of 28% (central review)/32% (investigator review),
`
`including a complete response rate of 7.5% (central review)/16% (investigator review). The
`
`median duration of response is 16.6 months (central review)/ 18.5 months (investigator review).
`
`The median duration of response for complete response is 16.6 months (central review)/26.7
`
`months (investigator review). Also significantly, with a median follow—up of 9.9 months,
`
`median overall survival is 19.0 months. The results of the Phase II study are described in the
`
`Goy er of. (2013) article enclosed herewith. The safety profile of lenalidomide in these patients
`
`was also manageable.
`
`7.
`
`It is my opinion that the efficacy ot‘lenalidomide in relapsed, refractory, or
`
`relapsed and refractory MC L demonstrated in this study would have been unexpected and
`
`surprising at the time the claimed invention was made, particularly in view of the unfavorable
`
`prognosis of the patients. The FDA granted fast track designation to lenalidomide based on its
`
`activity and tolerability in heavily pretreatment relapsed or refractory MCL patients who
`
`received prior bortezomib therapy. and approved icnalidomide for this indication based on the
`
`Phase [1 study results.
`
`8.
`
`I hereby declare that all statements made herein of my own knowledge are true
`
`and that all statements made on information and belief are believed to be true; and further that
`
`Lu
`
`Apotex EX. 1008, p. 3
`
`Apotex Ex. 1008, p. 3
`
`

`

`
`
`these statements were made with the knowledge that willful false statements and the like may be
`
`punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States
`
`Code, and that such willfiJl false statements may jeopardize the validity of any patent issuing
`
`from the present application.
`
`Dated:
`
`M15, 2.4;?)
`
`WWW—W
`
`Lei Zhang, MD.
`
`Apotex EX. 1008, p. 4
`
`Apotex Ex. 1008, p. 4
`
`

`

`
`
`
`
`Exhibit A
`
`Apotex EX. 1008, p. 5
`
`Apotex Ex. 1008, p. 5
`
`

`

`
`
`CURRICULUM VITAE
`
`Lei Zhang, M.D.
`
`Celgene Corporation
`86 Morris Avenue
`Summit. NJ 07901
`
`lei_zhang@celgene.com (work)
`
`PROFILE
`
`0
`
`0
`
`0
`
`I
`
`Clinical Research Physician responsible for oncology medical monitoring with
`extensive therapeutic knowledge ofoncology/general medicine, excellent
`management and communication skills.
`Clinical research professional with 15+ years in the pharmaceuticals industry, and
`molecular biology research
`Extensive experience in designing and managing oncology clinical trials (phase I-
`IV, including large global phase ill registration study, both in hematological
`malignancies and solid tumors)
`Strong regulatory registration expertise with significant contributions in several
`registration programs in career
`
`PROFESSIONAL EXPERIENCE:
`
`November 2008 7 Present, Ceigene Corporation, Summit, New Jersey
`Senior Medical Director, Clinical Research Physician,
`Oncology Clinical R 8: D, Lymphoma Program ~ Lenatidomide, Romitlepsin and BTK inhibitor
`CC292
`
`0
`
`Lead physician for global regulatory submission team in Mantle Cell Lymphoma registration
`program. Lead author of key sNDA documents including pivotal trial study report, lntergraded
`Summary of Efficacy, Intergraded Summary of Safety, and Clinical Overview in filing dossier.
`o Oversee the clinical and scientific activities in key global registration studies including Mantle Cell
`Lymphoma & Diffuse Large B cell Lymphoma studies in Lenalidomide Lymphoma Program.
`Provide leadership to clinical study team in the execution of clinical studies
`Develop clinical strategy in lymphoma program
`Design phase II and phase III clinical study protocol. manage the studies as medical monitor.
`Interactions with Key Opinion Leaders in lymphoma field worldwide.
`Interactions with health authorities both in the US and Europe.
`
`August 2004 — November 2008, Novartis Pharmaceuticals Corporation, Florham Park, New Jersey
`Clinical Research Physician, Oncology Global Development
`2004 — 2006
`PKC4 12 Program, AML, MDS, and GlST indications
`2006 — 2008
`LBH389 (Panobinostat, HDAC inhibitor} Program . Hodgkin and non-Hodgkin
`lymphoma indications
`
`o
`
`Developed global clinical strategy and clinical development plan ot‘project in global Phase Ill
`registration trial.
`- Oversaw all clinical development activities as clinical indication leader for multiple indications
`including leukemia. MDS, GIST, Hodgkin and non-Hodgkin lymphoma.
`Primary responsibility for the protocol development. medical monitoring. and clinical study report
`for all trials
`
`0
`
`0
`
`o
`
`Primary responsibility for the LBH589 health authority activities in lymphoma indication. Primary
`author of regulatory docsumcnts, such as briefing books. Successful Orphan Applications in US and
`EU (granted from both FDA and EMEAI’COMP}. pediatric waiver request in EU (granted from
`EMEAIPDCO)
`Represented clinical at l-lA meetings. including end ot‘Ph [1 meeting iv.-'FDA_ SPA meeting with
`FDA. scientific advice meeting with EMEAESAWP (Scientific Advice Working Party). etc.
`
`Apotex EX. 1008, p. 6
`
`Apotex Ex. 1008, p. 6
`
`

`

`I
`0
`
`Coilaborated with internal mold-functional teams, external Key Opinion Leaders, and C R05.
`Direct reports included 8 FTEs both in US and Switzerland
`
`1998 — Aug 2004, Eli Lilly and Company, Indianapolis, Indiana
`Senior Clinical Development Scientist, Oncology Global Team
`
`0
`
`0
`
`0
`
`Regulatory Submission/Registration Expertise
`0
`Significant contributions to the successful ALIMTAE Mesothelioma and Non-small Cell
`Lung Cancer NDA tiling as key Submission team member
`Experienced in global (US and EU} registration process, such as NBA submission
`document preparation. regulatory query responses, FDA audit, etc.
`o Coordinated the preparation activity for FDA ODAC meeting
`Recognized expert for the breadth ofclinical trial development knowledge, making high-value
`contributions on projects
`0
`Experienced in all phases of drug development, from early phase I development, phase 11
`study, to large global phase Ell registration study, and post-marketing phase IV study.
`0 Ultimately worked with all aspects in clinical trials, from protocol development, study
`start—up phase to database lock. final Study report writing and publications.
`Indications included Lung, Methothelioma, Gastric and Colorectal Cancers
`0
`Responsible for Annual 1ND safety reports and “3
`o
`o Other activities include:
`
`0
`
`0000
`
`GO
`
`Safety monitoring, safety review and analysis
`CRF development. clinical data review
`Managed study timeline and budget.
`CRO management. Setup the first ALIMTA collaboration trial with NSABP
`Effective liaison between global team and Japan leading to the successful Kiko meeting
`and ALIMTA first human close in Japan
`People management
`Initiated and led the development of cross function on-board training program. Led the
`SOP review and implementation process. Active members of Oncology Protocol Review
`Committee, Oncology SOP Review Committee, Study Development Process
`Optimization Working Group, Clinical Preceptor Program
`
`1997 , I998, Hoffmann-La Roche, Diagnostics Corp. USA, Indianapolis, Indiana
`Research Scientist, Roche Diagnostics Corp. USA
`Preclinical research in immunology. recombinant protein expression and purification
`
`1994 « 1997, Medical College of Virginia, Richmond, Virginia
`Research Scientist, Division of Biochemistry and Molecular Biology
`0 Molecular biology research
`0
`Experimental design, protocol development and data analysis
`
`1986 — 1990, Beijing Tiantan Hospital, Division of Internal Medicine, Beijing, China
`Staff Physician, Division of Internal Medicine
`
`Diagnosis and treatment of internal medicine diseases, including cardiovascular, endocrine, respiratory, G],
`and hematologic disorders including coagulation disorders, hematologic malignancies such as acute
`leukemia, myeioproliferativc disorders {c.g. chronic myeloid leukemia). lymphoproliferative disorders
`(Hodgkin lymphoma, non-l lodgkin lymphomas). and plasma cell dyscrasias ( e.g. multiple myoloma).
`
`EDUCATION
`
`M. Di Capital Medical University, Beijing, China, I986
`M. S. Biochemistry, Medical College of Virginia. Virginia Commonwealth University, Richmond, Virginia, USA
`1994
`
`PROFESSIONAL MEMBERSHIP
`
`American Society of Clinical Oncology
`American Society of Hematology
`American Association for Cancer Research
`
`Apotex EX. 1008, p. 7
`
`Apotex Ex. 1008, p. 7
`
`

`

`um.-.:_:-_-_:.2;4:'.5 .-;- .
`
`....-.--.«.._ -.:-
`
`.-:,: -;:..-‘.-.;;.-.;-.;..;,-=-,-',-5.22
`
`:
`
`
`
`ACHIEVEMENT AWARDS
`
`Oncology Global Development Vision Award, Excellence in Execution, June 2008, Novartis Oncology
`Passion, Quality, and Speed Award, November 2005, Novartis Oncology
`Technical Excellence Award for Successful ALIMTA'E NSCLC ODAC Meeting, August 2004, Eli Lilly &
`Company
`Scientific/Clinical Contribution Award, Corporate Clinical Development, February 2004, Eli Lilly &
`Company
`Individual Leadership Award in Customer Reiationship Management Award, Corporate Summit and
`Recognition Event, February 2002, Eli Lilly & Company
`
`PUBLICATIONS
`
`A. Goy, R. Sinha. M. E. Williams, S. K. Besisik. J. Drach. R. Ramchandren. M. J. Robertson, 1. Avivi, J.
`M. Rowe, R. Herbrecht, A. Van Hoof, M. Egyed, L. Zhang. S. Cicero, T. Fit, and T. Witzig. Phase 11
`Multicenter Study ofSingle-Agent Lenalidomide in Subjects With Mantle Cell Lymphoma Who Relapsed
`or Progressed After or Were Refractory to Bortezomib: The MCL-OO] Study (EMERGETM Trial). Blood
`(ASH Annual Meeting Abstract) 2012 Abstract # 905
`
`P. Zinzani], J. Vose, M. S. Czuczman, C. B. Reader, C. Haioun, J. Polikoff, L. Zhang, K. Prandi, J. Li,
`and T.E. Witzig. Phase II Multicenter study of the Safety and Efficacy of Single-agent lenalidomide in
`Patients with RelapsedJRefractory mantle Celi Lymphoma: Long-term Follow-up Analysis ofthe NHL-003
`Study. Blood (ASH Annual Meeting Abstract) 2012 Abstract# 2738
`
`M. Duvicl, J.C. Becker. 3. Belle. F. Vanaclocha, M. G. Bemengo, C. Lebbé, R. Dummer, S. Hirawat, L.
`Zhang, M. Marshood, G. Laird and H. M. Prince. Phase II Trial ofOral Panobinostat (LBH589) in Patients
`with Refractory Cutaneous T-Cell Lymphoma (CTCL). Blood (ASH Annual Meeting Abstracts) 2008 1 12:
`Abstract it 1005
`
`L. Zhang, D. Lebwohl, E. Masson, G. Laird, MR. Cooper, HM. Prince. Clinically relevant QTC
`prolongation is not associated with current dose schedule of LBHSSQ (panobinostat). JCO, Vol 26, No. 2,
`2008: 332-333
`
`M. Duvic, F. Vanaclocha, M. G. Bernengo, C. Okada, D. Breneman, P. L. Zinzani. L. Zhang, K. Bopp, G.
`Laird. S. Hirawat, M. Prince. Phase II study of oral panobinostat (LBJ-1589), a potent pan-deacetylase
`inhibitor, in patients with refractory Cutaneous T-cell Lymphoma (CTCL). Abstract #8555, ASCO 2008
`
`MG. Bemengo, F. Vanaclocha, M. Duvic, T. Kuzel, F. Kerdei, L. PintenBrown, A. Bosly, C. Okada, D.
`Breneman, P. Zinzani, J. Becker, L. Hughey, M. Ardaiz. J. Zain, L. Zhang, M. Marshood, K. Bopp, S.
`Hirawat, G Laird}, D. Johnson, H.M. Prince. Phase il Study ofOral Panobinostat (LBH589), a Potent Pan-
`Deacetylase Inhibitor, in Patients with Refractory Cutaneous T-Cell Lymphoma (CTCL). Abstract # 1279,
`EHA 2003
`
`F. Vanaclocha, MG. Bemengo, J. C. Becker, M. Duvic, L. Pinter«Brown, J. Zain, I... Zhang, S. Hirawat,
`G. Laird, H. M. Prince. Phase II trial of oral panobinostat (LBHSS9) in patients with refractory cutaneous
`T-cell lymphoma. ESMO 2008
`
`T. Fischer. F. Giles. R. Paquette, G. Schiller, G. Ehningcr. C. Schiffer. J. Cortes. H. Kantarjian. D.
`DcAngelo. F. Heidei, PS Cohen, R. Yu, S. Bilic, L-. Zhang, P. Phillips and R.M. Stone. Phase [B Studyof
`PKC4I2, an Oral FLT3 Kinase Inhibitor. in Sequential and Simultaneous Combinations with Daunorubicin
`and Cytarabine (DA) Induction and High-Dose Cytarabine Consolidation in Newly Diagnosed Patients with
`AML. 2006 EHA, abstract #0977
`
`P. Reichardt. D. Pink. T. Lindner, M. C. Heinrich, P. S. Cohen, L. Zhang, Y. Wang, R. Yu, A. Tsyrlova, S.
`Dimitrijevic, C. Bianke. A phase [III trial of the oral PKG-inhibitor PKC4I2 (PKC) in combination with
`imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. Journal
`ofClinical Oncology. 2005 ASCO Annual Meeting Proceedings. Vol 23, No. [65. Part I ofll (June |
`Supplement). 2005: 3016
`
`Apotex EX. 1008, p. 8
`
`Apotex Ex. 1008, p. 8
`
`

`

`R. M. Stone, T. Fischer. R. Paquette. G. Schiller, C. A. Schiffer, G. Ehninger, J. Cortes, l-l. Kantarjian, D.
`A. DeAngelo, R. Yu. L. Zhang, P.S. Cohen, Y. Wang, P. Phillips and F. Giles. Phase [B study ofPKC4l2.
`an oral FLT3 kinase inhibitor, in sequential and simultaneous combination with daunorubicin and
`cytarabine (DA) inductin and high dose cytarabine consolidation in newly diagnosed patients with AML.
`Blood, Vol l06, No. 1 1,2005: 1213. abstract #4 404
`
`
`
`Apotex EX. 1008, p. 9
`
`Apotex Ex. 1008, p. 9
`
`

`

`
`
`Exhibit B
`
`Apotex EX. 1008, p. 10
`
`Apotex Ex. 1008, p. 10
`
`

`

`
`
`
`Published Ahead of Print on September 3, 2013 as 10.1200!JCO.2013.49.2835
`The latest version is at http:ll'jco.ascopubsprgicgil'doim0120010002013.49.2835
`
`
`
`Andre Gov. John Theurei Cancer
`Center at Hackensack University Medi-
`cal Center, Hackenseck: Lc: Zheng.
`Sherri Cicero. and Tommy Fu. Celgene.
`Summit. NJ: Fla|ni Sinha. Emory Unrver-
`sity Wiriship Cancer Institute. Atlanta.
`GA; Michael E. Williams. University at
`Virginia Health Sysrem. Charlorresville.
`VA; Sevgi Kalayoglu Eesnstk. lslanoul
`UniverSIty Facuitv of Medicine. Istanbul.
`Turkey; Johannes Diach, Medical
`University of Vienna. Vienna. Austria:
`Radhakrishnan Ramchandren. Karma
`nos Cancer Institute. Detroit. MI; and
`Thomas E. Wirzig. Mayo Clinic.
`Rochester. MN.
`Published online ahead of print at
`wwwicocrg on September 3. 2013.
`Supported by Celgone.
`Presented in part at the 54th American
`Socrery oi l-lematolomI Meeting and
`EKDOSIElOD. Atlanta. GA. December
`8-] l. 2012.
`Authors' disclosures 01 potential oon-
`flicls of interest and author cor-Incu-
`rions are found at the end of this
`airicte.
`Clinical trial mtormanon: NCT00737529.
`
`Corresponding author: Andre Gov. MD,
`John Theorer Cancer Center at Hackcn-
`sack Unrversrrv Medical Center. 20
`Prospect Ave. Hacxensaclc. NJ DFEUIL
`e-mail: agoyfihumedcom.
`@3 2013 by American Society of Clinical
`Orcologr
`{1!327183W13r’3199‘ifli20 00
`DCl :
`it}.‘2-30r'JCO 2013.49.9335
`
`Single—Agent Lenalidomide in Patients With Mantle—Cell
`Lymphoma Who Relapsed or Progressed After or
`Were Refractory to Bortezomib: Phase II MCL—OOI
`(EMERGE) Study
`Andre Gay. Rajiif Siriha, Michael E. Wiiliams, Sevgi Kat'ayaglu Besrsik, [ohannes Dmdt,
`Radlmkrr'shmrri Ramchandren. Lei Zhimg, Sherri Cicero. Tommy Fu, and Thomas E. Wirzig
`
`Listen to the podcast by Dr Till at www.jc0.orgipodcasts
`
`a . 3_
`
`s._
`
`1.: i n'
`
`3 it c
`
`_T_
`
`Purpose
`Although dose-intensive strategies or high-dose therapy induction followed by autol0gous
`stem-coil transplantation have improved the outcome for patients with mantle-cell
`lymphoma
`{MCL}. most eventually relapse and subsequently respond poorly to additional therapy. Bort—
`ezomib (in the United States) and temsirolimus {in Europe] are currently the only two treatments
`approved for relapsed disease. Lenaildomide is an immunomodulatory agent with proven
`tumoricidal and antiproliferative activity in MCL. The MCL~001 lEMERGE)
`trial
`is a global.
`multicenter phase II study examining the safety and efficacy of lenalidornide in patients who had
`relapsed or were refractory to bortezomib.
`Patients and Methods
`Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease
`progression or intolerance. Primary and points were overall response rate {ORR} and duration of
`response lDORl; secondary and points included complete response lCFil rate. progression-free
`survival {PPS}. overall survival (08}. and safety.
`Results
`in all. 134 patients were enrolled with a median age of 67 years and a median of four prior
`therapies lrange. two to ‘IO prior therapies). The BBB was 28% {7.5% CR/CR unconfirmed} with
`rapid time to response lmedian. 2.2 months) and a median DOR of 16.6 months {95% Cl. 7.7 to
`26.7 months}. Median PFS was 4.0 months (95% CE. 3.6 to 5.6 months). and median 08 was 19.0
`months {95% CI. 12.5 to 23.9 months]. The most common grade 3 to 4 adverse events were
`neutropenie (43%), thrombocytopenia (28%}, anemia (11%]. pneumonia (8%). and fatigue (WE),
`Conclusion
`The MCL7001 study demonstrated durable efficacy of lenalidomide with a predictable safety
`profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were
`refractory to bortezomib.
`
`J Cii'n Oncol 31. @ 2013 by American Society of Clinical Oncology
`V“;
`
`
`
`Mantle cell lymphoma (MCL) is an uncommon
`subtype ofnon—l-iodgkin lymphoma (NHL).' ac-
`counting for 3% lo 6% of NHL.1 4 Median age at
`diagnosis is mid to late 605 and patients typically
`present with advanced-stage discase.2‘5" Al-
`though overall surviyal (US) has improved Over
`the last two decades, MCL remains challenging,
`Especially in the relapscdfrcfracrory setting in
`which median 08 is approximately 1
`l0 2 years
`with current therapies.“”
`
`Combination chemotherapy and immuno-
`therapy is the foundation of first—line MCL treat—
`ment and, when feasible, dose-intensive} induction
`strategies followed by high-dose therapy and ari—
`lologous stem—cell
`transplantation {HDT~ASC1‘)
`consolidation have improved outcomes.“ “5 Al-
`ternative options in older patients or those with co-
`morbidities include less intensive strategies {eg,
`bendamustine plus rituxirnab). some of which may
`incorporate maintenance strategies to improve du-
`ration of disease control.""""” Following relapse.
`there are limited options. with minimal benefit from
`
`”Q ?013 by Fir-“crises Sacra-tr of Chrrrca: Oncology
`Information downloaded from icoascopubsorg and provided by at Celgene on September 4. 2013 from 216.118.82.254
`Copyright© 2013 American Society at Clinical Oncology. All rights reserved.
`Copyright 2013 by American Society of Clinical Oncology
`
`1
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`Apotex EX. 1008, p. 11
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`Apotex Ex. 1008, p. 11
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`standard chemotherapy or HDT-ASCT, because patients often be-
`come chemotherapy resistantm’w‘30 Two therapeutic agents are
`currently approved in the relapsed/refractory setting: bortezot‘nib
`la proteasome inhibitor; United States) and temsirolimus (a mam-
`malian targctofrapamycin complex 1 inhibitor; Europe).""22 Both
`are limited by intravenous administration and short duration of
`response (£101033 37 substantiating the need for novel alternatives
`for these patients.
`Lenalidomide (Revlimid; Celgene, Summit, NI) is an immuno-
`modulatory agent initially studied in multiple myeloma and myclo-
`dysplastic syndromes.”31 Preclinical studies showed antitumor and
`antiproliferative activities in leukemia and lymphoma,
`including
`MCL.”2 '1" Two phase [1 studies (NHLeOOE and NHL-003) reported
`clinical activity of lenalidomide in heavily pretreated patients with
`relapsed! refractory aggressive NHL'E‘M including iviCL.37‘jig With a
`similar dosing schema (25 mg per day Orally for 21 of 28 days),
`responses were consistent between studies, including 35% overall
`response rate (ORR) for both (12% to 13% complete response [CR] ),
`median DOROFGJ months (NHLBOZ) and 10.6 months (NHLvOD3),
`and median progression-free survival (PFS) of4.0 months (NHL-002)
`and 3.7 months (NHL-003) across all histologiesdia" Interestingly,
`higher and more durable responses were seen in MCL versus other
`NHL subtypes. Patients with MCL in NHL—002 showed 53% ORR
`(20% CR), median DOR of 13.? months. and median PPS of 5.6
`months?“ Central review in the NHL-003 study showed 35% ORR
`(12% CR] CR unconfirmed [CRu]), median DOR of [6.3 months,
`and median PFS of 8.8 months.38 Responses were independent of
`baseline characteristics or prior therapies; most common grade 3 to 4
`adverse events (AE5) for patients with MCI. in NHL-002 and NHL—
`003 were neutropenia (40% and 46%) and thrombocytopenia (33%
`and 30%), respectively/97'5” On the basis of diese encouraging results
`and limited treatment options in relapsedfrefractory MCL, the MCL—
`001 (EMERGE) phase II study was designed to examine the safety and
`efficacy of single-agent lenalidornide in heavily pretreated patients
`who had relapsed, progressed, or were refractory to bortezomib.
`
`
`Patients
`The institutional review board or independent ethics committee at each
`participating institution reviewed and approved the study protocol, amend-
`ments, and patients written informed consent before study initiation. Study
`design and conduct were in accordance with ethical principles of Good Clinie
`cal Practice according to international Conference on Harmonization Har—
`monized Tripartite Guidelines and the Declaration of Helsinki.
`Key inclusion criteria were confirmed MCL diagnosis with cyclin-Dl
`overexpression by immunohistochemistry or ti I l;14)(q13;q32l translocation
`by fluorescent in situ hybridization. age 218 years, Eastern Cooperative On—
`cology Group (ECOG) performance score 0 to 3, absolute neutrophil count
`2 1,3001‘311, platelets L2 60,000,“;iL, and adequate organ function. Diagnosis
`criteria included measurable lesion if? 2 cm by computed tomography [CT] l.
`Patients were required to have prior anthracycline or niitoxantrone, cyclophos
`phamide, or rituxin-tab therapy and documented relapsed, refractory, or pro-
`gressive disease (PD) following bottc'zomib (alone or in combination}. The
`definition of relapse was within 1 year of the last dose of bortczotnib and
`Following an initial CR to a honemmib-containing regimen. Refractory to
`bonezomib was defined as PD without achieving at least a partial response
`(PR) during treatment after at least two cycles of a hortezomib-cnntaining
`regimen. I’D was within l year of the last dose of hortezomib after achiev—
`ing a PR to a bortezomih—containing regimen. Patients who relapsed after
`
`HDT-ASCT were eligible, and there was no limitation for the number of
`prior therapies.
`Key exclusion criteria included the presence ofCNS disease, cmatininc
`clearance (CrCl) < 30 mUmin, eligibility for HDT’ASCT or allogeneic stem?
`cell transplantation per investigator decision, corticosteroids E l week(> it)
`mg per day prednisone or equivalent), unwillingness to receive contraception
`or prophylaxis for deep vein thrombosis, desquamating rash with prior
`thalidomide, prior exposure to lcnalidomide, chemotherapy s 2 weeks.
`nitrosourea 5; 6 weeks. monoclonal antibody 5 8 weeks, radioimmuno-
`conjugate S. 12 weeks, or external radiotherapy ‘5 3 weeks.
`Study Design
`MCI—001 (EMERGE; NCT00737529) was a global, multicenter, single-
`arrn. open-label phase 11 study of safety and efficacy of single-agent lenalido-
`mide in patients who had relapsed, progressed, or were refractory to
`bortezornib. Primary end points were ORR and DOR; secondary end points
`included safety, CWCRu. time to response (Till). time to progression (TIP).
`time to treatment failure t‘i‘l‘F), FPS, and US.
`lenalidornide 25 mg ([0 ing for Grill 2 3D to < 60 mlJmin) was
`self—administered orally on days i through 31 of each 28~day cycle until PD,
`intolerance, or voluntary withdrawal. Dosing was based on prior NHL studies
`(including MCI.) 15"" and approved closing in multiple myeloma.”
`Dose modificationiinterruption was planned in the event of grade 2 2
`allergic reaction or hypersensitivity; > 3X upper iim it ofnormal AST, ALT, or
`bilirubin; grade 1 or higher tumor lysis syndrome (TLS; by Cairo-Bishop
`grading system“); sustained grade 2 3 neutropenia for a 7 days or associated
`widt fever l3: 385°C): thrombocytopenia ( platelets < 50,000i'pL); constipae
`tion', desquamating (blistering) rash (or grade 4 nondesquamating rash); ve-
`nous thrombosisr‘embolism; new peripheral neuropathy. tumor flare reaction
`tTFR}; or lenalidomide-related nonhematologic AE. Allopurinol 300 mg per
`day or equivalent was recommended for TLS prophylaxis with oral hydration
`during the first 7 days of treatment (or as indicated). Patients at high-risk for
`developing a thromboembolic event (TEE; defined as a history of TEE and/or
`concomitant medication with increased risk andi‘or known hypercoaguiable
`state regardless of thromboembolic history) received prophylast (eg, aspirin
`70 to 100 mg per day, low-molecular—weight heparin [LMWHL or warfarin.
`per investigator). Growth factors were not administered as prophylaxis but
`were allowed to treat severe hematologic events. Concomitant anticancer
`therapy was prohibited, although physiologic doses of steroids (5 10 mg per
`day) not prescribed for MCL were permitted.
`Response and Safety Assessments
`Safety assessments included ABS, pregnancy tests for females of child-
`bearing age, second primary malignancies (SPMs), TLS. and TFR, hematol—
`ogy. serum chemistry, and other laboratory tests. CT scans were performed
`every two cycles ('1: 7 days) throughout treatment and every 90 days (1 14
`days) after stoppingienalldomide until progression or initiation ofsubsequenr
`antilymphoma therapy. Confirmatory bone marrow aspirate and unilateral
`biopsy was required within 28 days for patients achieving CR {by CT).
`Eflicacy analyses were performed in the intent-to-treat patient popular
`tion as defined in the protocol. Response data were evaluated by investigators
`and an independent review committee (ie, central review) per modified Inter-
`national Workshop Lymphoma Response Criteriaf'l‘lmz Central reviewers
`prospectively reviewed cfi'icacy data to provide an objective, unbiased inde—
`pendent review ofclinical outcomes blinded to institution information, demo-
`graphic
`information, and investigator assessments. Central
`reviewers
`consisted offour experts in radiology and hernatolofiWoncology. Two radiol-
`ogists first evaluated medical imaging data in a blinded independent radiology
`renew. with adjudication by at thlrd radiologist as needed, followed by an
`independent overall hematologistl'oncologist review of radiology results in
`conjunction with pertinent clinical data to determine response. Central re-
`viewers provtded the primary efficacy results for this study.
`
`Statistical Analyses
`Primary efficacy end points were evaluated following six cycles (1 1
`month) oflenalidotnide or on treatment discontinuation. Patients discontin-
`uing before achieving a response or who smtched to another therapy were
`considered nonresponders. Response rates were calculated with two-sided
`
`2
`
`.14 IL'RV'AL t rr CLENJI‘AL 0m moor
`Q 2013 iv An‘urrcae Rnr-cry of C-rvca: O“(‘ology
`Information dovvnloaded from jeoescopubsorg and provided by at Celgeno on September 4. 2013 from 216.118.82.254
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`Apotex EX. 1008, p. 12
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`Apotex Ex. 1008, p. 12
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`Lanalidomide in Helspsadii-‘lafractory MCL Pus‘lhartazomib (MEL-001]
`
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`52
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`Tlhla t. Patient Demographics, Basetln