I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US008404 717B2
`
`c12) United States Patent
`Zeldis
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,404,717 B2
`*Mar. 26, 2013
`
`(54) METHODS OF TREATING
`MYELODYSPLASTIC SYNDROMES USING
`LENALIDOMIDE
`Inventor: Jerome B. Zeldis, Princeton, NJ (US)
`
`(75)
`
`(73) Assignee: Celgene Corporation, Summit, NJ (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`Appl. No.: 13/070,761
`Mar. 24, 2011
`Filed:
`Prior Publication Data
`
`(21)
`(22)
`(65)
`
`US 2011/0172273 Al
`
`Jul. 14, 2011
`
`Related U.S. Application Data
`
`(60) Continuation of application No. 12/777,765, filed on
`May 11, 2010, which is a continuation-in-part of
`application No. 11/985,032, filed on Nov. 12, 2007,
`now Pat. No. 7,863,297, which is a continuation of
`application No. 11/654,550, filed on Jan. 16, 2007,
`
`(Continued)
`
`(51)
`
`Int. Cl.
`A61K 31147
`(2006.01)
`A61K 31/445
`(2006.01)
`(52) U.S. Cl. ........... 514/323; 514/58; 514/319; 514/327
`(58) Field of Classification Search .................. 514/323,
`514/58, 319, 327
`See application file for complete search history.
`
`(56)
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`(Continued)
`Primary Examiner - Michael G. Hartley
`Jagadishwar Samala
`Assistant Examiner -
`Jones Day
`(74) Attorney, Agent, or Firm -
`ABSTRACT
`(57)
`Methods of treating, preventing and/or managing myelodys(cid:173)
`plastic syndromes are disclosed. Specific methods encom(cid:173)
`pass the administrations of 3-( 4-amino-l-oxo-l ,3-dihydro(cid:173)
`isoindol-2-yl)-piperidin-2,6-dione
`in combination with
`5-azacytidine.
`
`10 Claims, No Drawings
`
`DR. REDDY’S LABS., INC. EX. 1001 PAGE 1
`
`

`

`US 8,404,717 B2
`Page 2
`
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`now Pat. No. 7,393,863, which is a division of appli(cid:173)
`cation No. 10/411,649, filedonApr. 11, 2003, now Pat.
`No. 7,189,740.
`
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`15, 2002.
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`

`

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`Kantarjian, H.M., Thalidomide as anti-angiogenesis therapy (rx) in
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`of Hematology, Dec. 3-7, 1999.
`Raza, A., Lisak, L., Andrews, C., Little, L., Muzannnil, M., Alvi, S.,
`Mazzoran, L., Zorat, F., Akber, A., Ekbal, M., Razvi, S., Venugopal,
`P., Thalidomide produces transfusion independence in patients with
`long-standing refractory anemias and myelodysplastic syndromes
`(MDS). Abstract #2935, Amer. Soc. of Hematology, Dec. 3-7, 1999.
`Raza, A., Lisak, L., Andrews, C., Little, L., Zorat, F., Shetty, V., Alvi,
`S., Mundie, S.,Allampallam, K., Durandt, M., Ekbal, M., Muzannnil,
`M., Encouraging improvement in cytopenias of patients with
`myelodysplastic syndromes (MDS) with thalidomide. Abstract# 111,
`Amer. Soc. of Clinical Oncology, May 20-23, 2000.
`Raza, A., Lisak, L., Little, L., Dean, L., Gezer, S., Venugopal, V.,
`Sununary and future direction of anti-tumor necrosis factor (TNF)
`therapies in myelodysplastic syndromes (MDS). Abstract #2700,
`American Society of Hematology, May 12-17, 2001.
`Mundie, S., Zorat, F., Shetty, V., Allampallam, K., Alvi, S., Lisak, L.,
`Little, L., Dean, L., Nascimben, F., Ekbal, M., Durandt, M.,
`in
`Broderick, E., Venugopal, P., Raza, A., Thalidomide
`myelodysplasia. Abstract #626, American Society of Hematology,
`Dec. 1-5, 2000.
`Raga, A., Lisak, L., Little, L., Ekbal, M., Durandt, M., Ali, E.,
`Nascimben, F., Tareen, M., Venugopal, P., Thalidomide as a single
`agent or in combination with topotecan, pentoxifylline and/or enbrel
`in myelodysplastic syndromes (MDS). Abstract #627, American
`Society of Hematology, Dec. 1-5, 2000.
`Estey, E., Albitar, M., Cortes, J., Giles, F., Thomas, D., Koller, C.,
`Beran, M., Kantarjian, H., Addition of thalidomide(T) to chemo(cid:173)
`therapy did not increase remission rate in poor prognosis AML/MDS.
`Abstract #1394, American Society of Hematology, Dec. 1-5, 2000.
`Alvi, S., Henderson, B., Shaher, A., Dangerfield, B., Broderick, E.,
`Jafri, N., Tareen, M., Durandt, M., Galili, N., Borok, R.Z., Raza, A.,
`Determination of clonality in stromal and parenchymal cells pre and
`post thalidomide treatment in myelodysplasia. Abstract #1536,
`American Society of Hematology, Dec. 1-5, 2000.
`Alvi, S., Shaher, A., Henderson, B., Dar, S., Zorat, F., Broderick E.,
`Lisak, L., Durandt, M., Reddy, P., Mundie, S., Galili, N, Borok, R.Z.,
`Raza, A., Improved growth of stromal cells in long term bone marrow
`cultures (LTBMC) of myelodysplastic syndrome (MDS) patients
`treated with thalidomide. Abstract #1547, American Society of
`Hematology, Dec. 1-5, 2000.
`Dourado, C. Mc., Seixas-Silva Jr., J.A., Besa, E.C., Response to
`thalidomide in 9 patients with myelodysplastic syndromes: A prom(cid:173)
`ising treatment for early or post-chemotherapy in late forms ofMDS.
`Abstract #4855, American Society of Hematology, Dec. 1-5, 2000.
`Lisak, L.A., Little, L., Dean, L., Ekbal, M., Durandt, M., Hussain, M.,
`Kaistha, V., Raza, A., Delayed responses to thalidomide in patients
`with myelodysplastic syndromes. Abstract #4861, American Society
`of Hematology, Dec. 1-5, 2000.
`Anders, 0., Plath, F., Emmrich, J., Freund, M., Complete remission
`of
`therapy-resistant
`angiodysplasia of
`the
`stomach
`in
`myelodysplastic syndrome following thalidomide. Abstract #3820,
`American Society of Hematology, Dec. 7-11, 2001.
`Alvi, S., Shaher, A., Shaikh, M., Anthwal, S., Siddiqi, F., Akhtar, A.,
`Ashraf, H., Meager, R., Mundie, S., Shetty, V., Goldberg, C., Galili,
`N., Borok, R.Z., Raza, A., MDS patients with hematological response
`to thalidomide show enhanced in vitro growth potential. Abstract
`#1482, American Society of Hematology, Dec. 7-11, 2001.
`Alvi, S., Shaikh, M., Anthwal, S., Shaher, A., Tamosevieiene, D.,
`Novick,A., Reddy, P.,Allampallam, K., Hsu, W.T., Galili, N., Borok,
`R.Z., Raza, A., Cytogenetic and clonal profile of myelodysplastic
`syndromes (MDS) patients treated with thalidomide. Abstract #1483,
`American Society of Hematology, Dec. 7-11, 2001.
`Alvi, S., Anthwal, S., Shaikh, M., Shaher, A., Shetty, V., Mundie, S.,
`Reddy P., Allampallam, K., Bi, S., Zorat, F., Tamosveiciene, D.,
`Rasila, K., Meagher, R., Westbrook, C., Galili, N., Gezer, S.,
`Venugopal, P., Borok, R.Z., Raza, A., Thalidomide significantly aug(cid:173)
`ments proliferation and cytokine secretion to bone marrow cultures
`established from myelodysplastic syndrome (MDS) patients.
`Abstract #1484, American Society of Hematology, Dec. 7-11, 2001.
`Baker, A.F., Bellamy, W.T., Glinsmann-Gibson, B.J., Heaton, R.,
`Buresh, A., Grogan, T.M., List, A.F., Biological response to
`
`thalidomide in remitting patients with myelodysplastic syndrome
`(MDS): Evidence for induction of neoplastic vascular endothelial
`growth factor (VEGF) resistance. Abstract #1490, American Society
`of Hematology, Dec. 7-11, 2001.
`Musto, P., Falcone, A., Bodenizza, C., Sanpaolo, G., Matera, R.,
`Bisceglia, M., Carella, A.M., Thalidomide (THAL) significantly
`improves anemia in selected transfusion-dependent patients with
`myelodysplastic syndromes (MDS): relationship to serum and mar(cid:173)
`row levels of angiogenetic growth factors (AGF). Abstract #2606,
`American Society of Hematology, Dec. 7-11, 2001.
`Fabbri, A., Biscardi, M., Innocenti, F., Balestri, G., Gavazzi, S.,
`Bellesi, G., Grossi, A., Thalidomide in combination withAmifostine
`in the treatment of MDS: evaluation of clinical and laboratory find(cid:173)
`ings. Abstract #4819, American Society of Hematology, Dec. 7-11,
`2001.
`Raza, A., Lisak, L., Dutt, D., Dean, L., Fantroy, L., Ali, E., Gezer, S.,
`Hsu, W-T., Goldberg, C., Loew, J., Venugopal, P., Combination of
`thalidomide with pentoxifylline, ciprofloxacin, and dexamethasone
`(PCD) in patients with myelodysplastic syndromes (MDS). Abstract
`#4830, American Society of Hematology, Dec. 7-11, 2001.
`Raza, A., Dutt, D., Lisak, L., Dean, L., Fantroy, L., Gezer, S., Ali, E.,
`Goldberg, C., Loew, J., Hsu, W-T., Venugopal, P., Combination of
`thalidomide and enbrel for
`the
`treatment of patients with
`myelodysplastic syndromes (MDS). Abstract #4831. American Soci(cid:173)
`ety of Hematology, Dec. 7-11, 2001.
`Shetty, V., Allampallam, K., Hussaini, S., Townsend, W., Dutt, D.,
`Mundie, S., Alvi, S., Reddy, P.L., Ashraf, H., Galili, N., Saberwal,
`G.S., Anthwal, S., Shaikh, M.W., Heidelberg, A., Lisak, L., Gezer, S.,
`Venugopal, P., Raza, A., Effects ofanti-cytokine agents on apoptosis,
`proliferation, monocyte/macrophage number, microvessel density
`and cytokines following two successive clinical trials in 57 patients
`with myelodysplastic syndromes (MDS). Abstract #4837. American
`SocietyofHematology, Dec. 7-11, 2001.
`Barlogie, B., Desikan, R., Munshi, N., Siegel, D., Mehta, J., Singha!,
`S., Anaissie, E., Single Course D.T. Pace Anti-Angiochemotherapy
`Effects CR in Plasma Cell Leukemia and Fulminant Multiple
`Myeloma (MM). Abstract #4180. American Society of Hematology,
`Dec. 4-9, 1998.
`Hideshima, T., Chauhan, D., Shima, Y., Noopur, R., Davies, F.E., Tai,
`Y., Treon, S.P., Lin, B.K., Schlossman, R.L., Richardson, P.G.,
`Gupta, D., Muller, G.W., Stirling, D.I., Anderson, K.C., Thalidome
`(THAL) and its Analogs Overcome Drug Resistance of Human Mul(cid:173)
`tiple Myeloma (MM) Cells to Conventional Therapy. Abstract# 1313.
`American Society of Hematology, Dec. 1-5, 2000.
`Payvandi, F., Wu, L., Gupta, D., Hideshima, T., Haley, M., Muller, G.,
`Chen, R., Anderson, K.C., Stirling, D., Effects of a Thalidomide
`Analog on Binding Activity of Transcription Factors and Cell Cycle
`Progression of Multiple Myeloma Cell Lines. Abstract #2487.
`American Society of Hematology, Dec. 1-5, 2000.
`Davies, F.E., Raje, N., Hideshima, T., Lentzsch, S., Young, G., Tai, Y.,
`Lin, B.K., Podar, K., Chauhan, D., Treon, S.P., Gupta, D., Mitsiades,
`C., Mitsiades, N., Hayashi, T., Richardson, P.G., Schlossman, R.L.,
`Muller, G.W., Stirling, D. I., Anderson, K.C., Thalidomide (THAL)
`and Immunomodulatory Derivatives (IMiDS) Augment Natural
`Killer (NK) Cell Cytotocixity in Multiple Myeloma (MM). Abstract
`#3617. American Society of Hematology, Dec. 1-5, 2000.
`Hideshima, T., Chauhan, D., Castro, A., Hayashi, T., Mitsiades, C.,
`Mitsiades, N., Akiyama, M., Richardson, P.G., Schlossman, R.L.,
`Adams, J., Anderson, K.C., NF-KB as a Therapeutic Target in Mul(cid:173)
`tiple Myeloma (MM). Abstract #1581. American Society of Hema(cid:173)
`tology, Dec. 7-11, 2001.
`Lentsch, S., Rogers, M., Leblanc, R., Birsner, A., Shah, J., Anderson
`K., D' Amato R., 3-Amino-Phthalimido-Glutarimide (S-3APG)
`Inhibits Angiogenesis and Growth in Drug Resistant Multiple
`Myeloma (MM) in vivo. Abstract# 1976, American Society of Hema(cid:173)
`tology, Dec. 7-11, 2001.
`Park, Y., Kim, S.A., Kim, C.J., Chung, J.H., Mechanism of the Effect
`of Thalidomide on Human Multiple Myeloma Cells. Abstract #2685.
`American Society of Clinical Oncology, May 12-17, 2001.
`Payvandi, F., Wu, L., Haley M., Gupta, D., Zhang, L., Schafer, P.,
`Muller, G.W., Chen, R., Anderson, K.C., Stirling, D., Thalidomide
`Analogs IMiDS Inhibit Expression ofCyclooxygenase-2 in Multiple
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`DR. REDDY’S LABS., INC. EX. 1001 PAGE 4
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`

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`American Society of Hematology, Dec. 7-11, 2001.
`Mitsiades, N., Mitsiades, C., Poulaki, V., Akiyama, M., Tai, Y., Lin,
`B., Hayashi, T., Catley, L., Hideshima, T., Chauhan, D., Treon, S.P.,
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`tory Thalidomide Analogs (Imids) in Human Multiple Myeloma
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`Richardson, P.G., Schlossman, R.L., Hideshima, T., Davies, F.,
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`Phase 1 Study of Oral CC5013, an Immunomodulatory Thalidomide
`(Thal) Derivative, in Patients With Relapsed and Refractory Multiple
`Myeloma (MM). Abstract #3225. American Society of Hematology,
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`Zangari, M. Tricot, G., Zeldis, J., Eddlemon, P., Saghafifar, F ..
`Barlogie, B., Results of Phase 1 Study of CC5013, for the Treatment
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