I 1111111111111111 11111 1111111111 11111 11111 11111 1111111111 111111111111111111
`US007189740B2
`
`c12) United States Patent
`Zeldis
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,189,740 B2
`*Mar.13,2007
`
`(54) METHODS OF USING
`3-( 4-AMINO-OXO-1,3-DIHYDRO-ISOINDOL-
`2-YL)-PIPERIDINE-2,6-DIONE FOR THE
`TREATMENT AND MANAGEMENT OF
`MYELODYSPLASTIC SYNDROMES
`
`(75)
`
`Inventor: Jerome B. Zeldis, Princeton, NJ (US)
`
`(73) Assignee: Celgene Corporation, Summit, NJ
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`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.
`
`(21) Appl. No.: 10/411,649
`
`(22) Filed:
`
`Apr. 11, 2003
`
`(65)
`
`Prior Publication Data
`
`US 2004/0220144 Al
`
`Nov. 4, 2004
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/418,468, filed on Oct.
`15, 2002.
`
`(51)
`
`Int. Cl.
`A61K 31147
`(2006.01)
`A61K 311445
`(2006.01)
`(52) U.S. Cl. ......................... 514/323; 514/319; 514/58
`(58) Field of Classification Search ................ 514/323,
`514/58, 319
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`(Continued)
`
`Primary Examiner-Vickie Kim
`(74) Attorney, Agent, or Firm-Jones Day
`
`(57)
`
`ABSTRACT
`
`Methods of treating, preventing and/or managing myclod(cid:173)
`ysplastic syndromes are disclosed. Specific methods encom(cid:173)
`pass the administration of an immunomodulatory com(cid:173)
`pound, or a pharmaceutically acceptable salt, solvate,
`hydrate, stereoisomer, clathrate, or prodrug thereof, alone or
`in combination with a second active ingredient, and/or the
`transplantation of blood or cells. Specific second active
`ingredients are capable of affecting or blood cell production.
`Pharmaceutical compositions, single unit dosage forms, and
`kits suitable for use in methods of the invention are also
`disclosed.
`
`34 Claims, No Drawings CELGENE 2033
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`US 7,189,740 B2
`Page 2
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`agent of 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 didn 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 Soci(cid:173)
`ety 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 of
`MDS. 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, Ameri(cid:173)
`can 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., Shikh, 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., Tamoseviciene, 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
`augments 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.I., Heaton, R.,
`Buresh, A., Grogan, T.M., List, A.F., Bilogical 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 combinationa with
`Amifostine in the treatment of MDS: evalution of clinical and
`laboratory findings. Abstract #4819, American Society of Hematol(cid:173)
`ogy, 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
`Society 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 of anti-cytokine agents on
`apoptosis, proliferation, monobyte/macrophage number, microves(cid:173)
`sel density and cytokines following two seccessive clinical trials in
`57 patients with myelodysplastic syndromes (MDS). Abstract
`#4837. American Society of Hematology, Dec. 7-11, 2001.
`Barlogie, B., Desikan, R., Munshi, N., Siegel, D., Mehta, J.,
`Singha!, S., Anaissie, E., Single Course D.T. Pace Anti(cid:173)
`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
`Multiple 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., Schloss(cid:173)
`man, 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
`Multiple Myeloma (MM). Abstract #1581. American Society of
`Hematology, 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
`Hematology, 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 of Cyclooxygenase-2 in Mul(cid:173)
`tiple Myeloma Cell Line and LPS Stimulated PBMCs. Abstract
`#2689. American Society of Hematology, Dec. 7-11, 2001.
`
`

`

`US 7,189,740 B2
`Page 5
`
`Mitsiades, N., Mitsiades, C., Poulaki, V., Akiyama, M., Tai, Y., Lin,
`B., Hayashi, T., Catley, L., Hideshima, T., Chauhan, D., Treon, S.P.,
`Anderson, K.C., Apoptotic Signaling Induced By Immunomodula(cid:173)
`tory Thalidomide Analogs (Imids) in Human Multiple Myelorna
`Cells; Therapeutic Implications. Abstract #3224. American Society
`of Hematology, Dec. 7-11, 2001.
`Richardson, P.G., Schlossman, R.L., Hideshirna, T., Davies, F.,
`Leblanc, R., Catley, L., Doss, D., Kelly, K.A., McKenney, M.,
`Mechlowicz, J., Freeman, A., Deocampo, R., Rich, R., Ryoo, J.,
`Chauhan, D., Munshi, N., Weller, E., Zeldis, J., Anderson, K.C., A
`Phase I Study of Oral CC5013, an Immunomodulatory Thalidomide
`
`(THAL) Derivative, in Patients with Relapsed and Refractory
`Multiple Myeloma (MM). Abstract #3225. American Society of
`Hematology, Dec. 7-11, 2001.
`Zangari, M. Tricot, G., Zeldis, J., Eddlemon, P., Saghafifar, F.,
`Barlogie, B., Results of Phase 1 Study of CC5013, for the Treatment
`of Multiple Myeloma (MM) Patients Who Replase After High Dose
`Chemotherapy (HDCT). Abstract #3226. American Society of
`Hematology, Dec. 7-11, 2001.
`
`* cited by examiner
`
`

`

`US 7,189,740 B2
`
`1
`METHODS OF USING
`3-(4-AMINO-OXO-1,3-DIHYDRO-ISOINDOL-
`2-YL)-PIPERIDINE-2,6-DIONE FOR THE
`TREATMENT AND MANAGEMENT OF
`MYELODYSPLASTIC SYNDROMES
`
`This application claims priority to U.S. Provisional Patent
`Application No. 60/418,468 filed on Oct. 15, 2002, the
`entirety of which is incorporated herein by reference.
`
`1. FIELD OF THE INVENTION
`
`10
`
`2
`There are two subgroups of refractory anemia character(cid:173)
`ized by five percent or less myeloblasts in bone marrow: (1)
`refractory anemia (RA) and; (2) RA with ringed sideroblasts
`(RARS), defined morphologically as having 15% erythroid
`5 cells with abnormal ringed sideroblasts, reflecting an abnor(cid:173)
`mal iron accumulation in the mitochondria. Both have a
`prolonged clinical course and low incidence of progression
`to acute leukemia. Besa E. C., Med. Clin. North Am. 1992
`May, 76(3): 599-617.
`There are two subgroups of refractory anemias with
`greater than five percent mycloblasts: (1) RA with excess
`blasts (RAEB), defined as 6-20% myeloblasts, and (2)
`RAEB in transformation (RAEB-T), with 21-30% myelo(cid:173)
`blasts. The higher the percentage of myeloblasts, the shorter
`15 the clinical course and the closer the disease is to acute
`myelogenous leukemia. Patient transition from early to more
`advanced stages indicates that these subtypes are merely
`stages of disease rather than distinct entities. Elderly patients
`with MDS with trilineage dysplasia and greater than 30%
`myeloblasts who progress to acute leukemia are often con(cid:173)
`sidered to have a poor prognosis because their response rate
`to chemotherapy is lower than de nova acute myeloid
`leukemia patients. The World Health Organization (WHO)
`classification (1999) proposes to include all cases ofRAEB-
`25 T, or patients with greater than 20% myeloblasts, in the
`category of acute leukemia because these patients have
`similar prognostic outcomes. However, their response to
`therapy is worse than the de nova or more typical acute
`myelogenous leukemia or acute nonlymphocytic leukemia
`30 (ANLL) patient. Id.
`The fifth type of MDS, the most difficult to classify, is
`called chronic myclomonocytic leukemia (CMML). This
`subtype can have any percentage of myeloblasts but presents
`with a monocytosis of 1000/dL or more. It may be associated
`35 with splenomegaly. This subtype overlaps with a myelopro(cid:173)
`liferative disorder and may have an intermediate clinical
`course. It is differentiated from the classic chronic myelo(cid:173)
`cytic leukemia (CML) that is characterized by a negative Ph
`chromosome. The recent WHO classification (1999) pro-
`40 poses that juvenile and proliferative CMML be listed sepa(cid:173)
`rately from FAB under MDS/myeloproliferative disorder
`(MPD) with splenomegaly and greater than 13,000 total
`WBC. CMML is limited to monocytosis, less than 13,000/
`mm3 total leukocytes, and requires trilineage dysplasia. Id.
`45 Harris N. L., et al., J. Clin. Oneal. 1999 December, 17(12)