Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-11-29
2001-10-30
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S070100, C435S071100, C435S471000, C435S455000, C435S325000, C435S252300, C435S320100, C536S023100, C536S023500, C536S024310
Reexamination Certificate
active
06309860
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced in parentheses. Full citations for these publications may be found listed at the end of the specification. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein.
Recurrent chromosomal translocations recognized in the majority of lymphomas provide clues to mechanisms of lymphomagenesis. Immunoglobulin genes undergo specific rearrangements during differentiation of lymphoid cells and, errors in recombination lead to chromosome translocation and neoplastic transformation (Chaganti, R. S. K., 1991; Rabbits, T. H., 1994). Diffuse large cell lymphomas (DLCL) make up approximately 50% of non-Hodgkin lymphomas (Simon, R., et al., 1988) and show significant variability in terms of their pathologic manifestation, response to therapy and prognosis (Magrath, I., 1989). DLCL are also highly heterogeneous with respect to karyotypic abnormalities as well as underlying molecular lesions. So far, three genes have been identified whose normal pattern of expression is altered by a specific chromosomal translocation in DLCL, namely, MYC, BCL2 and BCL6, occurring in approximately 10%, 20% and 25% of DLCL respectively, as detected by either cytogenetic or molecular methods (Chaganti, R. S. K., et al., 1991; Rabbits, T. H., 1994; Ladanyi, M., 1991; Offit, K., 1991; Offit, K., 1994). The remaining DLCL exhibit a number of small subsets each characterized by a specific site of recurrent chromosomal rearrangement. The molecular genetic analysis of these sites can contribute significantly to our understanding of the mechanisms of B-cell lymphomagenesis.
One of the recurrent sites of rearrangement seen in 3-4% of DLCL cases is 15q11-13. A notable feature of this site is promiscuity of rearrangement. In addition to translocations involving the immunoglobulin gene sites 14q32 and 22q11, it exhibits translocations with multiple other sites, such as 9p13, 1p32, 7p13, 12q24 and 15q22. Translocations involving 15q11-13 have also been noted in non-lymphoid tumors (Mittelman, F., 1994). The 15q11-13 region has been implicated in genomic imprinting and contains putative genes for human imprinting related disorders such as Prader-Willi and Angelman syndromes. Another unusual feature of the region is the presence of orphan, presumably non-functional, copies of V and D segments of the immunoglobulin heavy chain gene (Tomlinson, I. M., et al., 1994; Wintle, R. F., 1994). The cloning of the t(14:15)(q32;q11-13) breakpoint from a DLCL case and the isolation of a new gene, here named, bcl-8 located at 15q11-13 and potentially involved in the pathogenesis of DLCL is reported.
SUMMARY OF THE INVENTION
This invention provides an isolated nucleic acid which encodes bcl-8.
This invention also provides a vector which includes the isolated nucleic acid which encodes bcl-8 and a host vector system which includes the vector.
This invention also provides a method of producing a polypeptide which comprises growing such a host vector system under suitable conditions permitting the production of the polypeptide and recovering the polypeptide so produced. This invention further provides a method of obtaining purified BCL-8.
This invention further provides the polypeptide encoded by the above-described isolated nucleic acid. Specifically, the invention provides purified BCL-8. In a specific embodiment, the purified BCL-8 is human BCL-8.
This invention also provides an antibody capable of specifically recognizing a polypeptide encoded by bcl-8. This antibody specifically recognizes human BCL-8.
This invention also provides an oligonucleotide of at least 15 nucleotides capable of specifically hybridizing with a sequence of nucleotides within a nucleic acid which encodes bcl-8. This invention also provides an isolated nucleic acid which includes the above-described oligonucleotide.
This invention provides an agent capable of blocking the expression of BCL-8.
This invention provides various methods of determining whether a subject is afflicted with diffuse large cell lymphoma.
This invention also provides various methods of determining whether a subject has a predisposition for diffuse large cell lymphoma.
This invention also provides various methods of treating a subject afflicted with diffuse large cell lymphoma.
This invention also provides various methods of preventing diffuse large cell lymphoma.
This invention also provides various pharmaceutical compositions that prevent diffuse large cell lymphoma in combination with a pharmaceutically acceptable carrier.
Further, this invention also provides various pharmaceutical compositions that treat diffuse large cell lymphoma in combination with a pharmaceutically acceptable carrier.
REFERENCES:
patent: 94/29343 (1994-12-01), None
Clontech Catalog. p. 214, 1993/1994.*
Hillier et al. Jul. 1995. GenBank Accession No. H20348.*
Chaganti, R.S.K., “New Insights into the genetics on non-Hodgkin's Lymphoma”,Int. Proc. J. 5:34-41 (1998). (Exhibit 2).
Chaganti, S.R. et al., “Involvement of BCL6 in Chromosomal Aberrations Affecting Band 3q27 in B-Cell Non-Hodgin Lymphoma”,Genes, Chromosomes&Cancer23: 323-327 (1998). (Exhibit 3).
Cigudosa, J.C., et al., “Cytogenetic Analysis of 363 Consecutively Ascertained Diffuse Large B-Cell Lymphomas”,Genes, Chromosomes&Cancer25:123-133 (1999). (Exhibit 4).
Dyomin V.G. et al. Cloning of the BCL8 gene involved in chromosomal translocations affecting band 15q11-13 in diffuse large-cell lymphomas.Blood. Dec. 1996, 10: 632A, Abstract 2518. (Exhibit 5).
Dyomin, V.G., et al., “BCL8, a novel gene involved in translocations affecting band 15q11-13 in diffuse large-cell lymphoma”,Proc. Natl. Acad. Sci. USA94: 5728-5732 (1997). (Exhibit 6).
Iida, S. et al., “Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma”Nature Genetics17:226-229 (1997). (Exhibit 7).
Levine E.G. et al. “Four new recurring translocations in non-Hodgkin lymphoma.”Blood. Oct. 1989, vol. 74(5) : 1796-1800, see entire document. (Exhibit 8).
Rao, P.H. et al., “Chromosomal and Gene Amplification in Diffuse Large B-Cell Lymphoma”,Blood92: 234-240 (1998). (Exhibit 9).
Chaganti Raju S. K.
Dalla-Favera Riccardo
Dyomin Vadim
Cooper & Dunham LLP
Myers Carla J.
The Trustees of Columbia University in the City of New York
White John P.
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