Abstract: Modified erythropoietin (EPO) polypeptides and other modified therapeutic polypeptides are provided. The EPO polypeptides and other therapeutic polypeptides are modified to exhibit physical properties and activities that differ from the unmodified EPO polypeptides and other unmodified therapeutic polypeptides, respectively. Nucleic acid molecules encoding these polypeptides also are provided. Also provided are methods of treatment and diagnosis using the polypeptides.

Abstract: The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.

Abstract: The present invention relates to nucleic acid molecules comprising a nucleic acid sequence coding for the ?- and the ?-chain of the human follicle stimulating hormone (FSH), respectively, which has been modified with respect to the codon usage in CHO cells. The present invention further relates to a recombinant nucleic acid molecule comprising such nucleic acid sequences and host cells containing such recombinant nucleic acid molecules, as well as their use in the production of recombinant human FSH. Finally, the present invention also relates to a method for producing host cells expressing human follicle stimulating hormone by transfecting cells in suspension culture under serum-free conditions with the recombinant nucleic acid molecule of the present invention.

Abstract: This invention relates to the field of glycoprotein hormone analogs and their uses as agonists, antagonists, targeting vectors, and immunogens. In particular, this invention describes a method for stabilizing a heterodimer that permits the preparation of functional glycoprotein hormone analogs. The analogs of present invention comprise at least one alpha subunit polypeptide and at least one beta subunit polypeptide, wherein the seatbelt region of the beta subunit is linked to the alpha subunit. The invention also provides for a beta subunit polypeptide wherein the C-terminal amino acid is from residue 10 to residue 20 of the seatbelt region.

Abstract: The present invention involves the identification and preparation of vascular endothelial growth factor-E (VEGF-E). VEGF-E is a novel polypeptide related to vascular endothelial growth factor (VEGF) and bone morphogenetic protein 1. VEGF-E has homology to VEGF including conservation of the amino acids required for activity of VEGF. VEGF-E can be useful in wound repair, as well as in the generation and regeneration of tissue.

Abstract: The invention concerns human thrombopoietin and in particular modified forms of thrombopoietin (TPO) with improved properties. The improved proteins contain amino acid substitutions at specific positions within the TPO molecule. The invention provides modified TPO molecules, preferably fusion proteins comprising immunoglobulin constant regions and modified human TPO, with improved biological activity concomitant with reduced immunogenic potential in the protein. The improved proteins are intended for therapeutic use in the treatment of diseases in humans.

Abstract: Culture media comprising manganese and methods of culturing cells to improve sialylation and glycosylation of glycoproteins are provided.

Abstract: The invention relates to novel neurogenin proteins, nucleic acids and antibodies.

Abstract: The present invention provides a method and system for producing a NELL protein. The method and system comprise a CELL encoding a NELL protein or peptide and a non-insect secretory signal peptide.

Abstract: The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.

Abstract: We provide a Chinese Hamster Ovary (CHO) cell which is capable of higher protein sialylation compared to a wild type Chinese Hamster Ovary cell, such as in the presence of functional GnT 1, in which the CHO cell is obtainable by selection with Ricinus communis agglutinin I (RCA-I).

Abstract: Novel compositions and methods for the high efficiency production of the transforming growth factor-beta (TGF?) supergene family of peptide growth factors are provided.

Abstract: FSH mutant with increased glycosylation and longer half-life is described. The use of this FSH mutant for inducing folliculogenesis in human patients is also described.

Abstract: The present invention relates to antibody molecules, in particular antibody molecules that bind Transforming Growth Factor beta (TGF?), and uses thereof. More particularly, the invention relates to antibody molecules that bind and preferably neutralise TGF?1, TGF?2 and TGF?3, so-called “pan-specific” antibody molecules, and uses of such antibody molecules. Preferred embodiments within the present invention are antibody molecules, whether whole antibody (e.g. IgG, such as IgG1 or IgG4) or antibody fragments (e.g. scFv, Fab, dAb).

Abstract: Disclosed are compositions and methods for increasing the longevity of a cell culture and permitting the increased production of proteins, preferably recombinant proteins, such as antibodies, peptides, enzymes, growth factors, interleukins, interferons, hormones, and vaccines. Cells transfected with an apoptosis-inhibiting gene or vector, such as a triple mutant Bcl-2 gene, can survive longer in culture, resulting in extension of the state and yield of protein biosynthesis. Such transfected cells exhibit maximal cell densities that equal or exceed the maximal density achieved by the parent cell lines. Transfected cells can also be pre-adapted for growth in serum-free medium, greatly decreasing the time required to obtain protein production in serum-free medium. In certain methods, the pre-adapted cells can be used for protein production following transformation under serum-free conditions. The method preferably involves eukaryotic cells, more preferably mammalian cells.

Abstract: The present invention relates to primary cultured adipocytes for gene therapy, where the adipocytes stably maintain a foreign gene encoding a protein that is secreted outside of cells. This invention provides cells suitable for gene therapy, which can replace bone marrow cells and liver cells used for conventional ex vivo gene therapy. The present invention established methods for transferring foreign genes into primary cultured adipocytes, which are suitable for ex vivo gene therapy; can be easily collected and implanted; and can be removed after implantation. Specifically, the present invention established these methods that use retroviral vectors. The present invention also established primary cultured adipocytes for gene therapy, where the adipocytes stably maintain a foreign gene encoding a protein that is secreted outside of cells.

Abstract: The invention provides FGFR fusion proteins, methods of making them, and methods of using them to treat proliferative disorders, including cancers and disorders of angiogenesis. The FGFR fusion molecules can be made in CHO cells and may comprise deletion mutations in the extracellular domains of the FGFRs which improve their stability. These fusion proteins inhibit the growth and viability of cancer cells in vitro and in vivo. The combination of the relatively high affinity of these receptors for their ligand FGFs and the demonstrated ability of these decoy receptors to inhibit tumor growth is an indication of the clinical value of the compositions and methods provided herein.

Abstract: A novel FSH mutant with increased glycosylation and longer half-lifes for use in inducing folliculogenesis in human patients is described. The FSH mutant permits the use of lower cumulative doses of FSH to achieve the same or better clinical result.

Abstract: Methods of preparing a NELL peptide are disclosed.

Abstract: A polypeptide and polynucleotides encoding same comprising one carboxy-terminal peptide (CTP) of chorionic gonadotrophin attached to an amino terminus of a cytokine and two carboxy-terminal peptides (CTP) of chorionic gonadotrophin attached to a carboxy terminus of a cytokine are disclosed. Pharmaceutical compositions comprising the polypeptide and polynucleotides of the invention and methods of using same are also disclosed.

Abstract: The present invention relates to epidermal growth factor (EGF) producing lactic acid bacteria and their use to increase intestinal villi height and to promote gut absorption. In particular, the invention relates to EGF producing Lactococcus lactis and Lactobacillus casei. The organisms may be especially useful to treat Short Bowel Syndrome.

Abstract: The present invention is in the field of the manufacture of recombinant proteins. More specifically, it relates to the use of a serum-free culture medium comprising an antioxidant for the production of recombinant dimeric gonadotropins. The antioxidant may be selected from the group consisting of L-glutathione, 2-mercaptoethanol, L-methionine and a combination of ascorbic acid and of (+)-alpha-tocoplierol.

Abstract: The present invention relates to a method for improving homogeneity and/or secretion of a recombinant protein of interest expressed in mammalian cells by replacing the endogenous signal peptide sequence of the DNA encoding the protein of interest with that of human hGH. Specifically, the present invention relates to a method wherein the protein of interest is a subunit of the follicle stimulating hormone (FSH). The invention also relates to DNA expression vectors containing the sequence encoding such proteins of interest fused to the signal peptide sequence of the hGH and to cells harbouring such vectors.

Abstract: The invention provides improved methods of recombinant protein production in cell culture. More specifically, the invention relates to the modulation of the IGF-1 signaling pathway in cells so as to improve production characteristics.

Abstract: The invention provides cells that produce increased levels of recombinant protein by modulating the activity of translational regulator gene products that are downstream targets of PKB alpha, methods of making such cells, and methods of using such cells. Such translational regulator gene products include 4E-BP1 and mTOR.

Abstract: The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Abstract: Novel fusion polypeptide ligands that bind Eph family receptors or the Tie-2 receptor are identified, and methods for making the fusion polypeptide ligands in biologically active form are described. Nucleic acids encoding these novel fusion polypeptide ligands enable production of the fusion polypeptide ligands. The method of making the nucleic acids and the fusion polypeptide ligands is broadly applicable to the production of polypeptide ligands in general, resulting in improved affinity and/or increased activity of the ligand when compared to its native form.

Abstract: The present invention is a recombinant vector encoding and expressing at least three or more costimulatory molecules. The recombinant vector may additionally contain a gene encoding one or more target antigens or immunological epitope thereof. The synergistic effect of them costimulatory molecules on the enhanced activation of T cells is demonstrated. The degree of T-cell activation using recombinant vectors containing genes encoding three costimulatory molecules was far greater than the sum of recombinant vector constructs containing one costimulatory molecule and greater that the use of two costimulatory molecules. Results employing the triple costimulatory vectors were most dramatic under conditions of either low levels of first signal or low stimulator to T-cell ratios. This phenomenon was observed with both isolated CD4+and CD8+T cells.

Abstract: The invention provides improved methods of recombinant protein production in cell culture. More specifically, the invention relates to the modulation of the IGF-1 signaling pathway in cells so as to improve production characteristics.

Abstract: Methods of production of desired recombinant proteins, polypeptides and peptides are disclosed which utilize mammalian host cells engineered for autonomous and regulated growth in low cost protein/serum-free culture media. Preferred host cells express insulin or an insulin-like growth factor, and/or transferrin and are engineered so that addition of an inducer (e.g., ZnCl2+CdCl2) halts growth and simultaneously induces the expression of the desired recombinant protein, polypeptide or peptide.

Abstract: The present invention relates to methods of production of the completely post-translationally modified protein by combination of cell-free protein synthesis and cell-free co- and post-translational modification. Previous cell-free protein synthesis system has only been capable of producing partially post-translationally modified protein but the present invention employs a co- and post-translational modification machinery that produces completely post-translationally modified protein.

Abstract: The gene coding for human erythropoietin (EPO) was obtained from human genomic DNA. Thc gene used does not include sequences from regions at i 5′ of the first translated ATG and ii 3′ of the stop codon of the EPO gene. The gene was cloned into an expression plasmid for eukaryotic cells that have as sole expression control elements the early promoter of the SV40 virus and its polyadenylation signal. Recombinant cells resulting from transfection with genetic constructs used provide an unexpectedly high level of protein expression of 50 mg of recombinant EPO per liter of culture medium per day.

Abstract: The present invention is directed to therapeutic methods that are based upon an ability to modulate cellular contraction. This is accomplished by administering agents that either inhibit or induce the activity of alpha-smooth muscle actin.

Abstract: Glycosylated or nonglycosylated proteins of the formula FSH&bgr;-(linker1)n1-LH&bgr;(1-X)-(linker2)n2-&agr; wherein FSH&bgr; is a vertebrate follicle stimulating hormone &bgr; subunit or a variant thereof; LH&bgr;(1-X) refer's to a &bgr; subunit of a vertebrate luteinizing hormone containing positions 1-X where X is an integer of 114-121 or a variant thereof; each “linker” is a hydrophilic, flexible amino acid sequence containing 1-100 amino acid residues; each n is a 0 or 1; and &agr; is the &agr; subunit of a vertebrate glycoprotein hormone or a variant thereof are useful in protocols to enhance fertility in humans and in animals.

Abstract: The present invention relates to transfected primary and secondary somatic cells of vertebrate origin, particularly mammalian origin, transfected with exogenous genetic material (DNA) that encodes erythropoietin or an insulinotropin (e.g., derivatives of glucagon-like peptide 1 (GLP-1)), methods by which primary and secondary cells are transfected to include exogenous genetic material encoding erythropoietin or an insulinotropin, methods of producing clonal cell strains or heterogenous cell strains that express erythropoietin or an insulinotropin, methods of gene therapy, in which the transfected primary or secondary cells are used, and methods of producing antibodies using the transfected primary or secondary cells.

Abstract: Compositions and methods for reducing ocular diseases by implanting in an eye of a subject a composition comprising encapsulated cells which produce polypeptides, more particularly polypeptides that exhibit neurotrophic and/or anti-angiogenic activity. The encapsulation prevents the entry of host immune cells in the microcapsule while permitting the release of the polypeptide outside of the microcapsule.

Abstract: The present invention is to methods of obtaining plant-derived compositions that inhibit apoptosis, the compositions obtained thereby, compositions comprising the composition, and methods of use thereof.

Abstract: The present invention involves the identification and preparation of vascular endothelial growth factor-E (VEGF-E). VEGF-E is a novel polypeptide related to vascular endothelial growth factor (VEGF) and bone morphogenetic protein 1. VEGF-E has homology to VEGF including conservation of the amino acids required for activity of VEGF. VEGF-E can be useful in wound repair, as well as in the generation and regeneration of tissue.

Abstract: Compositions and methods for reducing ocular diseases by implanting in an eye of a subject a composition comprising encapsulated cells which produce polypeptides, more particularly polypeptides that exhibit neurotrophic and/or anti-angiogenic activity. The encapsulation prevents the entry of host immune cells in the microcapsule while permitting the release of the polypeptide outside of the microcapsule.

Abstract: Described herein are vascular endothelial cell growth factor (VEGF) variants having modifications in the C-terminus heparin binding domain. The variants exhibit reduced clearance rates for systemic administration generally at lower doses compared with native VEGF thus providing variants having longer availability for therapeutic effect.

Abstract: The present invention provides a biologically active substance secreting hybrid gel, which consists essentially of a biopolymeric gel and cells containing an expression vector with a gene encoding the biologically active substance to produce the substance. According to the present invention, it is possible to develop a gene therapy by skin transplantation allowing stable drug medication for a long time; alleviating pains of patients; and allowing fine adjustment of the dosage and control of genes externally without using retrovirusderived vector that tend to invoke the risk of mutation to wild types as in the conventional prescription.

Abstract: The use of professional antigen presenting cells genetically modified to enhance expression of an immunostimulatory cytokine is disclosed for the treatment of individuals having tumors or infections. The genetically modified professional antigen presenting cells are injected directly at or near the site of the tumor or infection. Preferred professional antigen presenting cells include dendritic cells, and preferred immunostimulatory cytokines include interleukins such as IL-12.

Abstract: The invention is directed to purified and isolated novel ULBP polypeptides, the nucleic acids encoding such polypeptides, processes for production of recombinant forms of such polypeptides, antibodies generated against these polypeptides, fragmented peptides derived from these polypeptides, and the uses of the above. ULBP polypeptide can be found on the surface of human B cell lymphomas. Mammalian forms of ULBP polypeptide in isolated or purified forms are provided. In addition, isolated nucleic acids encoding ULBP polypeptides and expression vectors comprising a cDNA encoding ULBP polypeptides are provided. The ULBP polypeptides can be isolated or synthesized and used to prepare antibodies, and in particular monoclonal antibodies, against the polypeptides. The antibodies, in turn, are useful for detecting the presence of ULBP polypeptides in human cell samples, which can be correlated with the existence of a malignant condition in a patient.

Abstract: The present invention involves the identification and preparation of vascular endothelial growth factor-E (VEGF-E). VEGF-E is a novel polypeptide related to vascular endothelial growth factor (VEGF) and bone morphogenetic protein 1. VEGF-E has homology to VEGF including conservation of the amino acids required for activity of VEGF. VEGF-E can be useful in wound repair, as well as in the generation and regeneration of tissue.

Abstract: The present invention provides a method of screening for a compound that binds to a selected nuclei acid comprising contacting compound fluorescently labeled by a fluorescent protein with a cell having a plurality of copies of the nucleic acid in an array such that the nuclei acid can be directly detected when bound by fluorescently labeled compound; and directly detecting the location of fluorescence within the cell, fluorescence aggregated at the site of the nuclei acid array indicating a compound that binds to the selected nucleic acid. In particular compounds such a transcription factors can be screened. Reagents for such method are provided including a mammalian cell having a plurality of steroid receptor response elements in an array such that the response element can be directly detected when bound by fluorescently labeled steroid receptor and a chimeric protein comprising a fluorescent protein fused to a steroid receptor.

Abstract: Vectors which establish controlled expression of recombinant GHRH genes within tissues at certain levels. The vector includes a 5′ flanking region which includes necessary sequences for expression of a nucleic acid cassette, a 3′ flanking region including a 3′UTR and/or 3′NCR, and a linker which connects the 5′ flanking region to a nucleic acid sequence. The linker has a position for inserting a nucleic acid cassette. The linker does not contain the coding sequence of a gene that the linker is naturally associated with. The 3′ flanking region is 3′ to the position for inserting the nucleic acid cassette.

Abstract: The invention provides improved methods of recombinant protein production in cell culture. More specifically, the invention relates to the modulation of the IGF-1 signaling pathway in cells so as to improve production characteristics.

Abstract: Recombinant materials are provided for the production of the &agr;-glycoprotein hormone subunit. These muteins have utility as antagonists and in altering pharmacokinetic activity of these hormones.

Abstract: The present invention is to methods of obtaining plant-derived compositions that inhibit apoptosis, the compositions obtained thereby, compositions comprising the composition, and methods of use thereof.

Abstract: A biochemically defined culture medium for culturing engineered Chinese hamster ovary (CHO) cell lines, which is essentially free from protein, lipid and carbohydrate isolated from an animal source, having water, an osmolality regulator, a buffer, an energy source, amino acids including L-glutamine, an inorganic or recombinant iron source, and a synthetic or recombinant growth factor, and optionally non-ferrous metal ions vitamins and cofactors. Also cells adapted to grow in such a culture medium. REEXAMINATION RESULTS The questions raised in reexamination request no. 90/006656, filed Jun. 2, 2003 have been considered and the results thereof are reflected in this reissue patent which constitutes the reexamination certificate required by 35 U.S.C. 307 as provided in 37 CFR 1.570(e), for ex parte reexaminations, or the reexamination certificate required by 35 U.S.C. 316 as provided in 37 CFR 1.997(e) for inter partes reexaminations.