Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Polymers from only ethylenic monomers or processes of...
Reexamination Certificate
2002-09-03
2004-06-22
Choi, Ling-Siu (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Polymers from only ethylenic monomers or processes of...
C526S348000, C526S346000, C526S303100, C526S242000, C526S274000
Reexamination Certificate
active
06753396
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a method for the production of new template-textured materials in the form of template-textured polymers (TTP) with high binding specificity and selectivity on a solid support and their use in substance-specific separation and analytics of materials.
In life sciences and biotechnology, new efficient separation and purification strategies and detection methods for substances such as enzymes, monoclonal antibodies, recombinant proteins or small biomolecules are being required. Similarly, this applies to synthetic active substances, and especially to those having a complex structure or/and relatively high molecular weight or/and limited stability.
In all these fields of use, there is an ongoing search for substance-specific high-performance materials, with high flexibility in adapting to the particular substances or active agents being required. Solid materials (particles, films, vessels, filters, membranes) are preferably used to make phase separation of solid and fluid flows of material easier. In contrast to separation methods based on dissimilar physical properties, chemical affinity to the support is a precondition for substance-specific separation. Substance specificity can be achieved via interactions between biological or biomimetic ligands and receptors. For affinity separations, either specific, yet highly sensitive biological ligands/receptors (e.g. antibodies, enzymes), or relatively unspecific synthetic ligands (e.g. dyes, metal chelates) have been used to date; examples are chromatography, solid-phase extraction, membrane separation, solid-phase assays, or sensors.
Non-porous films, layers or particles having affinity ligands on their surfaces exhibit a low specific surface area and thus, limited binding capacity. Porous materials having a larger specific surface area typically involve restricted binding capacity as a result of diffusion-related limitations. Analogous limitations may occur in packed particles. Directionally permeable porous filters or membranes are therefore particularly attractive alternative materials. Established membrane processes using porous membranes, such as micro- or ultrafiltration, operate according to the size exclusion principle. The separation of substances of similar molecular size using porous membranes additionally requires specific (affinity) interactions with the membrane.
The major motivation in using affinity membranes is the possibility of directional flow onto separation-specific groups (ligands/receptors) present in the pores at high density, enabling a dramatic improvement in effectiveness (less pressure drop, shorter residence time, higher flow rate, rarely diffusion-related limitations in pores, more rapid equilibration) as compared to analogous processes using particles. Such affinity membranes can be used in the separation of materials, e.g. purification, preferably of proteins, but also of many other substances (e.g. peptides, nucleic acid derivatives, carbohydrates, or various toxins, herbicides, pesticides), and even cells. Also, decontamination of material flows is a field of use for such membranes, involving many applications. Furthermore, affinity membranes provide many potential uses in analytics, e.g. in highly selective sample accumulation, e.g. by solid-phase extraction, or in the form of a quantitative determination of a substance on an affinity membrane, e.g. by means of ELISA.
A highly attractive alternative to biological or biomimetic affinity ligands/receptors for the separation or analytics of materials has been developed in recent years, involving the use of specific, yet exceedingly robust functional cavities (“molecular impressions”) in synthetic polymers, produced via molecularly texturing polymerization (G. Wulff, Angew. Chem. 107, 1995, 1958; A. G. Mayes, K. Mosbach, Trends Anal. Chem. 16, 1997, 321; K. Haupt, K. Mosbach, Trends Biotechnol. 16, 1998, 468). To this end, polymerization of monomers is effected in the presence of template molecules (e.g. protein, nucleic acid, low-molecular weight organic substance) capable of forming a complex with a functional monomer, which complex is relatively stable during polymerization. After washing out the template, the materials thus produced are ready again to specifically bind template molecules. The polymers thus synthesized are referred to as template-textured polymers (TTP) or molecularly textured polymers (see FIG.
1
).
Any substance having a well-defined three-dimensional morphology can be used as a template in the synthesis of TTP. Consequently, the classes of substances range from small molecules up to particles such as viruses, bacteria or cells. Compounds involving biological functions, such as peptides, nucleic acids or carbohydrates, are of particular interest. The recognition of templates by TTP is based on a combination of various factors such as reversible covalent or non-covalent bonding, electrostatic and hydrophobic interactions, hydrogen bonding and morphological complementarity. Which of these factors will dominate depends on template structure and properties, the functional monomer, the polymer structure, and the conditions of binding. In contrast to the covalent approach in TTP synthesis, which requires complex syntheses of template/monomer conjugates, the non-covalent approach is much more flexible. Frequently, electrostatic interactions are suitable in template recognition by TTP in hydrophobic solvents. In contrast, the morphological specificity and possibly, hydrophobic interactions are most important in template recognition in polar solvents. Preferably, TTP should be synthesized under conditions where strong, yet reversible interactions between polymer and template are favored. On the other hand, a combination of much weaker bonds including hydrogen bridges and hydrophobic interactions might be favorable for large molecules (about 200-1,000,000 Da). For small molecules (50-200 Da), a few strong interactions such as ionic bonds are necessary to obtain high affinity TTP. For example, the related production of polymeric sorbents in the presence of small organic molecules (U.S. Pat. No. 5,110,833) or macro-molecular substances (U.S. Pat. No. 5,372,719), or the synthesis of acrylamide or agarose gels in the presence of proteins (U.S. Pat. Nos. 5,728,296, 5,756,717) have been described. Peptide- or protein-specific sorbents produced using “surface texturing” of metal chelate structures on specifically functionalized particles (U.S. Pat. No. 5,786,428), or of carbohydrates in a plasma-polymerized layer have also been reported. TTP membranes produced using a special “surface texturing” process have also been described (WO 00/07702). A significant improvement in the synthesis of TTPs from aqueous solutions and for use in aqueous systems has been achieved by means of a special “surface texturing” process using special aqueous reaction solutions (patent application DE 198 42 641.1). In all these cases, good affinities for the respective template have been obtained.
The use of artificial antibodies and receptors produced by molecular texturing might involve enormous advantages, because these structures are much more stable compared to their natural analogues. Also, in principle, they can be synthesized for any substance (even for those having less pronounced antigenic properties, such as small molecules or immunosuppressives), and their production is much easier and more cost-effective compared to corresponding biomolecules. A crucial problem still restricting the potential uses of TTP is that non-specific interactions occur to a massive extent in addition to the desired affinity of the “molecular impressions” achieved by the TTP synthesis. In those few examples where TTP as a “plastic antibody” in assays is reported to have a remarkable template selectivity (relatively low “cross reactivity” to similar substances), only very few template impressions in the TTP and thus, those having the highest affinity are utilized (K. Haupt, K. Mosbach, Trends Biotechnol. 16, 1998, 468). In general, de
Matuschewski Heike
Piletsky Sergey A.
Schedler Uwe
Sergeyeva Tatinna
Ulbricht Mathias
Choi Ling-Siu
Elipsa GmbH
Norris McLaughlin & Marcus PA
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