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Chemical amplification for the synthesis of patterned arrays

a technology of patterned arrays and synthesis methods, applied in bulk chemical production, nuclear tetramethylamine libraries, biomass after-treatment, etc., can solve the problems of geysen et al., which is limited to producing 96 different polymers on pins spaced in the dimensions of a standard microliter plate, and achieves high synthesis fidelity, small synthesis feature, and improved synthesis resolution

Inactive Publication Date: 2006-06-29
AFFYMETRIX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes improved methods for forming high-density arrays of peptides, polynucleotides, and other polymer sequences using combinatorial solid phase synthesis. These methods involve the use of photosensitive compounds, also known as catalysts, that are activated by radiation to remove protective groups from linker molecules and allow them to react with synthesis intermediates or other compounds. The use of these catalysts and autocatalytic compounds has led to the development of new methods and devices for synthesizing these polymer sequences. The invention provides novel methods for synthesizing high-density arrays of polymer sequences that are faster and more efficient than previous methods.

Problems solved by technology

For example, the technique discussed in Geysen et al. is limited to producing 96 different polymers on pins spaced in the dimensions of a standard microliter plate.

Method used

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  • Chemical amplification for the synthesis of patterned arrays
  • Chemical amplification for the synthesis of patterned arrays
  • Chemical amplification for the synthesis of patterned arrays

Examples

Experimental program
Comparison scheme
Effect test

example i

Removal of Protecting Groups by Acid Amplification

[0086] Efficient removal of protective groups as taught by the present invention is demonstrated in the following experiment.

[0087] A system using an ester of toluenesulfonic acid as a PAAC and an autocatalytic ester of pentafluorobenzoic acid (1,4-cyclohex-2-enediylbis-(pentafluorobenzoate)) as an enhancer was employed. An experiment was conducted to determine time and intensity required to achieve efficient deprotection.

[0088] The synthesis of 1,4-cyclohex-2-enediylbis-(pentafluorobenzoate) and 2-nitro-3,4-dimethoxybenzyl tosylate were carried out according to Houlihan et al., Chemistry of Mat. 3:462-471, 1991. The yields were 54% and 62%, respectively.

[0089] Solutions containing poly (methyl methacrylate) (PMMA, average molecular weight of 15,000 dalton) (14.0 wt %), 1,4-cyclohex-2-enediylbis-(pentafluorobenzoate) (7.0 wt %), and 2-nitro-3,4-dimethoxybenzyl tosylate (0.5, 0.8, 1.2, 1.6, or 2.3 wt %) in cyclohexanone were spin ...

example ii

High Resolution Synthesis of Polynucleotide and Hybridization with an Polynucleotide Probe

[0094] Another important consideration for applying the techniques disclosed herein is whether the deprotection procedure interferes with the subsequent synthesis and functioning of the desired polymer arrays. The following experiment shows that functional polynucleotide arrays were synthesized by the method of the current invention.

[0095] A combination of a PAC and an enhancer in the form of a masked acid was used to synthesize a standard checkerboard pattern of an polynucleotide on a glass slide. The resulting glass slide containing polynucleotide arrays was hybridized to a complementary polynucleotide probe to test resolution and integrity of the arrays.

[0096] Solutions containing poly (methyl methacrylate) (PMMA, average molecular weight 15,000) (14.0 wt %), 1,4-cyclohex-2-enediyl-bis(pentafluorobenzoate) (7.0 wt %), and 2-nitro-3,4-dimethoxybenzyl tosylate (1, 2 wt %) in cyclohexanone w...

example iii

Lithographic Evaluation

[0103] As shown in FIG. 4, the high contrast observed in photo processes reflects the nonlinearity of the response as a function of the irradiation dose. In traditional photo resists, this nonlinearity stems from the solubility behavior of the polymer. Although the catalytic photo process described in this application does not involve a development step, nonlinear behavior was observed. This probably results from a titration effect: a quantity of acid must accumulate before the DMT group is removed.

[0104] The lithographic behavior of the process was evaluated by spin coating a 0.5 μm thick film of poly (methyl methacrylate) (PMMA) containing the nitrobenzyl ester PAC (0.5 wt %) and the enhancer (8 wt %) having the following structures:

onto a glass substrate bearing covalently bound polynucleotides whose terminal 5′ hydroxyl groups were DMT protected. The coated substrate was prebaked at 85° C. for 2 min, irradiated with varying doses at 365 nm, and postba...

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Abstract

Radiation-activated catalysts (RACs), autocatalytic reactions, and protective groups are employed to achieve a highly sensitive, high resolution, radiation directed combinatorial synthesis of pattern arrays of diverse polymers. When irradiated, RACs produce catalysts that can react with enhancers, such as those involved in autocatalytic reactions. The autocatalytic reactions produce at least one product that removes protecting groups from synthesis intermediates. This invention has a wide variety of applications and is particularly useful for the solid phase combinatorial synthesis of polymers.

Description

STATEMENT OF RELATED APPLICATIONS [0001] This application claims priority from U.S. patent application Ser. No. 10 / 840,841, filed May 7, 2004; which is a continuation application of U.S. patent application Ser. No. 09 / 578,282, filed May 25, 2000; which is a continuation application of U.S. patent application Ser. No. 08 / 969,227, filed Nov. 13, 1997, now U.S. Pat. No. 6,083,697; and U.S. provisional application No. 60 / 030,826, filed Nov. 14, 1996; all of which are hereby incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Embodiments of the present invention relate to spatially defined chemical synthesis involving lithographic processes. In particular, embodiments of the present invention are directed to novel methods and compositions for synthesizing arrays of diverse polymer sequences, such as polypeptides and polynucleotides. According to a specific aspect of the invention, a method of synthesizing diverse polymer sequences, such as peptides or polynucleotides, is ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68C12M1/34C07H21/04B01J19/00C12N15/09C07B51/00C07B61/00C07H21/00C07K1/04C07K1/06C12Q1/6837C40B40/06C40B50/14C40B60/14
CPCB01J19/0046B01J2219/00427B01J2219/00432B01J2219/00497B01J2219/00527B01J2219/00529B01J2219/00576B01J2219/00585B01J2219/00596B01J2219/00605B01J2219/00608B01J2219/0061B01J2219/00612B01J2219/00617B01J2219/00626B01J2219/00637B01J2219/00659B01J2219/00675B01J2219/00711B01J2219/00722B82Y30/00C07B61/00C07B2200/11C07H21/00C07H21/04C07K1/04C07K1/045C12Q1/6837C40B40/06C40B50/14C40B60/14Y02P20/55
Inventor BEECHER, JODYGOLDBERG, MARTINMCGALL, GLENN
Owner AFFYMETRIX INC
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