Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-11-28
2002-07-09
Fredman, Jeffrey (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S063000, C536S024300
Reexamination Certificate
active
06416953
ABSTRACT:
TECHNICAL FIELD
This invention relates to design and synthesis of modified synthetic nucleic acid polymers/oligomers with directly incorporated electronic/photonic transfer properties. In particular, it relates to the property of extended directional non-radiative energy transfer. These unique components can be programmed to self-assemble and organize into larger more complex structures. The directly incorporated electronic/photonic functional properties allow connections and novel mechanisms to be formed within the organized structures. The combination of the properties allows ultimately for the creation of useful photonic and photovoltaic devices, DNA bio-sensors, and DNA diagnostic assay systems.
BACKGROUND OF THE INVENTION
The fields of molecular electronics/photonics and nanotechnology offer immense technological promise for the future. Nanotechnology is defined as a projected technology based on a generalized ability to build objects to complex atomic specifications. Drexler,
Proc. Natl. Acad. Sci USA,
78:5275-5278, (1981). Nanotechnology means an atom-by-atom or molecule-by-molecule control for organizing and building complex structures all the way to the macroscopic level. Nanotechnology is a bottom-up approach, in contrast to a top-down strategy like present lithographic techniques used in the semiconductor and integrated circuit industries. The success of nanotechnology will be based on the development of programmable self-assembling molecular units and molecular level machine tools, so-called assemblers, which will enable the construction of a wide range of molecular structures and devices. Drexler, in “Engines of Creation,” Doubleday Publishing Co., New York, N.Y. (1986). Thus, one of the first and most important goals in nanotechnology is the development of programmable self-assembling molecular construction units.
Present molecular electronic/photonic technology includes numerous efforts from diverse fields of scientists and engineers. Carter, ed. in “Molecular Electronic Devices II,” Marcel Dekker, Inc, New York, N.Y. (1987). Those fields include organic polymer based rectifiers, Metzger et al., in “Molecular Electronic Devices II,” Carter, ed., Marcel Dekker, New York, N.Y., pp. 5-25 (1987), conducting conjugated polymers, MacDiarmid et al.,
Synthetic Metals,
18:285 (1987), electronic properties of organic thin films or Langmuir-Blogett films, Watanabe et al.,
Synthetic Metals,
28:C473 (1989), molecular shift registers based on electron transfer, Hopfield et al.,
Science,
241:817 (1988), and a self-assembly system based on synthetically modified lipids which form a variety of different “tubular” microstructures. Singh et al., in “Applied Bioactive Polymeric Materials,” Plenum Press, New York, N.Y., pp. 239-249 (1988). Molecular optical or photonic devices based on conjugated organic polymers, Baker et al.,
Synthetic Metals,
28:D639 (1989), and nonlinear organic materials have also been described. Potember et al.,
Proc. Annual Conf. IEEE in Medicine and Biology,
Part 4/6:1302-1303 (1989).
However, none of the cited references describe a sophisticated or programmable level of self-organization or self-assembly. Typically the actual molecular component which carries out the electronic and/or photonic mechanism is a natural biological protein or other molecule. Akaike et al.,
Proc. Annual Conf. IEEE in Medicine and Biology,
Part 4/6:1337-1338 (1989). There are presently no examples of a totally synthetic programmable self-assembling molecule which produces an efficient electronic or photonic structure, mechanism or device.
Progress in understanding self-assembly in biological systems is relevant to nanotechnology. Drexler,
Proc. Natl. Acad. Sci USA,
78:5275-5278 (1981). Drexler, in “Engines of Creation,” Doubleday Publishing Co., New York, N.Y. (1986). Areas of significant progress include the organization of the light harvesting photosynthetic systems, the energy transducing electron transport systems, the visual process, nerve conduction and the structure and function of the protein components which make up these systems. The so called bio-chips described the use of synthetically or biologically modified proteins to construct molecular electronic devices. Haddon et al.,
Proc. Natl. Acad. Sci. USA,
82:1874-1878 (1985). (McAlear et al., in “Molecular Electronic Devices II,” Carter ed., Marcel Dekker, Inc., New York, N.Y., pp. 623-633 (1987). Some work on synthetic proteins (polypeptides) has been carried out with the objective of developing conducting networks. McAlear et al., in “Molecular Electronic Devices,” Carter ed., Marcel Dekker, New York, N.Y., pp. 175-180 (1982). Other workers have speculated that nucleic acid based bio-chips may be more promising. Robinson et al., “The Design of a Biochip: a Self-Assembling Molecular-Scale Memory Device,”
Protein Engineering,
1:295-300 (1987).
Great strides have also been made in our understanding of the structure and function of the nucleic acids, deoxyribonucleic acid or DNA, Watson, et al., in “Molecular Biology of the Gene,” Vol. 1, Benjamin Publishing Co., Menlo Park, Calif. (1987), which is the carrier of genetic information in all living organisms. In DNA, information is encoded in the linear sequence of nucleotides by their base units adenine, guanine, cytosine, and thymidine (A, G, C, and T). Single strands of DNA (or polynucleotides) have the unique property of recognizing and binding, by hybridization, to their complementary sequence to form a double stranded nucleic acid duplex structure. This is possible because of the inherent base-pairing properties of the nucleic acids; A recognizes T, and G recognizes C. This property leads to a very high degree of specificity since any given polynucleotide sequence will hybridize only to its exact complementary sequence.
In addition to the molecular biology of nucleic acids, great progress has also been made in the area of the chemical synthesis of nucleic acids (16). This technology has developed so automated instruments can now efficiently synthesize sequences over 100 nucleotides in length, at synthesis rates of 15 nucleotides per hour. Also, many techniques have been developed for the modification of nucleic acids with functional groups, including: fluorophores, chromophores, affinity labels, metal chelates, chemically reactive groups and enzymes. Smith et al.,
Nature,
321:674-679 (1986); Agarawal et al.,
Nucleic Acids Research,
14:6227-6245 (1986); Chu et al.,
Nucleic Acids Research,
16:3671-3691 (1988).
An impetus for developing both the synthesis and modification of nucleic acids has been the potential for their use in clinical diagnostic assays, an area also referred to as DNA probe diagnostics. Simple photonic mechanisms have been incorporated into modified oligonucleotides in an effort to impart sensitive fluorescent detection properties into the DNA probe diagnostic assay systems. This approach involved fluorophore and chemiluminescent-labeled oligonucleotides which carry out Forster nonradiative energy transfer. Heller et al., in “Rapid Detection and Identification of Infectious Agents,” Kingsbury et al., eds., Academic Press, New York, N.Y. pp. 345-356 (1985). Forster nonradiative energy transfer is a process by which a fluorescent donor (D) group excited at one wavelength transfers its absorbed energy by a resonant dipole coupling process to a suitable fluorescent acceptor (A) group. The efficiency of energy transfer between a suitable donor and acceptor group has a 1/r
6
distance dependency (see Lakowicz et al., in “Principles of Fluorescent Spectroscopy,” Plenum Press, New York, N.Y., Chap. 10, pp. 305-337 (1983)).
In the work of Heller et al., supra, two fluorophore labeled oligonucleotides are designed to bind or hybridize to adjacent positions of a complementary target nucleic acid strand and then produce efficient fluorescent energy transfer in terms of re-emission by the acceptor. The first oligonucleotide is labeled in the 3′ terminal position with a suitable donor group, and the second is labeled in the 5′ t
Fredman Jeffrey
Lyon & Lyon LLP
Nanogen Inc.
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