Chemistry: analytical and immunological testing – Optical result
Reexamination Certificate
1999-02-17
2001-09-11
Snay, Jeffrey (Department: 1743)
Chemistry: analytical and immunological testing
Optical result
C436S172000, C422S082050, C422S082090
Reexamination Certificate
active
06287869
ABSTRACT:
FIELD OF THE INVENTION
The field of the present invention is analytic instruments using lasers for supplying incident radiation to an unknown sample, and more particularly analytic instruments using sputtering metal ion lasers.
BACKGROUND OF THE INVENTION
The background for and disclosure of the invention are explained with reference to the following patents and publications each of which is hereby incorporated by reference as if set forth in full herein:
(1) Milofsky, R. E. and E. S. Yeung, “Native Fluorescence Detection of Nucleic Acids and DNA Restriction Fragments in Capillary Electrophoresis”,
Anal. Chem
., vol. 65, (1993): pp. 153-157;
(2) Chi, Z., X. G. Chen, J. S. W. Holtz and S. A. Asher, “UV Resonance Raman-Selective Amide Vibrational Enhancement: Quantitative Methodology for Determining Protein Secondary Structure”,
Biochemistry
, Vol. 37, (1988): pp. 2854-2864;
(3) Thomas, G. J.,
Spectroscopy of Biological Systems
, Ed. Clark, R. J. and R. E. Hester, John Wiley (1986);
(4) Cho, N., Song, S., and S. A. Asher, “UV Resonance Raman and Excited-State Relaxation Rate Studies of Hemoglobin”,
Biochemistry
, Vol. 33, (1994): pp. 5932-5941;
(5) Cho, N., and S. A. Asher, “UV Resonance Raman and Absorption Studies of Angiotensin II Conformation in Lipid Environments”,
Biospectroscopy
, Vol. 2, (1996): pp. 71-82;
(6) Chronister, E. L., Corcoran, R. C. Song, L., and El-Sayed, M.,
Proc. Nat'l Acad. Sci
. (USA), Vol. 83, (1986): pp. 8580-8583;
(7) Barry, B., and R. A. Mathies,
Biochemistry
, Vol. 26, (1987): pp. 59-64;
(8) Asher, S. A.,
Methods in Enzuymology
, Vol 76, (1981): pp. 371-383;
(9) Spiro, R. G.,
Biological Applications of Raman Spectroscopy
: Vol II, John Wiley (1987);
(10) Asher, S. A.,
Ann. Rev. Phys. Chem
., Vol. 39, (1988): pp. 537-542;
(11) Asher, S. A., Johnson, C. R. and J. Murtaugh, Rev. Sci. lnstr. Vol. 54, (1983): pp. 1657-1659;
(12) Asher, S. A.,
Anal. Chem
., Vol. 65, No.4, (Feb.15, 1993): pp. 201-210.
(13) Gerstenberger, et al., “Hollow Cathode Metal Ion Lasers”,
IEEE J. Quantum Elect
., vol. QE-16, No. 8, (August 1980): pp. 820-834;
(14) U.S. Pat. No. 4,641,313, entitled “Room Temperature Metal Vapour Laser”, to Tobin;
(15) McNeil, et al., “Ultraviolet Laser Action From Cu ll in the 2500-A Region”,
App. Phys. Letters
, vol. 28, No.4, (Feb. 15, 1976): pp. 207-209;
(16) Warner, et al., “Metal-Vapor Production by Sputtering in a Hollow-Cathode Discharge: Theory and Experiment”,
J. App. Phys
., vol. 50, No 9, (September 1979): pp. 5694-5703;
(17) Solanki, et al., “Multiwatt Operation of Cull and Agll Hollow Cathode Lasers”,
IEEE J. Quant Elect
, vol. QE-16, No.12, (December 1980): pp. 1292-1294.
(18) Arslanbekov, et al., “Self-consistent Model of High Current Density Segmented Hollow Cathode Discharges”,
J. App. Phys
., vol. 81, No 2, (January 1997): pp. 1-7;
(19) U.S. Pat. No. 5,311,529, entitled “Liquid Stabilized Internal Mirror Lasers”, to Hug; and
(20) U.S. Pat. No. 4,953,176, entitled “Angular Optical Cavity Alignment Adjustment Utilizing Variable Distribution Cooling”, to Ekstrand.
Existing lasers which emit in the deep ultraviolet between 200 nm and 300 nm have serious limitations in one or more of the following: (1) the selection of emission wavelengths, (2) average or instantaneous output power, (3) power consumption, (4) reliability, (5) size, (6) weight, and (7) cost. Because laser sources without these limitations have never been developed and commercialized, a wide range of commercial analytical instrumentation that could benefit from such sources have never been enabled.
Capillary electrophoresis, high performance liquid chromatography, laser-induced fluorescence, fluorescence microscopy, and Raman spectroscopy are emerging as powerful analytical tools for a wide range of biological and chemical research. In addition, these instrumental techniques are being increasing used in commercial applications such as product inspection during the manufacture of pharmaceutical and medical products, manufactured food products and other chemical products.
Capillary electrophoresis (CE) allows rapid separation of complex chemical and biochemical mixtures. Laser induced fluorescence (LIF) allows the sensitive detection of analytes. Raman spectroscopy (RS) allows a high level of chemical specificity. The sensitivity and selectivity of these analytical instruments are today considerably enhanced when combined with a laser, which emits in the deep UV between 200 nm and 300 nm. The principle limitation to widespread commercial use of these systems is lack of commercially suitable UV lasers, particularly associated with limitations in emission wavelengths, duty cycle, size, power consumption, complexity, cost and reliability of existing lasers. A need exists in these fields for improved laser systems, particularly in the deep UV, that overcome these disadvantages either singly or in combination.
Capillary electrophoresis continues to evolve as a powerful analytical method for separation and analysis of complex chemical analytes. A major direction of development in CE is toward smaller capillaries, allowing faster separations. As capillary diameters decrease below 50 microns and head toward 20 or even 10 microns, the problem of providing enough light to excite fluorescence in a sample being examined determines the detection limit. This is discussed in reference (1) by Milofsky and Yeung, 1993. When capillary diameters were larger, deuterium lamps were employed to excite native fluorescence in biomolecules. However, as capillary diameters decrease, deuterium lamps no longer have sufficient source radiance at the desirable deep UV wavelengths to enable them to be employed. Lasers have been recognized as the solution to this problem. However, because lasers of reasonable cost and size only emit in the visible or near IR, fluorescent dye derivatization techniques were developed to enable the use of these lasers for detection. Derivatization with fluorescent labels limits the types of molecules which can be studied, reduces CE's ability to find unexpected analytes in complex systems, may perturb the very cellular chemistry being studied, and can reduce overall sensitivity. A sensitive native CE/LIF detection method for nucleic acids and DNA restriction fragments has already been demonstrated as described in reference (1) by Milofsky and Yeung in 1993. Both the 275.4 nm line of an argon ion laser and the 248 nm line from a waveguide KrF laser were able to excite native fluorescence in the nucleic acids with a few mW of laser power. Detection limits for guanosine and adenosine monophosphate of 1.5×10
−8
and 5×10
−8
M, respectively, were as much as three orders of magnitude lower than UV fluorescent tag detection. However, the complexity and cost of the laser employed severely restrict the general utility of this technique. A need exists in this field for improved laser systems with reduced complexity and/or cost to make practical the above noted applications.
Raman spectroscopy has been demonstrated as a uniquely important technique for analyzing biological structure and function. Traditional Raman spectroscopy has been used to study a wide range of biological molecules such as protein secondary structure, nucleic acid folding and membrane phase transitions as described in reference (2) by Chi, et al., 1988. Most of this work has examined purified chemical systems, such as polymers, proteins, and nucleic acid systems, but a number of studies have probed complicated systems such as industrial and environmental samples, as well as DNA structure in whole viruses as described in reference (3) by Thomas, 1986.
The aromatic ring structures of tyrosine, tryptophane, and phenylalanine offer excellent LIF and UV resonance Raman (UVRR) cross-sections. The abundance of these three targets in the vast majority of proteins has made possible such investigations as the determination of protein acid denaturation using UVRR, characterization of excited-state relaxation rates in hemoglobin as described in reference (4) by Cho, et al., 19
Hug William F.
Reid Ray D.
Smalley Dennis R.
Snay Jeffrey
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