Author: claimsbot

1. An assay method for assaying for holoTC in a sample, said method comprising contacting said sample with a specific binding partner for holoTC and detecting the resultant conjugates of holoTC and the specific binding partner, wherein:
said specific binding partner is a specific binding partner for holoTC having a specificity for holoTC over apoTC of at least 40-fold, and
said specific binding partner also has affinity for at least one constrained peptide comprising the motif SFFYSLCYCW (SEQ ID NO: 9), relative to apoTC of at least 40-fold.
2. The method of claim 1, wherein said specific binding partner binds to at least one point in at least one of the regions I, II or III of human TC;
I) Leu 39 to Lys 77 and Thr 265 to Lys 269
II) Ile 161 to Val 243
III) Arg 271 to Asp 297.
3. The method of claim 1, wherein the binding of said specific binding partner to holoTC is blocked by a specific biding partner for an overlapping site on both holoTC and apoTC.
4. The method of claim 1, wherein said specific binding partner is an antibody, a single chain antibody, and antibody fragment or an antibody construct.
5. The method of claim 1, wherein said conjugates of holoTC and the specific binding partner are detected directly by means of a property of the conjugate.
6. The method of claim 1 wherein said conjugates of holoTC and the specific binding partner are detected indirectly by detecting further conjugates formed in competition or by detecting a conjugate of the specific binding partner, holoTC and a further ligand.
7. The method of claim 1, wherein said specific binding partner for holoTC is immobilised or immobilisable and is used to capture holoTC.
8. The method of claim 1, wherein said specific binding partner for holoTC is used to detect holoTC which is captured by an immobilised or immobilisable secondary ligand.
9. The method of claim 1 comprising the use of a constrained peptide mimotope comprising the motif SFFYSLCYCW (SEQ ID NO: 9) or a construct of two or more such mimotopes.
10. The method of claim 9, wherein said mimotope is used as a competitior for holoTC in binding to said specific binding partner for holoTC.
11. The method of claim 1 comprising
i) contacting a liquid sample from a subject with an immobilised or immobilisable specific binding partner for holoTC whereby to form a holoTC:sbp conjugate,
ii) contacting the specific binding partner with a secondary ligand for TC or holoTC such that the secondary ligand binds to the bound holoTC to form a sbp:holoTC:secondary ligand conjugate;
iii) separating the unbound secondary ligand from the sbp:holoTC; secondary ligand conjugate;
iv) optionally releasing the holoTC:sbp:secondary ligand conjugate from being immobilised andor releasing a holoTC:secondary ligand conjugate from the sbp;
v) optionally adding a cosubstrate or tertiary ligand to facilitate detection of the holoTC:sbp:secondary ligand conjugate or a holoTC:secondary ligand conjugate;
vi) detecting holoTC:sbp:secondary ligand conjugate or a holoTC:secondary ligand conjugate; and
vii) relating the detected amount of holoTC:sbp:secondary ligand conjugate to the concentration of holoTC in the liquid sample to provide a measurement of the holoTC present in the liquid sample.
12. The method of claim 11 further comprising relating the concentration of holoTC present in the liquid sample to the presence or absence of cobalamin deficiency in the subject.
13. The method of claim 1 additionally comprising measuring apoTC or total TC.

The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.

1. A method for treating the surface of a substrate with a surface treatment composition, wherein the surface treatment composition comprises a liquid medium containing a complexing agent as a metal deposition preventive, the complexing agent comprising at least one member selected from the following Group A complexing agents and at least one member selected from the group consisting of the following Groups Bl to B6 complexing agents:
Group A: complexing agents having an aromatic hydrocarbon ring in the molecular structure thereof and at least one of an OH group andor an O group bonded directly to a carbon atom constituting the ring;
Group B1: complexing agents having at least one nitrogen atom as a donor atom-in the molecular structure thereof;
Group B2: complexing agents having at least one atom selected from halogen, sulfur and carbon atoms as a donor atom in the molecular structure thereof;
Group B3: complexing agents having at least one oxygen atom as a donor atom in the molecular structure thereof, but not having a carbonyl group and a carboxyl group and not having any one of nitrogen, halogen, sulfur and carbon atoms as a donor atom;
Group B4: carboxylic acid type complexing agents having at least one carboxyl group in the molecular structure thereof, but not having any one of nitrogen, halogen, sulfur and carbon atoms as a donor atom and not having a carbonyl group and a hydroxyl group;
Group B5: hydroxymono- or di-carboxylic acid type complexing agents having at most 4 hydroxyl groups in the molecular structure thereof, but not having any one of nitrogen, halogen, sulfur and carbon atoms as a donor atom and not having a carbonyl group; and
Group B6: complexing agents having at least one carbonyl group in the molecular structure thereof.
2. The method according to claim 1, wherein the Group B1 complexing agents having at least one nitrogen atom as a donor atom, have at least one coordinate group selected from the group consisting of an amino group, an imino group, a nitrilo group (tertiary nitrogen atom), a thiocyanate group, a hydroxyamino group, a hydroxyimino group, a nitro group, a nitroso group, a hydrazino group, a hydrazono group, a hydrazo group, an azo group, an azoxy group, a diazonium group and an azido group.
3. The method according to claim 1, wherein the Group B1 completing agents have an iminocarboxylic acid group or a heterocyclic polycyclic amino group.
4. The method according to claim 1, wherein the Group B2 complexing agents having a halogen atom as a donor atom, are hydrofluoric acid, hydrochloric acid, hydrogen bromide or hydrogen iodide or their salts.
5. The method according to claim 1, wherein the Group B2 complexing agents having a sulfur atom as a donor atom, have at least one coordinate group expressed by the formula HS, S2, S2O32, RS, RCOS, RCSS or CS32, or are selected from thiol, sulfide or thiocarbonyl compounds expressed by RSH, R2S or R2CS (provided that R in the above formulas is an alkyl group, R is an alkyl group or an alkenyl group, and they may be connected with each other to form a ring containing a sulfur atom).
6. The method according to claim 1, wherein the Group B2 complexing agents having a carbon atom as a donor atom, have at least one coordinate group expressed by the formula NC, RNC or RCC (provided that R in the formulas is an alkyl group).
7. The method according to claim 1, wherein the Group B3 complexing agents have at least one coordinate group selected from a hydroxyl group, a phosphonic acid group, a sulfonic acid group and an ether group.
8. The method according to claim 1, wherein the Group B3 complexing agents are oxo acid or its salt or ester.
9. The method according to claim 8, wherein the oxo acid is sulfonic acid, phosphoric acid, condensed phosphoric acid, boric acid, silicic acid, carbonic acid, nitric acid, nitrous acid, perchloric acid, chloric acid, chlorous acid or hypochlorous acid.
10. The method according to claim 1, wherein the Group B4 complexing agents are selected from C2-C3 saturated aliphatic mono- or di-carboxylic acids or their salts.
11. The method according to claim 1, wherein the Group B5 completing agents are hydroxymono- or di-carboxylic acids having one or two hydroxyl groups in the molecular structure thereof.
12. The method according to claim 1, wherein the Group B6 complexing agents do not contain any one of nitrogen, halogen, sulfur and carbon atoms as a donor atom in the molecular structure thereof.
13. The method according to claim 1, wherein the Group B6 complexing agents have at least 2 carbonyl groups in the molecular structure thereof.
14. The method according to claim 1, wherein the Group A complexing agents have at least two OH groups andor O groups in the molecular structure thereof.
15. The method according to claim 1, wherein the content of the metal deposition preventive is from 107 to 2 wt %.
16. The method according to claim 14, wherein the content of the metal deposition preventive is from 106 to 0.5 wt %.
17. The method according to claim 1, wherein the liquid medium is an alkaline aqueous solution.
18. The method according to claim 16, wherein the alkaline aqueous solution contains ammonia and hydrogen peroxide.
19. A surface treatment composition comprising a liquid medium containing a complexing agent as a metal deposition preventive, the complexing agent comprising at least one member selected from the following Group A complexing agents and at least one member selected from the group consisting of the following Groups B1 to B6 complexing agents:
Group A: complexing agents having an aromatic hydrocarbon ring in the molecular structure thereof and at least one of an OH group andor an O group bonded directly to a carbon atom constituting the ring;
Group B1: complexing agents having at least one nitrogen atom as a donor atom in the molecular structure thereof;
Group B2: complexing agents having at least one atom selected from halogen, sulfur and carbon atoms as a donor atom in the molecular structure thereof;
Group B3: complexing agents having at least one oxygen atom as a donor atom in the molecular structure thereof, but not having a carbonyl group and a carboxyl group and not having any one of nitrogen, halogen, sulfur and carbon atoms as a donor atom;
Group B4: carboxylic acid type complexing agents having at least one carboxyl group in the molecular structure thereof, but not having any one of nitrogen, halogen, sulfur and carbon atoms as a donor atom and not having a carbonyl group and a hydroxyl group;
Group B5: hydroxymono- or di-carboxylic acid type complexing agents having at most 4 hydroxyl groups in the molecular structure thereof, but not having any one of nitrogen, halogen, sulfur and carbon atoms as a donor atom and not having a carbonyl group; and
Group B6: complexing agents having at least one carbonyl group in the molecular structure thereof.
20. A method for treating the surface of a substrate with a surface treatment composition, the surface treatment composition contains at least one complexing agent selected from the group consisting of ethylenediaminediorthohydroxyphenylacetic acid, 2-hydroxy-1-(2-hydroxy-5-methylphenylazo)-4-naphthalenesulfonic acid, diammonium 4,4-bis(3,4-dihydroxyphenylazo)-2,2-stilbenedisulfonate, Pyrocatechol Violet, o,o-dihydroxyazobenzene, 12-dihydroxy-5-nitro-1,2-azonaphthalene-4-sulfonic acid and N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid, as a metal deposition preventive in a liquid medium.
21. The method according to claim 19, wherein the metal deposition preventive is ethylenediamine diorthohydroxyphenyl acetic acid.
22. The method according to claim 19, wherein the content of the metal deposition preventive is from 107 to 2 wt %.
23. The method according to claim 19, wherein the liquid medium is an alkaline aqueous solution.
24. The method according to claim 22, wherein the alkaline aqueous solution contains ammonia and hydrogen peroxide.
25. A surface treatment composition containing at least one complexing agent selected from the group consisting of ethylenediamine diorthohydroxyphenyl acetic acid, 2-hydroxy-1-(2-hydroxy-5-methylphenylazo)-4-naphthalenesulfonic acid, diammonium 4,4-bis(3,4-dihydroxyphenylazo)-2,2-stilbenedisulfonate, Pyrocatechol Violet, o,o-dihydroxyazobenzene, 12-dihydroxy-5-nitro-1,2-azonaphthalene-4-sulfonic acid and N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid, as a metal deposition preventive in a liquid medium.
26. The surface treatment composition according to claim 24, wherein the metal deposition preventive is ethylenediamine diorthohydroxyphenyl acetic acid.
27. A method for treating the surface of a substrate with a surface treatment composition, wherein the surface treatment composition is a composition containing an oxidizing agent and an organic complexing agent having an OH group bonded directly to an aromatic hydrocarbon group in a liquid medium and the concentration of the oxidizing agent is from 1 ppm to 3 wt %.
28. The method according to claim 26, wherein the organic complexing agent is a complexing agent having at least 2 OH groups bonded directly to an aromatic hydrocarbon group in one molecule.
29. The method according to claim 26, wherein the liquid medium contains at least 2 complexing agents and at least one of the complexing agents is a complexing agent not having an OH group bonded directly to an aromatic hydrocarbon group in a molecule.
30. The method according to claim 28, wherein the complexing agent not having an OH group bonded directly to an aromatic hydrocarbon group is a complexing agent selected from the group consisting of Groups B1 to B6.
31. The method according to claim 26, wherein the oxidizing agent is from 100 ppm by weight to 3% by weight of hydrogen peroxide.
32. The method according to claim 26, wherein the liquid medium contains at most 3 wt % of ammonia.
33. A surface treatment composition containing an oxidizing agent and an organic complexing agent having an OH group bonded directly to an aromatic hydrocarbon group in a liquid medium, wherein the concentration of the oxidizing agent is from 1 ppm by weight to 3% by weight.
34. A method for treating the surface of a substrate with an alkaline surface treatment composition containing ammonia, water and an organic complexing agent having a cyclic structure in the molecular structure thereof and at least one of an OH group andor an O group bonded to a carbon atom constituting the cyclic structure as a metal deposition preventive in a liquid medium, wherein an ammonia component evaporated during the surface treatment is supplied with an ammonia aqueous solution containing the organic complexing agent.
35. The method according to claim 33, wherein the concentration of ammonia is from 0.1 to 35 wt % and the concentration of the organic complexing agent is from 107 to 2 wt % in the liquid medium.
36. The method according to claim 33, wherein the liquid medium further contains hydrogen peroxide.
37. The method according to claim 35, wherein the concentration of the hydrogen peroxide is from 100 ppm by weight to 3 wt %.
38. The method according to claim 33, wherein the organic complexing agent has a cyclic structure in the molecular structure thereof and has at least 2 OH groups andor O groups bonded directly to a carbon atom constituting the cyclic structure.
39. The method according to claim 33, wherein the ammonia aqueous solution supplied contains ammonia at a concentration of from 0.1 to 35 wt %, an organic complexing agent at a concentration of from 107 to 5 wt % and a metal impurity at a concentration of at most 104 wt % per metal.
40. The method according to claim 33, wherein the composition further contains an organic completing agent selected from the group consisting of the above Groups B1 to B6 as an organic complexing agent.
41. A method for treating the surface of a substrate with a surface treatment composition, wherein the surface treatment composition is a composition obtained by adding a highly pure ethylenediaminediorthohydroxyphenylacetic acid containing at most 5 ppm of at least one metal element of Fe, Al and Zn or its ammonium salt, as a metal deposition preventive to a liquid medium.
42. The method according to claim 40, wherein the highly pure ethylenediaminediorthohydroxyphenylacetic acid or its ammonium salt contains at most 5 ppm of Fe, at most 2 ppm of Al and at most 2 ppm of Zn.
43. A highly pure ethylenediaminediorthohydroxyphenylacetic acid or its ammonium salt, in which the content of at least one metal element of Fe, Al and Zn is at most 5 ppm.
44. A surface treatment composition containing the highly pure ethylenediamineorthohydroxyphenylacetic acid or its ammonium salt according to claim 42.
45. The surface treatment composition according to claim 43, which contains from 107 to 5 wt % of ethylenediaminediorthohydroxyphenylacetic acid, from 0.1 to 35 wt % of ammonia and at most 5 ppb of at least one metal element of Fe, Al and Zn.
46. A method for purifying a highly pure ethylenediaminediorthohydroxyphenylacetic acid or its ammonium salt, which comprises dissolving ethylenediaminediorthohydroxyphenylacetic acid or its salt in an acidic or alkaline solution, removing insoluble impurities by filtration, precipitating a crystal of ethylenediaminediorthohydroxyphenylacetic acid by neutralization and separating the crystal from the solution.
47. The method according to claim 45, wherein the separation of the insoluble impurities by filtration is conducted by a filter having an opening diameter of at most 0.5 m.

That which is claimed is:

1. A device for detecting the application of a high voltage to an internal node of an integrated circuit comprising a high-voltage divider circuit and a threshold detection circuit receiving a signal at input given by the output node of the divider circuit and giving a threshold crossing detection signal at output, wherein said detection circuit is a circuit connected between the logic supply voltage and the ground, the detection device furthermore comprising a negative feedback loop at output of the divider circuit to limit the voltage build-up at the output node of the divider circuit after the crossing of the detection threshold.
2. A detection device according to claim 1, wherein said negative feedback loop is connected at output to an internal node of the divider circuit located between the high-voltage node and the output node of the divider circuit.
3. A detection device according to claim 2, wherein the divider circuit comprises a first resistor connected between the high-voltage node and said internal node, a transistor connected between said internal node and the output node with its gate receiving the logic supply voltage and a second resistor connected between the output node and the ground.
4. A detection device according to claim 3, wherein the first resistor and the second resistor are elements capable of withstanding the high voltage.
5. A device according to claim 4, wherein the first resistor is formed by at least two standard MOS transistors in series having their gates connected to the output node or to the internal node of the divider circuit.
6. A device according to any of the above claims, wherein the negative feedback loop comprises a resistor connected between the high-voltage node and an internal node, a first transistor connected between this internal node and the logic supply voltage, with its gate connected to the output node of the divider circuit, and a second transistor, connected between the internal node of the divider circuit and the logic supply voltage, with its gate connected to the internal node of the loop.
7. A detection device according to the previous claim, wherein the resistor of the loop is of the type capable of withstanding the high voltage.
8. A detection device according to claim 7, wherein the resistor of the loop is formed by at least two series-connected standard MOS transistors having their gates connected to the output node or to the internal node of the divider circuit.
9. A detection device according to any of the previous claims, wherein the detection circuit comprises an inverter.
10. A detection device according to any of the previous claims, made with MOS or CMOS technology.

The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.

1. A thermoanalytical sensor comprising:
a substrate that can conduct a heat flow between a heat source that is thermally coupled to the substrate and at least one measurement position that is formed on the sensor; and
a thermocouple arrangement formed on a substantially planar surface of the substrate to deliver a thermoelectric signal, wherein the thermocouple arrangement comprises:
a serial chain of thermocouple junctions that are composed of two different thermocouple materials serially connected to form a thermocouple column, wherein the serial chain of thermocouple junctions extends in an azimuthal direction around a center of the measurement position;
at least one interstitial area of the surface is azimuthally confined between a first thermocouple junction closest to the center and two immediately neighboring second thermocouple junctions in the serial chain;
wherein the chain comprises a first thermocouple junction connected to a second thermocouple junction of the chain, and a third thermocouple junction connected to a fourth thermocouple junction of the chain, such that the first, second, third, and fourth thermocouple junctions are arranged at different radial distances from the center of the measurement position.
2. A thermoanalytical sensor according to claim 1, wherein thermocouple material between the first and second thermocouple junctions in the serial chain extends in a shape of rectilinear strip-sections.
3. A thermoanalytical sensor according to claim 1, wherein thermocouple material between the third and fourth thermocouple junctions that are immediate neighbors in the serial chain and lie within the same interstitial area extends in a shape of rectilinear strip sections.
4. A thermoanalytical sensor according to claim 1, wherein the thermocouple material runs from the fourth thermocouple junctions of the chain to the third thermocouple junctions of the chain, and includes azimuthally-directed strip sections.
5. A thermoanalytical sensor according to claim 1, wherein connector terminals are formed on the surface of the substrate, said connector terminals being respectively connected to two ends of the thermocouple column, wherein the thermoelectric signal delivered by the thermocouple column can be tapped from said connector terminals.
6. A thermoanalytical sensor according to claim 1, wherein the substrate is a ceramic material.
7. A thermoanalytical sensor according to claim 1, wherein the first thermocouple junction lies on a first circle whose midpoint is located at the center of the measurement position, the second thermocouple junctions lie on a second circle concentric to and with a larger radius than the first circle, the third thermocouple junction lies on a third circle that is concentric to the first circle and has a radius that is larger than the radius of the first circle and smaller than the radius of the second circle, and the fourth thermocouple junction lies on a fourth circle that is concentric to the first circle and has a larger radius than the second circle.
8. A thermoanalytical sensor according to claim 7, wherein the thermocouple junctions of a chain are arranged on their respective circles at equal angular intervals.
9. A thermoanalytical sensor according to claim 1, wherein a plurality of the measurement positions are arranged on the sensor.
10. A thermoanalytical sensor according to claim 9, wherein two of the measurement positions are arranged on the sensor.
11. A thermoanalytical sensor according to claim 9, wherein four measurement positions are arranged on the sensor in a configuration where a straight connecting line between centers of one pair of the measurement positions perpendicularly bisects a straight line between the centers of the other pair, and vice versa.
12. A thermoanalytical sensor according to claim 1, wherein the substrate is a ceramic substrate whose thermal conductivity is not larger than 5 Watt per meter and Kelvin.
13. A thermoanalytical sensor according to claim 12, wherein the substrate comprises a glass-ceramic material.
14. A thermoanalytical sensor according to claim 12, wherein the substrate is a ceramic substrate whose thermal conductivity is not larger than 3 Watt per meter and Kelvin.
15. A thermoanalytical sensor according to claim 12, wherein the substrate is a ceramic substrate whose thermal conductivity is not larger than 2 Watt per meter and Kelvin.
16. A thermoanalytical sensor according to claim 1, wherein a further thermocouple arrangement is formed at the measurement position on the surface of the substrate for delivering a thermoelectric signal representing absolute temperature at the measurement position, and connector terminals for tapping the thermoelectric signal representing the absolute temperature are formed on the surface of the substrate.
17. A thermoanalytical sensor according to claim 16, wherein the thermocouple arrangement that serves to deliver the thermoelectric signal representing the absolute temperature comprises an area containing a first thermocouple material, said area being delimited by the thermocouple junctions which surround the measurement position, and further comprises a connector portion leading from said delimited area containing the first thermocouple material to one of the connector terminals that are arranged on the surface.
18. A thermoanalytical sensor according to claim 17, wherein said delimited area containing the first thermocouple material is configured in a shape of a circular ring.
19. A thermoanalytical sensor according to claim 18, wherein in the delimited area containing the first thermocouple material, a thermocouple junction is formed with a second thermocouple material that is different from the first thermocouple material and extends to a connector terminal that is formed on the surface.
20. A thermoanalytical sensor according to claim 19, wherein two measurement positions are formed on the sensor, a connection is formed on the substrate between the second thermocouple materials of the two measurement positions, and said connection leads to a common connector terminal.
21. A thermoanalytical sensor according to claim 19, wherein thermocouple arrangements that are formed on the substrate are configured as thick film arrangements.
22. A thermoanalytical sensor according to claim 19, wherein two measurement positions are formed on the sensor, a connection is formed on the substrate between two electrically equivalent ends of respective thermocouple columns at the measurement positions, and other ends of the two thermocouple columns are connected to connector terminals that are formed on the substrate and serve to tap a difference between respective thermoelectric signals of the two thermocouple columns.
23. A thermoanalytical sensor according to claim 22, wherein the connection is connected to a common connector terminal that is formed on the substrate.