1. A device comprising:
an oscillator to generate a periodic signal;
a clock buffer to receive the periodic signal and to convert the periodic signal into a periodic clock signal;
a switch positioned between the oscillator and the clock buffer, the switch including a control input that controls whether the switch is in an open state or a closed state, where the switch, when in the open state, prevents the oscillator from receiving noise from the clock buffer; and
a switch control circuit, an output of the switch control circuit being connected to the control input of the switch, to control the switch so that the switch is in the open state during startup of the oscillator and the switch is in the closed state thereafter.
2. The device of claim 1, further comprising:
a linear regulator connected to provide regulated power to the oscillator.
3. The device of claim 1, where the switch control circuit further includes:
a delay element to delay an enable signal and transmit a delayed version of the enable signal to the switch, where the enable signal controls startup of the oscillator.
4. The device of claim 3, where the delay element delays the enable signal for at least one millisecond.
5. The device of claim 1, where the periodic signal generated by the oscillator includes a differential signal.
6. The device of claim 1, where the periodic signal generated by the oscillator includes a single signal.
7. The device of claim 1, further comprising:
one or more functional components that use clock signals generated based on the periodic signal;
a first power supply to power the oscillator; and
a second power supply, separate from the first power supply, to power the one or more functional components.
8. The device of claim 7, further comprising:
a printed circuit board that contains the oscillator, the switch, the switch control circuit, and the one or more functional components, where the first and second power supply provide separate power and ground connections to the printed circuit board.
9. The device of claim 1, where the switch includes a mechanical relay.
10. The device of claim 1, where the switch uses field effect transistors (FETs).
11. The device of claim 1, where the switch operates to isolate the oscillator from high frequency noise generated by components that use the period signal during startup of the oscillator.
12. A device comprising:
a clock distribution circuit;
a plurality of functional components connected to receive one or more clock signals from the clock distribution circuit; and
a clock circuit including
an oscillator,
a clock buffer to receive an output from the oscillator and to convert the output signal into a periodic clock signal that is passed to the clock distribution circuit,
a switch connected to the oscillator and the clock buffer, where the switch is to pass to the oscillator or isolate from the oscillator, noise from at least one of the clock buffer or the clock distribution circuit, and
a switch control circuit to control the switch so that the switch isolates, from the oscillator, the noise during an initial startup of the oscillator.
13. The device of claim 12, where the clock circuit further includes:
a linear regulator connected to provide regulated power to the oscillator.
14. The device of claim 12, where the switch control circuit further includes:
a delay element to delay an enable signal before transmitting the enable signal to the switch.
15. A system comprising:
a printed circuit board including:
a clock distribution circuit;
a plurality of functional components connected to receive one or more clock signals from the clock distribution circuit; and
a clock circuit including
an oscillator,
a clock buffer to receive an output from the oscillator and to convert the output signal into a periodic clock signal that is passed to the clock distribution circuit,
a switch connected to the oscillator and the clock buffer, where the switch is to pass to or isolate from the oscillator, noise from at least one of the clock buffer or the clock distribution circuit, the switch being controlled so that the switch isolates the noise during an initial startup of the oscillator and passes the noise thereafter;
a first power supply connected to the printed circuit board to supply power to the plurality of functional components; and
a second power supply connected to the printed circuit board to supply power to the clock circuit.
16. The system of claim 15, where the clock circuit further includes:
a linear regulator to provide regulated power to the oscillator.
17. The system of claim 15, where clock circuit further includes:
a delay element to delay a control signal the enables the oscillator to produce an output, the delay element outputting a delayed version of the control signal to the switch.
18. A method comprising
generating, by an oscillator associated with a device, a periodic signal;
receiving, by a clock buffer associated with the device, the periodic signal, where the clock buffer converts the periodic signal into a periodic clock signal; and
controlling, by the device, a switch positioned between the oscillator and the clock buffer, where the switch is in an open state or a closed state, and where the switch, when in the open state, prevents the oscillator from receiving noise from the clock buffer,
where controlling the switch includes:
causing the switch to be in the open state during a startup of the oscillator, and
causing the switch to be in the closed state after the startup of the oscillator.
19. The method of claim 18, further comprising:
providing, via a linear regulator included in the device, regulated power to the oscillator.
20. The method of claim 18, where the startup of the oscillator is in response to an enable signal, and where the method further comprises:
transmitting a delayed version of the enable signal to the switch to control the switch.
21. The method of claim 18, where the periodic signal generated by the oscillator includes a differential signal.
22. The method of claim 18, where the periodic signal generated by the oscillator includes a single signal.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. A method of designing a humanized immunoglobulin (Ig) chain having a framework region from a human acceptor immunoglobulin and complementarity determining regions (CDR’s) from a donor immunoglobulin capable of binding to an antigen, said method comprising the steps of substituting at least one human framework amino acids of the acceptor immunoglobulin with a corresponding amino acid from the donor immunoglobulin at a position in the immunoglobulins where:
(a) the amino acid is immediately adjacent to one of the CDR’s; or
(b) the amino acid is predicted to have a side chain atom whose Van der Waals surface is within about 3 of the CDR’s in a three-dimensional immunoglobulin model and to be capable of interacting with the antigen or with the CDR’s of the humanized immunoglobulin; with the proviso that when the chain is a heavy chain at least one of the substituted amino acids is capable of interacting with CDR’s 2 or 3.
2. A method according to claim 1, wherein the humanized immunoglobulin chain comprises in addition to the CDR’s at least three amino acids from the donor immunoglobulin chosen by criteria (a) or (b).
3. A method of claim 1, further comprising the prior step of comparing the framework or variable region amino acid sequence of the donor Ig with corresponding sequences in a collection of human Ig chains; and selecting to provide the human Ig framework one of the about three most homologous sequences from the collection.
4. A method according to claim 3, wherein the human Ig framework sequence is selected from a collection of at least about ten Ig chain sequences.
5. An immunoglobulin comprising two lightheavy chain pairs, wherein at least one chain is designed in accordance with claim 1.
6. An immunoglobulin according to claim 1, which is specifically reactive with an antigen at an affinity of at least about 108 M1 or stronger.
7. An immunoglobulin according to claim 1, wherein the designed chain is a light chain comprising about 214 amino acids or a heavy chain comprising about 446 amino acids.
8. A DNA sequence which upon expression encodes a humanized immunoglobulin chain according to claim 1.
9. A method for improving the affinity of a humanized immunoglobulin (Ig) to an antigen, by replacing amino acids of the human Ig framework with one to three or more amino acids from the donor Ig framework at positions where:
(a) the amino acid in the human framework region of the first immunoglobulin is rare for said position and the corresponding amino acid in the donor immunoglobulin is common for said position in human immunoglobulin sequences; or
(b) the amino acid is immediately adjacent to one of the CDR’s; or
(c) the amino acid is predicted to have a side chain atom whose Van der Waals surface is within about 3 of the CDR’s in a three-dimensional immunoglobulin model and to be capable of interacting with the antigen or the CDR’s of the humanized immunoglobulin.
10. A method according to claim 9, wherein the additional amino acids comprise up to three amino acids, each of which is immediately adjacent to one of the CDR’s.
11. A method according to claim 9, wherein the additional amino acids comprise at least two amino acids from the donor Ig which are predicted by modelling to be capable of interacting with the antigen or the CDR’s.
12. A method according to claim 9, wherein the humanized Ig has an affinity to the antigen within about 2 fold of the donor Ig.
13. A method of producing a humanized immunoglobulin containing a heavy chain and a light chain designed in accordance with claim 9, said method comprising: culturing a host capable of expressing said heavy chain, said light chain, or both, under conditions suitable for production of said chains; and
recovering from the culture said humanized immunoglobulin.
14. A polynucleotide composition comprising a DNA sequence coding for a humanized immunoglobulin designed in accordance with claim 9.
15. A method of producing an improved humanized immunoglobulin comprising expressing the polynucleotide composition of claim 14.
16. A composition comprising a substantially pure humanized immunoglobulin capable of inhibiting binding of human interleukin-2 (IL-2) to a human IL-2 receptor.
17. A composition according to claim 16, wherein the immunoglobulin exhibits a binding affinity to a human IL-2 receptor of about 108 M1 or stronger.
18. A composition according to claims 16, wherein the immunoglobulin comprises complementarity determining regions from one immunoglobulin and framework regions from at least one different immunoglobulin.
19. A recombinant immunoglobulin composition comprising a human framework and one or more foreign complementarity determining regions (CDRs) not naturally associated with the framework, wherein said immunoglobulin is capable of binding to a human interleukin-2 receptor.
20. A composition according to claim 19, wherein all of the foreign CDR’s are anti-Tac CDRs and the framework is an Eu immunoglobulin framework.
21. A composition according to claim 19, wherein the immunoglobulin is an IgG1 immunoglobulin isotype.
22. An immunoglobulin according to claim 19, which is capable of blocking the binding of interleukin-2 (IL-2) to human IL-2 receptors.
23. An immunoglobulin according to claim 19, wherein the human-like framework regions comprise amino acids sequences from at least two human immunoglobulins.
24. A method of treating T-cell mediated disorders in a human patient, said method comprising administering to said patient a therapeutically effective dose of an immunoglobulin according to claim 19.
25. A composition comprising a substantially pure humanized immunoglobulin specifically reactive with the p75 chain of the human IL-2 receptor.
26. A composition according to claim 25, wherein the immunoglobulin exhibits a binding affinity to a human IL-2 receptor of about 107 M1 or stronger.
27. A composition according to claim 25, wherein the immunoglobulin comprises one or more foreign CDRs substantially homologous to a CDR from an immunoglobulin reactive with human p75 protein.
28. A composition according to claim 25, wherein the immunoglobulin is capable of blocking the binding of interleukin-2 (IL-2) to the p75 chain of human IL-2 receptors.
29. A composition according to claim 25, wherein the humanized immunoglobulin comprises the human framework regions having amino acids sequences from at least two human immunoglobulins.
30. A humanized immunoglobulin capable of binding to human interleukin-2 receptors, said immunoglobulin comprising one or more complementarity determining regions (CDR’s) from mik-1 antibody in a human framework.
31. A humanized immunoglobulin according to claim 30, wherein the human framework is substantially homologous to an Lay immunoglobulin framework.
32. A humanized immunoglobulin according to claim 30 which is capable of blocking the binding of IL-2 to interleukin-2 receptors on human T-cells.
33. A method of treating T-cell mediated disorders in a human patient, said method comprising administering to said patient a therapeutically effective dose of an immunoglobulin according to claim 30.
34. A humanized immunoglobulin according to claim 30 which is complexed to a cytotoxic agent.
35. A composition comprising a substantially pure humanized immunoglobulin specifically reactive with a herpes simplex virus-specific epitope.
36. A composition according to claim 35, wherein the epitope is on a viral surface glycoprotein.
37. A composition according to claim 36, wherein the glycoprotein is gB or gD.
38. A composition comprising a substantially pure humanized immunoglobulin capable of inhibiting binding of a herpes simplex virus (HSV) protein to a mouse monoclonal antibody specifically reactive with said protein, wherein the humanized immunoglobulin comprises at least one complementarity determining region (CDR) from the mouse monoclonal antibody.
39. A composition according to claim 38, wherein the humanized immunoglobulin exhibits a binding affinity of about 107 M1 or stronger.
40. A composition according to claim 38 wherein said immunoglobulin is capable of binding to type 1 or 2 herpes simplex virus (HSV).
41. A composition according to claim 38, wherein the immunoglobulin comprises one or more CDR’s substantially homologous to a CDR from an immunoglobulin reactive with HSV glycoprotein of gB, gD, gG or gH.
42. A composition according to claim 38, wherein the immunoglobulin is an IgG1 immunoglobulin isotype.
43. A humanized immunoglobulin capable of binding to herpes simplex virus, said immunoglobulin comprising one or more complementarity determining regions (CDR’s) from a mouse monoclonal antibody in a human framework, wherein the mouse antibody is Fd 79 or Fd 138-80.
44. A humanized immunoglobulin according to claim 43, wherein the human framework is substantially homologous to an Eu or a Pom immunoglobulin framework.
45. A humanized immunoglobulin according to claim 43 which is capable of neutralizing HSV.
46. A method of treating herpes simplex virus mediated disorders in a human patient, said method comprising administering to said patient a therapeutically effective dose of an immunoglobulin according to claim 38.
47. A composition comprising a substantially pure humanized immunoglobulin specifically reactive with a CD33 antigen epitope.
48. A composition according to claim 47, wherein a variable region of at least one chain of the immunoglobulin comprises three complementarity determining regions (CDR’s) from a non-human antibody in a human framework.
49. A composition according to claim 48, wherein the chain is the heavy chain.
50. A composition according to claim 48, wherein the non-human antibody is M195.
51. A composition comprising a substantially pure humanized immunoglobulin capable of inhibiting binding of CD33 antigen to a mouse monoclonal antibody specifically reactive with said antigen, wherein the humanized immunoglobulin comprises at least one complementarity determining region (CDR) from the mouse monoclonal antibody.
52. A composition according to claim 51, wherein the humanized immunoglobulin exhibits a binding affinity of about 107 M1 or stronger.
53. A composition according to claim 51, which is capable of blocking the binding of mouse M195 antibody to human cells.
54. A composition according to claim 51, wherein the humanized immunoglobulin comprises a human framework substantially homologous to Eu immunoglobulin framework.
55. A humanized immunoglobulin according to claim 51 which is of capable mediating antibody-dependent cellular cytotoxicity in the presence of human target and effector cells.
56. A method of treating myeloid cell-mediated disorders in a human patient, said method comprising administering to said patient a therapeutically effective dose of a composition according to claim 51.
57. A composition according to claim 51, wherein the immunoglobulin is conjugated to a cytoxic agent.
58. A composition comprising a substantially pure humanized immunoglobulin specifically reactive with a human cytomegalovirus-specific epitope.
59. A composition according to claim 58, wherein a variable region of at least one chain comprises three complementarity determining regions from a non-human immunoglobulin chain in a human framework.
60. A composition according to claim 58, wherein the epitope is on a viral surface glycoprotein.
61. A composition according to claim 60, wherein the glycoprotein is gB or gH.
62. A composition comprising a substantially pure humanized immunoglobulin capable of inhibiting binding of a cytomegalovirus (CMV) protein to a mouse monoclonal antibody specifically reactive with said protein, wherein the humanized immunoglobulin comprises at least one complementarity determining region (CDR) from the mouse monoclonal antibody.
63. A composition according to claim 62, wherein the humanized immunoglobulin exhibits a binding affinity of about 107 M1 or stronger.
64. A recombinant immunoglobulin composition comprising a human framework and one or more foreign complementarity determining regions (CDR’s) not naturally associated with the framework, wherein said immunoglobulin is capable of binding to CMV.
65. A composition according to claim 64, wherein all of the foreign CDR’s are located on heavy chains of the immunoglobulin.
66. A composition according to claim 64, wherein the immunoglobulin is an IgG1 immunoglobulin isotype.
67. A composition according to claim 64 wherein the immunoglobulin is capable of blocking the binding of CMV to human cells.
68. An immunoglobulin according to claim 64, wherein the framework regions comprise amino acids sequences from at least two human immunoglobulins.
69. A humanized immunoglobulin capable of binding to cytomegalovirus, said immunoglobulin comprising one or more complementarity determining regions (CDR’s) from a mouse monoclonal antibody in a human framework, wherein the mouse antibody is CMV5, CMV109 or CMV115.
70. A humanized immunoglobulin according to claim 69, wherein the human framework is substantially homologous to an Eu or a Wol immunoglobulin framework.
71. A humanized immunoglobulin according to claim 69 which is capable of neutralizing CMV.
72. A method of treating cytomegalovirus mediated disorders in a human patient, said method comprising administering to said patient a therapeutically effective dose of an immunoglobulin according to claim 69.
73. A method of treating cytomegalovirus mediated disorders in a human patient, said method comprising administering to said patient a therapeutically effective dose of a combination of two or more immunoglobulins according to claims 69.
74. A composition comprising a substantially pure humanized immunoglobulin specifically reactive with human -IFN.
75. A composition according to claim 74, wherein a variable region of at least one chain comprises three complementarity determining regions (CDR’s) from a non-human antibody in a human framework.
76. A composition according to claim 75, wherein the non-human antibody is AF2.
77. A composition according to claim 74 capable of inhibiting binding of human -IFN to a human -IFN receptor.
78. A recombinant immunoglobulin composition comprising a human framework and one or more complementarity determining regions (CDR’s) not naturally associated with the framework, wherein said immunoglobulin is capable of specifically inhibiting biniding of human -IFN to a human -IFN receptor.
79. A composition according to claim 78, wherein one or more of the foreign CDR’s are substantially homologous to a CDR from the AF2 antibody.
80. A composition according to claim 78, wherein the immunoglobulin is an IgG1 immunoglobulin isotype.
81. A composition according to claim 78, wherein the immunoglobulin is capable of blocking the binding of human -IFN antibody to human cells.
82. A method of treating autoimmune disorders in a human patient, said method comprising administering to said patient a therapeutically effective dose of a composition according to claim 78.
83. A composition according to claim 20, wherein the immunoglobulin is conjugated to a cytotoxic agent.
84. A composition according to claim 35, wherein the immunoglobulin is conjugated to a cytotoxic agent.
85. A composition according to claim 64, wherein the immunoglobulin is conjugated to a cytotoxic agent.