1. A hierarchical interconnect architecture for a field programmable gate array integrated circuit including a plurality of logic function blocks, the architecture including:
a third level including:
a plurality of third groups of functional logic blocks at the third level, wherein:
each third group spans a third length and a third width, and
a set of third routing resources that includes:
a plurality of freeway routing channels associated with each third group of functional logic blocks, each freeway routing channel associated with one of the third groups including a plurality of interconnect conductors configured to make programmable connections to functional logic blocks in other ones of the third groups; and
a second level including:
a plurality of second groups of functional logic blocks at the second level, wherein:
each second group spanning a second length and a second width, and
the number of functional logic blocks in the third groups is greater than the number of functional logic blocks in the second groups,
a set of second routing resources that includes:
a plurality of expressway routing channels including a plurality of interconnect conductors configured to make programmable connections between different ones of the functional logic blocks in the second group and to interconnect conductors in the set of third routing resources; and
a first level including:
a plurality of first groups of functional logic blocks at the first level, wherein:
each first group spans a first length and a first width,
the number of functional logic blocks in the second groups is greater than the number of functional logic blocks in the first groups,
each of the plurality of groups of functional blocks comprises a plurality of clusters, each cluster comprising at least one LUT and at least one DFF; and
a set of first routing resources;
a block connect routing channel including a plurality of interconnect conductors configured to make programmable connections between different ones of the functional logic blocks in the second group and to interconnect conductors in the set of second routing resources;
a local mesh routing channel including a plurality of interconnect conductors configured to make programmable connections between adjacent ones of the functional logic blocks in a single one of the first groups of the functional logic blocks;
a direct connect routing channel including a plurality of interconnect conductors configured to make programmable connections between selected elements of adjacent ones of the functional logic blocks in a single one of the first groups of the functional logic blocks.
2. The hierarchical interconnect architecture of claim 1 wherein:
programmable connections are made using reprogrammable elements.
3. The hierarchical interconnect architecture of claim 2 wherein:
the reprogrammable elements are SRAM switches.
4. The hierarchical interconnect architecture of claim 2 wherein:
the programmable connections between ones of the third group of functional logic blocks are made in a plurality of first programmable matrices of reprogrammable switches.
5. The hierarchical interconnect architecture of claim 1 wherein:
the interconnect conductors in the plurality of freeway routing channels have a length substantially equal to one of the third length and the third width.
6. The hierarchical interconnect architecture of claim 1 wherein:
programmable connections between different ones of the functional logic blocks in the second group and to interconnect conductors in the set of third routing resources are made in a plurality of second programmable matrices of reprogrammable switches.
7. The hierarchical interconnect architecture of claim 1 wherein:
programmable connections between different ones of the functional logic blocks in the second group and to interconnect conductors in the set of second routing resources are made in a plurality of third programmable matrices of reprogrammable switches.
8. The hierarchical interconnect architecture of claim 1 wherein:
each cluster comprises:
a plurality of three input LUTs, each having three inputs and an output;
a two input LUT; and
a DFF having an input and an output.
9. The hierarchical interconnect architecture of claim 8 wherein:
in each cluster:
the output of a first three input LUT is programmably coupled via a first programmable switch to the input of the DFF, and
the output of a second three input LUT is programmably coupled via a second programmable switch to the input of the DFF.
10. The hierarchical interconnect architecture of claim 9 wherein:
each cluster further comprises:
a first inverter having an output and an input programmably coupled to the output of the first three input LUT via a third programmable switch; and
a second inverter having an output and an input programmably coupled to the output of the second three input LUT via a fourth programmable switch.
11. The hierarchical interconnect architecture of claim 10 wherein:
in each cluster:
the output of the DFF is programmably coupled via a fifth programmable switch to the input of the first inverter; and
the output of the DFF is programmably coupled via a sixth programmable switch to the input of the second inverter.
12. The hierarchical interconnect architecture of claim 10 wherein:
each cluster is associated with:
a first output switch box having an input programmably coupled to the output of the first inverter via a seventh programmable switch and coupled to the output of the second inverter via a eighth programmable switch; and
a second output switch box having an input programmably coupled to the output of the first inverter via a ninth programmable switch and coupled to the output of the second inverter via a tenth programmable switch.
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 composition comprising a hepatitis C virus (HCV) E1E2 antigen and a submicron oil-in-water emulsion that lacks N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1-2-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy)-ethylamine (MTP-PE), wherein the submicron oil-in-water emulsion is capable of enhancing the immune response to the HCV E1E2 antigen.
2. The composition of claim 1, wherein the HCV E1E2 antigen comprises a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
3. The composition of claim 2, wherein the HCV E1E2 antigen comprises the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
4. The composition of claim 1, further comprising an immunostimulatory nucleic acid sequence (ISS).
5. The composition of claim 4, wherein the ISS is a CpG oligonucleotide.
6. The composition of claim 5, wherein the CpG oligonucleotide comprises the sequence 5-X1X2CGX3X4, where X1 and X2 are a sequence selected from the group consisting of GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT and TpG; and X3 and X4 are selected from the group consisting of TpT, CpT, ApT, ApG, CpG, TpC, ApC, CpC, TpA, ApA, GpT, CpA, and TpG, wherein p signifies a phosphate bond.
7. The composition of claim 5, wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT.
8. The composition of claim 7, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1).
9. The composition of claim 7, wherein the CpG oligonucleotide comprises the sequence 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
10. The composition of claim 1, wherein the submicron oil-in-water emulsion comprises:
(1) a metabolizable oil, wherein the oil is present in an amount of 0.5% to 20% of the total volume; and
(2) an emulsifying agent, wherein the emulsifying agent is present in an amount of 0.01% to 2.5% by weight (wv), and wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter.
11. The composition of claim 10, wherein the oil is present in an amount of 1% to 12% of the total volume and the emulsifying agent is present in an amount of 0.01% to 1% by weight (wv).
12. The composition of claim 10, wherein the emulsifying agent comprises a polyoxyethylene sorbitan mono-, di-, or triester andor a sorbitan mono-, di-, or triester.
13. The composition of claim 10, wherein the submicron oil-in-water emulsion comprises 4-5% wv squalene, 0.25-1.0% wv polyoxyelthylenesorbitan monooleate, andor 0.25-1.0% sorbitan trioleate.
14. The composition of claim 13, wherein the submicron oil-in-water emulsion consists essentially of 5% by volume of squalene; and one or more emulsifying agents selected from the group consisting of polyoxyelthylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (wv).
15. The composition of claim 14, wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (wv).
16. A composition comprising a hepatitis C virus (HCV) E1E2 antigen and an immunostimulatory nucleic acid sequence (ISS), wherein the ISS is capable of enhancing the immune response to the HCV E1E2 antigen.
17. The composition of claim 16, wherein the ISS is a CpG oligonucleotide.
18. The composition of claim 17, wherein the HCV E1E2 antigen comprises a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
19. The composition of claim 18, wherein the HCV E1E2 antigen comprises the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
20. The composition of claim 16, wherein the CpG oligonucleotide comprises the sequence 5-X1X2CGX3X4, where X1 and X2 are a sequence selected from the group consisting of GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT and TpG; and X3 and X4 are selected from the group consisting of TpT, CpT, ApT, ApG, CpG, TpC, ApC, CpC, TpA, ApA, GpT, CpA, and TpG, wherein p signifies a phosphate bond.
21. The composition of claim 16, wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT.
22. The composition of claim 21, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1).
23. The composition of claim 21, wherein the CpG oligonucleotide comprises the sequence 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
24. A composition comprising:
(a) a hepatitis C virus (HCV) E1E2 antigen comprising a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C;
(b) a submicron oil-in-water emulsion capable of enhancing the immune response to the HCV E1E2 antigen, wherein the submicron oil-in-water emulsion comprises (i) a metabolizable oil, wherein the oil is present in an amount of 1% to 12% of the total volume, and (ii) an emulsifying agent, wherein the emulsifying agent is present in an amount of 0.01% to 1% by weight (wv) and comprises polyoxyethylene sorbitan mono-, di-, or triester andor a sorbitan mono-, di-, or triester, wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter; and
(c) a CpG oligonucleotide, wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT.
25. The composition of claim 24, wherein the HCV E1E2 antigen comprises the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
26. The composition of claim 24, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1).
27. The composition of claim 24, wherein the CpG oligonucleotide comprises the sequence 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
28. The composition of claim 24, wherein the submicron oil-in-water emulsion comprises 4-5% wv squalene, 0.25-1.0% wv polyoxyelthylenesorbitan monooleate, andor 0.25-1.0% sorbitan trioleate, and optionally, N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1-2-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy)-ethylamine (MTP-PE).
29. The composition of claim 24, wherein the submicron oil-in-water emulsion consists essentially of 5% by volume of squalene; and one or more emulsifying agents selected from the group consisting of polyoxyelthylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (wv).
30. The composition of claim 29, wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (wv).
31. A composition comprising:
(a) a hepatitis C virus (HCV) E1E2 antigen comprising the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C;
(b) a submicron oil-in-water emulsion capable of enhancing the immune response to the HCV E1E2 antigen, wherein the submicron oil-in-water emulsion comprises 4-5% wv squalene, 0.25-1.0% wv polyoxyelthylenesorbitan monooleate, andor 0.25-1.0% sorbitan trioleate, and optionally, N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1-2-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy)-ethylamine (MTP-PE), wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter; and
(c) a CpG oligonucleotide, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1) or the sequence 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
32. The composition of claim 31, wherein the HCV E1E2 antigen consists of the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
33. The composition of claim 32, wherein the submicron oil-in-water emulsion consists essentially of (i) 5% by volume of squalene; and (ii) one or more emulsifying agents selected from the group consisting of polyoxyelthylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (wv).
34. The composition of claim 33, wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (wv).
35. A method of stimulating an immune response in a vertebrate subject which comprises administering to the subject a therapeutically effective amount of a hepatitis C virus (HCV) E1E2 antigen and a submicron oil-in-water emulsion that lacks N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1-2-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy)-ethylamine (MTP-PE), wherein the submicron oil-in-water emulsion is capable of increasing the immune response to the HCV E1E2 antigen.
36. The method of claim 35, wherein the submicron oil-in-water emulsion is present in the same composition as the antigen.
37. The method of claim 35, wherein the HCV E1E2 antigen comprises a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
38. The method of claim 35, wherein the HCV E1E2 antigen comprises the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
39. The method of claim 33, further comprising administering an immunostimulatory nucleic acid sequence (ISS) to the subject, wherein the ISS is capable of enhancing the immune response to the E1E2 antigen.
40. The method of claim 39, wherein the ISS is a CpG oligonucleotide.
41. The method of claim 40, wherein the CpG oligonucleotide comprises the sequence 5-X1X2CGX3X4, where X1 and X2 are a sequence selected from the group consisting of GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT and TpG; and X3 and X4 are selected from the group consisting of TpT, CpT, ApT, ApG, CpG, TpC, ApC, CpC, TpA, ApA, GpT, CpA, and TpG, wherein p signifies a phosphate bond.
42. The method of claim 40, wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT.
43. The method of claim 42, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1).
44. The method of claim 42, wherein the CpG oligonucleotide comprises the sequence 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
45. The method of claim 35, wherein the submicron oil-in-water emulsion comprises:
(1) a metabolizable oil, wherein the oil is present in an amount of 0.5% to 20% of the total volume; and
(2) an emulsifying agent, wherein the emulsifying agent is present in an amount of 0.01% to 2.5% by weight (wv), and wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter.
46. The method of claim 45, wherein the oil is present in an amount of 1% to 12% of the total volume and the emulsifying agent is present in an amount of 0.01% to 1% by weight (wv).
47. The method of claim 45, wherein the emulsifying agent comprises a polyoxyethylene sorbitan mono-, di-, or triester andor a sorbitan mono-, di-, or triester.
48. The method of claim 47, wherein the submicron oil-in-water emulsion comprises 4-5% wv squalene, 0.25-1.0% wv polyoxyelthylenesorbitan monooleate, andor 0.25-1.0% sorbitan trioleate.
49. The method of claim 48, wherein the submicron oil-in-water emulsion consists essentially of 5% by volume of squalene; and one or more emulsifying agents selected from the group consisting of polyoxyelthylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (wv).
50. The method of claim 49, wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (wv).
51. A method of stimulating an immune response in a vertebrate subject which comprises administering to the subject a therapeutically effective amount of a hepatitis C virus (HCV) E1E2 antigen and an immunostimulatory nucleic acid molecule (ISS), wherein the ISS is capable of increasing the immune response to the HCV E1E2 antigen.
52. The method of claim 51, wherein the ISS is a CpG oligonucleotide.
53. The method of claim 52, wherein the CpG oligonucleotide is present in the same composition as the antigen.
54. The method of claim 52, wherein the HCV E1E2 antigen comprises a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
55. The method of claim 54, wherein the HCV E1E2 antigen comprises the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
56. The method of claim 52, wherein the CpG oligonucleotide comprises the sequence 5-X1X2CGX3X4, where X1 and X2 are a sequence selected from the group consisting of GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT and TpG; and X3 and X4 are selected from the group consisting of TpT, CpT, ApT, ApG, CpG, TpC, ApC, CpC, TpA, ApA, GpT, CpA, and TpG, wherein p signifies a phosphate bond.
57. The method of claim 52, wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT.
58. The method of claim 57, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1).
59. The method of claim 57, wherein the CpG oligonucleotide comprises the sequence 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
60. A method of stimulating an immune response in a vertebrate subject which comprises administering to the subject a therapeutically effective amount of a composition comprising:
(a) a hepatitis C virus (HCV) E1E2 antigen comprising a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C;
(b) a submicron oil-in-water emulsion capable of enhancing the immune response to the HCV E1E2 antigen, wherein the submicron oil-in-water emulsion comprises (i) a metabolizable oil, wherein the oil is present in an amount of 1% to 12% of the total volume, and (ii) an emulsifying agent, wherein the emulsifying agent is present in an amount of 0.01% to 1% by weight (wv) and comprises polyoxyethylene sorbitan mono-, di-, or triester andor a sorbitan mono-, di-, or triester, wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter; and
(c) a CpG oligonucleotide, wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT.
61. The method of claim 60, wherein the HCV E1E2 antigen comprises the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
62. The method of claim 60, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1).
63. The method of claim 60, wherein the CpG oligonucleotide comprises the sequence 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
64. The method of claim 60, wherein the submicron oil-in-water emulsion comprises 4-5% wv squalene, 0.25-1.0% wv polyoxyelthylenesorbitan monooleate, andor 0.25-1.0% sorbitan trioleate, and optionally, N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1-2-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy)-ethylamine (MTP-PE).
65. The method of claim 64, wherein the submicron oil-in-water emulsion consists essentially of 5% by volume of squalene; and one or more emulsifying agents selected from the group consisting of polyoxyelthylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (wv).
66. The method of claim 65, wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (wv).
67. A method of stimulating an immune response in a vertebrate subject which comprises administering to the subject a therapeutically effective amount of a composition comprising:
(a) a hepatitis C virus (HCV) E1E2 antigen comprising the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C;
(b) a submicron oil-in-water emulsion capable of enhancing the immune response to the HCV E1E2 antigen, wherein the submicron oil-in-water emulsion comprises 4-5% wv squalene, 0.25-1.0% wv polyoxyelthylenesorbitan monooleate, andor 0.25-1.0% sorbitan trioleate, and optionally, N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1-2-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy)-ethylamine (MTP-PE), wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter; and
(c) a CpG oligonucleotide, wherein the CpG oligonucleotide comprises the sequence 5-TCCATGACGTTCCTGACGTT-3(SEQ ID NO: 1) or 5-TCGTCGTTTTGTCGTTTTGTCGTT-3(SEQ ID NO: 5).
68. The method of claim 67, wherein the HCV E1E2 antigen consists of the sequence of amino acids depicted at positions 192-809 of FIGS. 2A-2C.
69. The method of claim 68, wherein the submicron oil-in-water emulsion consists essentially of (i) 5% by volume of squalene; and (ii) one or more emulsifying agents selected from the group consisting of polyoxyelthylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (wv).
70. The method of claim 69, wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (wv).
71. A method of making a composition comprising combining a submicron oil-in-water emulsion that lacks N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1-2-dipalmitoyl-sn-glycero-3-huydroxyphosphoryloxy)-ethylamine (MTP-PE), with a hepatitis C virus (HCV) E1E2 antigen.
72. The method of claim 71, further comprising combining an immunostimulatory nucleic acid sequence (ISS) with the E1E2 antigen and the submicron oil-in-water emulsion.
73. A method of making a composition comprising combining an immunostimulatory nucleic acid sequence (ISS) with a hepatitis C virus (HCV) E1E2 antigen.