1. A diagnostic method for the specific detection of an RNA analyte in a sample, said method comprising:
a) processing a sample to allow for or enhance discrimination between an RNA analyte and non-analyte nucleic acids present in said sample;
b) contacting said sample with an oligonucleotide probe having a detectable label under conditions such that a first base region of said probe stably and specifically hybridizes to a second base region of said RNA analyte to form a probe:analyte hybrid containing at least one ribonucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety, wherein said probe does not stably hybridize under said conditions to non-analyte nucleic acids present in said sample, and wherein said probe is free in solution when contacted with said sample; and
c) determining whether said hybrid is present in said sample as an indication of the presence or absence of said RNA analyte in said sample.
2. The method of claim 1, wherein said first base region contained within said hybrid includes a cluster of at least 4 ribonucleotides modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
3. The method of claim 1, wherein said first base region contained within said hybrid includes at least one nucleotide which is not a ribonucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
4. The method of claim 1, wherein each nucleotide of said probe is a ribonucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
5. The method of claim 1, wherein said probe includes a conjugate molecule.
6. The method of claim 2, wherein said probe includes a conjugate molecule joined to said probe at a site located within the cluster of said first base region.
7. The method of claim 1, wherein said probe is between 10 and 100 bases in length.
8. The method of claim 1, wherein said probe is between 10 and 16 bases in length.
9. The method of claim 1, wherein said label is a chemiluminescent or a fluorescent agent.
10. The method of claim 1, wherein said RNA analyte consists of ribosomal RNA.
11. The method of claim 1, wherein said sample contains DNA.
12. The method of claim 1, wherein said second base sequence is contained in a product of an amplification procedure.
13. The method of claim 12, wherein said amplification procedure is a transcription-based method of amplification.
14. The method of claim 1 further comprising the step of quantifying said target organism or virus determined to be present in said sample.
15. The method of claim 12 further comprising the step of quantifying said RNA analyte determined to be present in said sample.
16. The method of claim 1, wherein said RNA analyte is directly or indirectly immobilized by a solid support in said processing step.
17. The method of claim 1 further comprising the step of providing to said sample a nuclease inhibitor other than a polynucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety of a ribonucleotide.
18. The method of claim 1, wherein said sample is obtained from a clinical source, an environmental source or a food source.
19. The method of claim 1, wherein said determining step provides an indication of the presence or absence of a particular species of microorganisms in said sample.
20. The method of claim 1, wherein said determining step provides an indication of the presence or absence of a virus in said sample.
21. The method of claim 20, wherein said sample contains chromosomal DNA.
22. The method of claim 1, wherein said sample is obtained from a human.
23. The method of claim 1, wherein said RNA analyte consists of mRNA.
24. The method of claim 1, wherein said RNA analyte consists of tRNA.
25. The method of claim 1 further comprising contacting said sample with one or more helper probes.
26. The method of claim 1, wherein the rate of hybridization of said probe to said second base region is greater than the rate of hybridization of said probe containing an unmodified form of said first base region having the same base sequence and length to said second base region under identical nucleic acid conditions.
27. The method of claim 26, wherein the unmodified form of said first base region consists of deoxynucleotides.
28. The method of claim 27, wherein said probe hybridizes to said second base region at least about 1.6-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
29. The method of claim 27, wherein said probe hybridizes to said second base region at least about 2.0-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
30. The method of claim 27, wherein said probe hybridizes to said second base region at least about 2.3-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
31. The method of claim 27, wherein said probe hybridizes to said second base region at least about 2.6-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
32. The method of claim 27, herein said probe hybridizes to said second base region at least about 2.9-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
33. The method of claim 27, wherein said probe hybridizes to said second base region at least about 3.1-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
34. The method of claim 1, wherein said contacting step is not followed by the addition of a nuclease to said sample.
35. The method of claim 1, wherein said first base region targets a double-stranded region contained within said second base region.
36. The method of claim 1 further comprising providing to said sample a detergent.
37. The method of claim 36, wherein said first base region targets a double-stranded region contained within said second base region.
38. A diagnostic method for the specific detection of an RNA analyte in a sample, said method comprising:
a) contacting a sample with an oligonucletide probe having a detectable label in the presence of a detergent under conditions such that a first base region of said probe stably and specifically hybridizes to a second base region of an RNA analyte to form a probe:analyte hybrid containing at least one ribonucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety, wherein said probe does not stably hybridize under said conditions to non-analyte nucleic acids present in said sample; and
b) determining whether said hybrid is present in said sample as an indication of the presence or absence of said RNA analyte in said sample.
39. The method of claim 38, wherein said first base region contained within said hybrid includes a cluster of at least 4 ribonucleotides modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
40. The method of claim 38, wherein said first base region contained within said hybrid includes at least one nucleotide which is not a ribonucleolide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
41. The method of claim 38, wherein each nucleotide of said probe is a ribonucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
42. The method of claim 38, wherein said probe includes a conjugate molecule.
43. The method of claim 39, wherein said probe includes a conjugate molecule joined to said probe at a site located within the cluster of said first base region.
44. The method of claim 38, wherein said probe is between 10 and 100 bases in length.
45. The method of claim 38, wherein said probe is between 10 and 16 bases in length.
46. The method of claim 38, wherein said label is a chemiluminescent or a fluorescent agent.
47. The method of claim 38, wherein said RNA analyte consists of ribosomal RNA.
48. The method of claim 38, wherein said sample contains DNA.
49. The method of claim 38, wherein said second base sequence is contained in a product of an amplification procedure.
50. The method of claim 49, wherein said amplification procedure is a transcription-based method of amplification.
51. The method of claim 38 further comprising the step of quantifying said RNA analyte determined to be present in said sample.
52. The method of claim 49 further comprising the step of quantifying said RNA analyte determined to be present in said sample.
53. The method of claim 38, wherein at least one of said probe and said RNA analyte is directly or indirectly immobilized by a solid support.
54. The method of claim 38 further comprising the step of providing to said sample a nuclease inhibitor other than a polynucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety of a ribonucleotide.
55. The method of claim 38, wherein said sample is obtained from a clinical source, an environmental source or a food source.
56. The method of claim 38, wherein said determining step provides an indication of the presence or absence of a particular species of microorganisms in said sample.
57. The method of claim 38, wherein said determining step provides an indication of the presence or absence of a virus in said sample.
58. The method of claim 57, wherein said sample contains chromosomal DNA.
59. The method of claim 38, wherein said sample is obtained from a human.
60. The method of claim 38, wherein said RNA analyte consists of mRNA.
61. The method of claim 38, wherein said RNA analyte consists of tRNA.
62. The method of claim 38 further comprising contacting said sample with one or more helper probes.
63. The method of claim 38, wherein the rate of hybridization of said probe to said second base region is greater than the rate of hybridization of said probe containing an unmodified form of said first base region having the same base sequence and length to said second base region under identical nucleic acid conditions.
64. The method of claim 63, wherein the unmodified form of said first base region consists of deoxynucleotides.
65. The method of claim 64, wherein said probe hybridizes to said second base region at least about 1.6-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
66. The method of claim 64, wherein said probe hybridizes to said second base region at least about 2.0-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
67. The method of claim 64, wherein said probe hybridizes to said second base region at least about 2.3-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
68. The method of claim 64, wherein said probe hybridizes to said second base region at least about 2.6-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
69. The method of claim 64, wherein said probe hybridizes to said second base region at least about 2.9-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
70. The method of claim 64, wherein said probe hybridizes to said second base region at least about 3.1-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
71. The method of claim 38, wherein said contacting step is not followed by the addition of a nuclease to said sample.
72. The method of claim 38, wherein said probe is free in solution during said contacting step.
73. A diagnostic method for the specific detection of an RNA analyte in a sample, said method comprising:
a) contacting a sample with an oligonucleotide probe having a detectable label under conditions such that a first base region of said probe stably and specifically hybridizes to a second base region present in an RNA analyte to form a probe:analyte hybrid containing at least one ribonucleotide modified to include a 240 -O-methyl substitution to the ribofuranosyl moiety, said first base region targeting a double-stranded region contained within said second base region, wherein said probe does not stably hybridize under said conditions to non-analyte nucleic acids present in said sample, and wherein said probe is free in solution when contacted with said sample; and
b) determining whether said hybrid is present in said sample as an indication of the presence or absence of said RNA analyte in said sample.
74. The method of claim 73, wherein said first base region contained within said hybrid includes a cluster of at least 4 ribonucleotides modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
75. The method of claim 73, wherein said first base region contained within said hybrid includes at least one nucleotide which is not a ribonucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
76. The method of claim 73, wherein each nucleotide of said probe is a ribonucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety.
77. The method of claim 73, wherein said probe includes a conjugate molecule.
78. The method of claim 74, wherein said probe includes a conjugate molecule joined to said probe at a site located within the cluster of said first base region.
79. The method of claim 73, wherein said probe is between 10 and 100 bases in length.
80. The method of claim 73, wherein said probe is between 10 and 16 bases in length.
81. The method of claim 73, wherein said label is a chemiluminescent or a fluorescent agent.
82. The method of claim 73, wherein said RNA analyte consists of ribosomal RNA.
83. The method of claim 73, wherein said sample contains DNA.
84. The method of claim 73, wherein said second base sequence is contained in a product of an amplification procedure.
85. The method of claim 84, wherein said amplification procedure is a transcription-based method of amplification.
86. The method of claim 73 further comprising the step of quantifying said RNA analyte determined to be present in said sample.
87. The method of claim 84 further comprising the step of quantifying said RNA analyte determined to be present in said sample.
88. The method of claim 73, wherein at least one of said probe and said RNA analyte is directly or indirectly immobilized by a solid support.
89. The method of claim 73 further comprising the step of providing to said sample a nuclease inhibitor other than a polynucleotide modified to include a 2\u2032-O-methyl substitution to the ribofuranosyl moiety of a ribonucleotide.
90. The method of claim 73, wherein said sample is obtained from a clinical source, an environmental source or a food source.
91. The method of claim 73, wherein said determining step provides an indication of the presence or absence of a particular species of microorganisms in said sample.
92. The method of claim 73, wherein said determining step provides an indication of the presence or absence of a virus in said sample.
93. The method of claim 92, wherein said sample contains chromosomal DNA.
94. The method of claim 73, wherein said sample is obtained from a human.
95. The method of claim 73, wherein said RNA analyte consists of mRNA.
96. The method of claim 73, wherein said RNA analyte consists of tRNA.
97. The method of claim 73 further comprising contacting said sample with one or more helper probes.
98. The method of claim 73, wherein the rate of hybridization of said probe to said second base region is greater than the rate of hybridization of said probe containing an unmodified form of said first base region having the same base sequence and length to said second base region under identical nucleic acid conditions.
99. The method of claim 98, wherein the unmodified form of said first base region consists of deoxynucleotides.
100. The method of claim 99, wherein said probe hybridizes to said second base region at least about 1.6-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
101. The method of claim 99, wherein said probe hybridizes to said second base region at least about 2.0-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
102. The method of claim 99, wherein said probe hybridizes to said second base region at least about 2.3-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
103. The method of claim 99, wherein said probe hybridizes to said second base region at least about 2.6-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
104. The method of claim 99, wherein said probe hybridizes to said second base region at least about 2.9-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
105. The method of claim 99, wherein said probe hybridizes to said second base region at least about 3.1-fold faster than said probe containing the unmodified form of said first base region does under said conditions.
106. The method of claim 73, wherein said contacting step is not followed by the addition of a nuclease to said sample.
107. The method of claim 1, wherein said probe:analyte hybrid forms in solution, provided said RNA analyte is present in said sample.
108. The method of claim 72, wherein said probe:analyte hybrid forms in solution, provided said RNA analyte is present in said sample.
109. The method of claim 73, wherein said probe:analyte hybrid forms in solution, provided said RNA analyte is present in said sample.
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 delivery device that comprises:
a fluid cartridge holder comprising a cartridge containing fluid,
a housing,
a piston drive mechanism situated within the housing and comprising a hollow piston rod and a drive-shaft,
which hollow piston rod has an internal thread on at least a portion of its inner surface and a non-circular outer section,
and which drive-shaft has an external thread which mates with the internal thread of the hollow piston rod forming a thread connection and being axially restrained in the proximal direction relative to the housing,
a piston drive mechanism for rotating the drive-shaft such that upon activation of the driving mechanism the piston rod is forced to move axially in the distal direction causing ejection of the fluid from the cartridge, the delivery device further characterized in that the internal threads on the hollow piston rod and the external threads on the drive shaft are not exposed when the cartridge holder is removed.
2. A delivery device according to claim 1 wherein the piston rod is prevented from rotating by a locking bush with an inner profile which mates with the non-circular outer section of the piston rod, and wherein the housing comprises a concentrically arranged outer housing-tube and an inner housing-tube.
3. A delivery device according to claim 2 wherein the piston drive mechanism is connected to the housing via a one way ratchet such that the piston rod is prevented from moving axially.
4. A delivery device according to claim 3 wherein the piston drive mechanism is connected to the housing via a one way ratchet such that the piston rod is prevented from moving axially in the proximal direction.
5. A delivery device according to claim 4 wherein the drive-shaft is connected to the housing via a one way ratchet such that the drive shaft is prevented from rotating in the direction which would result in movement of the piston rod axially in the proximal direction.
6. A delivery device according to claim 1 wherein the housing comprises a concentrically arranged outer housing-tube and an inner housing-tube.
7. A delivery device according to claim 6 wherein the piston drive mechanism is located within the inner housing-tube.
8. A delivery device according to claim 7 wherein the piston drive mechanism is connected to the inner housing-tube via a one way ratchet such that the piston rod is prevented from moving axially.
9. A delivery device according to claim 8 wherein the piston drive mechanism is connected to the inner housing-tube via a one way ratchet such that the piston rod is prevented from moving axially in the proximal direction.
10. A delivery device according to claim 9 wherein the drive-shaft is connected to the inner housing-tube via a one way ratchet such that the drive-shaft is prevented from rotating in the direction which would result in movement of the piston axially.
11. A delivery device according to claim 10 wherein the drive-shaft is connected to the inner housing-tube via a one way ratchet such that the drive-shaft is prevented from rotating in the direction which would result in movement of the piston axially in the proximal direction.
12. A delivery device according to claim 11 wherein the drive-shaft comprises ratchet teeth that inter digit correspondingly located teeth on the inner housing-tube to form the one-way ratchet.
13. A delivery device according to claim 12 wherein the ratchet teeth are present on the drive-shaft.
14. A delivery device according to claim 13 wherein the ratchet teeth are present on the proximal region of the drive-shaft.
15. A delivery device according to claim 2 wherein the locking bush is located between the piston rod and the inner housing-tube.
16. A delivery device according to claim 15 wherein the locking bush is located between the distal end of the piston rod and the inner housing-tube.
17. A delivery device according to claim 16 in which the inner profile of the locking bush are protrusions that mate with longitudinal channels that traverse the length of the non-circular outer portion of the piston rod, thereby preventing the piston rod from rotating.
18. A delivery device according to claim 17 in which the locking bush further comprises an outer toothed surface.
19. A delivery device according to claim 18 wherein the portions of the inner housing-tube are further molded as two sprung clips.
20. A delivery device according to claim 19 wherein the portions of the distal portion of the inner housing-tube are further molded as two sprung clips.
21. A delivery device according to claim 20 wherein the sprung clips further comprise an inner toothed surface that engage with the outer toothed surface of the locking bush.
22. A delivery device according to claim 1 further comprising:
a dose setting means comprising,
an outer dose-drum located within the housing, wherein the outer dose-drum and the housing are mated by a non locking helical thread-rib arrangement,
an inner dose-drum rotationally connected to the drive-shaft and located within the outer dose-drum and capable of being rotationally connected or disconnected from the outer dose-drum, so that when rotationally disconnected, the outer dose-drum can be rotated spirally outwards in the proximal direction to set a dose, or spirally inwards to set a lower dose; and when rotationally connected to the outer dose-drum will transmit the rotation of the outer dose-drum to the drive-shaft forcing the piston rod out.
23. A delivery device according to claim 22 further comprising:
a dose setting means comprising,
an outer dose-drum located within the housing, wherein the outer dose-drum and the housing are mated by a non locking helical thread-rib arrangement,
an inner dose-drum rotationally connected to the drive-shaft and located within the outer dose-drum and capable of being rotationally connected or disconnected from the outer dose-drum, so that when rotationally disconnected, the outer dose-drum can be rotated spirally outwards in the proximal direction to set a dose, or spirally inwards to set a lower dose; and when rotationally connected to the outer dose-drum will transmit the rotation of the outer dose-drum to the drive-shaft forcing the piston rod out in the distal direction.
24. A delivery device according to claim 23 wherein the outer dose-drum and the inner dose-drum are located between the outer housing-tube and inner housing-tube.
25. A delivery device according to claim 24 in which the outer dose-drum and the outer housing-tube are mated by a helical thread-rib arrangement.
26. A delivery device according to claim 25 wherein,
when the piston drive mechanism is activated, the inner dose-drum, that is rotationally connected to the drive-shaft, gets rotationally connected with the outer dose-drum, and will transmit the rotation of the outer dose-drum to the drive-shaft which in turn forces the piston rod to move axially;
and when the driving mechanism is not activated, the inner dose-drum, that is rotationally connected to the drive-shaft, gets rotationally disconnected from the outer dose-drum, so that the outer dose-drum can be rotated spirally outwards to set a dose, and spirally inwards to set a lower dose.
27. A delivery device according to claim 26 wherein,
when the piston drive mechanism is activated, the inner dose-drum, that is rotationally connected to the drive shaft, gets rotationally connected with the outer dose-drum, and will transmit the rotation of the outer dose-drum to the drive-shaft which in turn forces the piston rod to move axially in the distal direction;
and when the driving mechanism is not activated, the inner dose-drum, that is rotationally connected to the drive-shaft, gets rotationally disconnected from the outer dose-drum, so that the outer dose-drum can be rotated spirally outwards in the proximal direction to set a dose, and spirally inwards to set a lower dose.
28. A delivery device according to claim 27 wherein the inner surface of the inner dose-drum is rotationally connected to the drive-shaft.
29. A delivery device according to claim 28 wherein the inner surface of the inner dose-drum is rotationally connected to legs present on the drive-shaft.
30. A delivery device according to claim 29 wherein the inner surface of the inner dose-drum is rotationally connected to legs present on the proximal portion of the drive-shaft.
31. A delivery device according to claim 30 wherein the said legs are connected to channels that traverse the inner surface of the inner dose-drum.
32. A delivery device according to claim 22 wherein the piston drive mechanism is activated by depressing a thumb pad.
33. A delivery device according to claim 32 wherein,
when the piston drive mechanism is activated, the inner dose-drum, that is rotationally connected to the drive-shaft by legs, gets rotationally connected with the outer dose-drum, and will transmit the rotation of the outer dose-drum to the drive-shaft which in turn forces the piston rod to move axially,
and when the driving mechanism is inactivated, the inner dose-drum, that is rotationally connected to the drive-shaft, gets rotationally disconnected from the outer dose-drum, so that the outer dose-drum can be rotated spirally outwards to set a dose, and spirally inwards to set a lower dose.
34. A delivery device according to claim 33 wherein,
when the piston drive mechanism is activated, the inner dose-drum, that is rotationally connected to the drive-shaft by legs, gets rotationally connected with the outer dose-drum, and will transmit the rotation of the outer dose-drum to the drive-shaft which in turn forces the piston rod to move axially in the distal direction;
and when the driving mechanism is inactivated, the inner dose-drum, that is rotationally connected to the drive-shaft, gets rotationally disconnected from the outer dose-drum, so that the outer dose-drum can be rotated spirally outwards in the proximal direction to set a dose, and spirally inwards to set a lower dose.
35. A delivery device according to claim 34 that further comprises, on the outer surface of the inner dose-drum, sprung ridge teeth that contact with inner mating teeth that are arrayed along the inner circumference of the outer dose-drum such that the said sprung ridge teeth and inner mating teeth mate with each other at an angle to the axis of rotation.
36. A delivery device according to claim 35 that further comprises, on the outer surface of the inner dose-drum, close to its proximal end, sprung ridge teeth that contact with inner mating teeth that are arrayed along the inner circumference of the outer dose-drum on the proximal end, such that the said sprung ridge teeth and inner mating teeth mate with each other at an angle to the axis of rotation.
37. A delivery device according to claim 36 that further comprises,
on the outer surface of the inner dose-drum but located distal to the sprung ridge teeth, engagement teeth,
on the outer dose-drum, circularly arrayed teeth, the location being distal with respect to that of the engagement teeth,
the relative location of the engagement teeth and the circularly arrayed teeth with respect to each other being such that, when the thumb pad is depressed, the said engagement teeth and circularly arrayed teeth get interlocked, and when the thumb pad is released, the axial spring force between the sprung ridge teeth and the mating teeth force the interlock between the engagement teeth and the circularly arrayed teeth apart.
38. A delivery device according to claim 37 that further comprises,
on the outer surface of the inner dose-drum on its proximal region, but located distal to the sprung ridge teeth, engagement teeth,
on the proximal region of the outer dose-drum, circularly arrayed teeth, the location being distal with respect to that of the engagement teeth,
the relative location of the engagement teeth and the circularly arrayed teeth with respect to each other being such that, when the thumb pad is depressed, the said engagement teeth and circularly arrayed teeth get interlocked, and when the thumb pad is released, the axial spring force between the sprung ridge teeth and the mating teeth force the interlock between the engagement teeth and the circularly arrayed teeth apart.
39. A deliver device according to claim 38 wherein when the piston drive mechanism is activated, the engagement teeth and the circularly arrayed teeth are interlocked, and the inner dose-drum is rotationally connected with the outer dose-drum, and transmits the rotation of the outer dose-drum to the drive-shaft which in turn forces the piston rod to move axially, and
when the drive mechanism is inactivated, the interlock between the engagement teeth and the circularly arrayed teeth are parted, and inner dose-drum is rotationally disconnected with the outer dose-drum, so that the outer dose-drum can be rotated spirally outwards to set a dose, and spirally inwards to set a lower dose.
40. A deliver device according to claim 39 wherein when the piston drive mechanism is activated, the engagement teeth and the circularly arrayed teeth are interlocked, and the inner dose-drum is rotationally connected with the outer dose-drum, and will transmit the rotation of the outer dose-drum to the drive-shaft which in turn forces the piston rod to move axially in the distal direction, and
when the drive mechanism is inactivated, the interlock between the engagement teeth and the circularly arrayed teeth are parted, and inner dose-drum is rotationally disconnected with the outer dose-drum, so that the outer dose-drum can be rotated spirally outwards in the proximal direction to set a dose, and spirally inwards to set a lower dose.
41. A delivery device according to claim 40 wherein the drive mechanism comprises a thumb pad.
42. A delivery device according to claim 41 wherein the thumb pad is present at the inner dose-drum.
43. A delivery device according to claim 42 wherein the thumb pad is present at the proximal end of the inner dose-drum.
44. A delivery device according to claim 43 wherein the thumb pad is free to rotate on a bearing surface at the proximal end of the inner dose-drum.
45. A delivery device according to claim 44 wherein the drive mechanism is activated by depressing the thumb pad.