Canadian Patents Database / Patent 2733436 Summary

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(12) Patent: (11) CA 2733436
(54) English Title: MASS SPECTROMETER
(54) French Title: SPECTROMETRE DE MASSE
(51) International Patent Classification (IPC):
  • H01J 49/26 (2006.01)
(72) Inventors :
  • BATEMAN, ROBERT HAROLD (United Kingdom)
  • HOYES, JOHN BRIAN (United Kingdom)
  • WILDGOOSE, JASON LEE (United Kingdom)
(73) Owners :
  • MICROMASS UK LIMITED (United Kingdom)
(71) Applicants :
  • MICROMASS UK LIMITED (United Kingdom)
(74) Agent: RIDOUT & MAYBEE LLP
(74) Associate agent:
(45) Issued: 2014-12-23
(22) Filed Date: 2003-05-16
(41) Open to Public Inspection: 2003-11-17
Examination requested: 2011-03-02
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country/Territory Date
0211373.6 United Kingdom 2002-05-17
0212641.5 United Kingdom 2002-05-31

English Abstract

A mass spectrometer is disclosed comprising an ion detector 4 positioned upstream of a quadrupole mass filter/analyser 2. Ions are passed through the quadrupole mass filter/analyser 2, are stored in an ion trap and are then passed back through the same mass filter/analyser 2 before being detected by the upstream ion detector 4. MS/MS experiments can be performed using apparatus having only a single mass filter/analyser 2.


French Abstract

Un spectromètre de masse est présenté comportant un détecteur d'ion (4) positionné en amont d'un filtre/analyseur de masse quadripolaire (2). Les ions traversent le filtre/analyseur de masse quadripolaire (2) sont stockés dans un piège à ions et retraversent le même filtre/analyseur (2) avant d'être détectés par le détecteur d'ion (4) en amont. Les expériences MS/MS peuvent être réalisées à l'aide d'un appareil comportant un seul filtre/analyseur de masse (2).


Note: Claims are shown in the official language in which they were submitted.

33
Claims
1. A mass spectrometer comprising:
an ion source;
a mass filter/analyser;
an upstream ion trap arranged upstream of said mass filter/analyser;
a downstream ion trap arranged downstream of said mass filter/analyser; and
a downstream ion detector arranged downstream of said downstream ion trap;
wherein said mass filter/analyser is arranged to mass filter ions emitted from
said ion
source so that ions having a specific mass to charge ratio are onwardly
transmitted and ions
having other mass to charge ratios are attenuated by said mass filter and
wherein ions
onwardly transmitted by said mass filter are arranged to be substantially
fragmented and
wherein said fragment ions are arranged to be accumulated in said downstream
ion trap,
wherein said downstream ion trap then releases said fragment ions and at least
some of said
fragment ions are passed back upstream through said mass filter/analyser which
is operated
in a wide band pass mode so as to transmit substantially all said fragment
ions wherein said
fragment ions are arranged to be accumulated in said upstream ion trap,
wherein said
upstream ion trap then releases said fragment ions and at least some of said
fragment ions
are passed through said mass filter/analyser which is arranged to mass analyse
or mass filter
said fragment ions and wherein said fragment ions are transmitted by said
downstream ion
trap without said ions being substantially fragmented and are then detected by
said
downstream ion detector.
2. A mass spectrometer as claimed in claim 1, wherein said ion source is
selected from
the group consisting of: (i) Electrospray ("ESI") ion source; (ii) Atmospheric
Pressure Chemical
Ionisation ("APCI") ion source; (iii) Atmospheric Pressure Photo Ionisation
("APPI") ion source;
(iv) Matrix Assisted Laser Desorption Ionisation ("MALDI") ion source; (v)
Laser Desorption
Ionisation ("LDI") ion source; (vi) Inductively Coupled Plasma ("ICP") ion
source; (vii) Electron
Impact ("El") ion source; (viii) Chemical Ionisation ("CI") ion source; (ix) a
Fast Atom
Bombardment ("FAB") ion source; and (x) a Liquid Secondary Ions Mass
Spectrometry
("LSIMS") ion source.

34
3. A mass spectrometer as claimed in claim 1 or 2, wherein when ions are
arranged to be
fragmented at least 50% of the ions enter either said downstream ion trap or
said upstream ion
trap with an energy greater than or equal to 10 eV for a singly charged ion or
greater than or
equal to 20 eV for a doubly charged ion such that said ions are caused to
fragment.
4. A mass spectrometer as claimed in claim 1, 2 or 3, wherein said
downstream ion trap
or said upstream ion trap is maintained in use at a pressure greater than or
equal to 0.0001
mbar.
5. A mass spectrometer as claimed in claims 1-4, wherein said downstream
ion trap or
said upstream ion trap is maintained in use at a pressure less than or equal
to 10 mbar.
6. A mass spectrometer as claimed in claims 1-5, wherein said downstream
ion trap or
said upstream ion trap is maintained in use at a pressure of between 0.0001
and 10 mbar.
7. A mass spectrometer as claimed in claims 1-6, wherein said downstream
ion trap or
said upstream ion trap are selected from the group consisting of: (i) an ion
funnel comprising a
plurality of electrodes having apertures therein through which ions are
transmitted, wherein the
diameter of said apertures becomes progressively smaller or larger; (ii) an
ion tunnel
comprising a plurality of electrodes having apertures therein through which
ions are
transmitted, wherein the diameter of said apertures remains substantially
constant; and (iii) a
stack of plate, ring or wire loop electrodes.
8. A mass spectrometer as claimed in claims 1-7, wherein said downstream
ion trap or
said upstream ion trap comprise a plurality of electrodes, each electrode
having an aperture
through which ions are transmitted in use.
9. A mass spectrometer as claimed in claim 7 or 8, wherein each electrode
has a
substantially circular aperture.




35
10. A mass spectrometer as claimed in claim 8 or 9, wherein the diameter of
the apertures
of at least 50% of the electrodes forming said downstream ion trap or said
upstream ion trap
are less than or equal to 10 mm.
11. A mass spectrometer as claimed in claim 8, 9 or 10, wherein at least
50% of the
electrodes forming said downstream ion trap or said upstream ion trap have
apertures which
are substantially the same size or area.
12. A mass spectrometer as claimed in any of claims 8-11, wherein the
thickness of at
least 50% of said electrodes is less than or equal to 3 mm.
13. A mass spectrometer as claimed in claims 1-12, wherein said downstream
ion trap or
said upstream ion trap consists of: (i) 10-20 electrodes; (ii) 20-30
electrodes; (iii) 30-40
electrodes; (iv) 40-50 electrodes; (v) 50-60 electrodes; (vi) 60-70
electrodes; (vii) 70-80
electrodes; (viii) 80-90 electrodes; (ix) 90-100 electrodes; (x) 100-110
electrodes; (xi) 110-120
electrodes; (xii) 120-130 electrodes; (xiii) 130-140 electrodes; (xiv) 140-150
electrodes; or (xv)
more than 150 electrodes.
14. A mass spectrometer as claimed in claims 1-13, wherein said downstream
ion trap or
said upstream ion trap has a length selected from the group consisting of: (i)
less than 5 cm;
(ii) 5-10 cm; (iii) 10-15 cm; (iv) 15-20 cm; (v) 20-25 cm; (vi) 25-30 cm; and
(vii) greater than 30
cm.
15. A mass spectrometer as claimed in any of claims 8-14, wherein at least
10% of said
electrodes are connected to both a DC and an AC or RF voltage supply.
16. A mass spectrometer as claimed in any of claims 8-15, wherein axially
adjacent
electrodes are supplied with AC or RF voltages having a phase difference of
180°.
17. A mass spectrometer as claimed in any of claims 1-6, wherein said
downstream ion
trap or said upstream ion trap comprise a segmented rod set.


36

18. A mass spectrometer as claimed in claims 1-17, wherein said downstream
ion trap or
said upstream ion trap comprise a housing having an upstream opening for
allowing ions to
enter said downstream ion trap or said upstream ion trap or said second
upstream ion trap and
a downstream opening for allowing ions to exit said downstream ion trap or
said upstream ion
trap or said second upstream ion trap.
19. A mass spectrometer as claimed in claim 18, wherein said downstream ion
trap or said
upstream ion trap further comprise an inlet port through which a collision gas
is introduced.
20. A mass spectrometer as claimed in claim 19, wherein said collision gas
comprises air
or one or more inert gases or one or more non-inert gases.
21. A mass spectrometer as claimed in claims 1-20, wherein said downstream
ion detector
is selected from the group consisting of: (i) a Micro Channel Plate ("MCP")
ion detector; (ii) an
electron-multiplier ion detector; and (iii) a phosphor or scintillator in
conjunction with a photo-
multiplier ion detector.
22. A mass spectrometer as claimed in claims 1-21, wherein said downstream
ion detector
forms part of a further mass analyser, said further mass analyser selected
from the group
consisting of: (i) a Time of Flight mass analyser; (ii) a quadrupole mass
analyser; (iii) a
Penning or Fourier Transform Ion Cyclotron Resonance ("FTICR") mass analyser;
(iv) a 2D or
linear quadrupole ion trap; and (v) a Paul or 3D quadrupole ion trap.
23. A mass spectrometer as claimed in claims 1-22, wherein said downstream
ion trap or
said upstream ion trap may be operated in one of more of the following modes:
(i) an ion
trapping mode wherein one or more trapping voltages are applied to prevent
ions from exiting
from one or more ends of said ion trap; (ii) an ion guide mode wherein no
trapping voltages
are applied and hence all ions received by said ion trap are substantially
onwardly transmitted
by said ion trap; (iii) a fragmentation mode wherein the ion trap is arranged
to be maintained at
a pressure or ions are arranged to enter the ion trap with an energy such that
the ions are
substantially fragmented within the ion trap; and (iv) an ion trapping and
fragmentation mode
wherein one or more trapping voltages are applied to prevent ions from exiting
from one or
more ends of said ion trap and wherein the ion trap is arranged to be
maintained at a pressure


37

or ions are arranged to enter the ion trap with an energy such that the ions
are substantially
fragmented within the ion trap.
24. A mass spectrometer as claimed in claims 1-23, wherein said mass
filter/analyser is
selected from the group consisting of: (i) a quadrupole rod set mass
filter/analyser; (ii) a
magnetic sector mass analyser; and (iii) a Time of Flight mass analyser.
25. A method of mass spectrometry, comprising:
providing an ion source, a mass filter/analyser arranged downstream of said
ion
source, an upstream ion trap arranged upstream of said mass filter/mass
analyser, a
downstream ion trap arranged downstream of said mass filter/analyser, and a
downstream ion
detector arranged downstream of said downstream ion trap;
arranging said mass filter/analyser to mass filter ions emitted from said ion
source so
that ions having a specific mass to charge ratio are onwardly transmitted and
ions having other
mass to charge ratios are substantially attenuated by said mass filter;
fragmenting said ions onwardly transmitted by said mass filter;
accumulating said fragment ions in said downstream ion trap;
releasing said fragment ions from said downstream ion trap;
passing at least some of said fragment ions back upstream through said mass
filter/analyser which is operated in a wide band pass mode so as to transmit
substantially all
said fragment ions wherein said fragment ions are arranged to be accumulated
in said
upstream ion trap;
releasing said fragment ions from said upstream ion trap;
passing at least some of said fragment ions through said mass filter/analyser
which is
arranged to mass analyse or mass filter said fragment ions;
transmitting said fragment ions through said downstream ion trap without said
fragment
ions being substantially further fragmented; and
detecting said ions with said downstream ion detector.

Note: Descriptions are shown in the official language in which they were submitted.


CA 02733436 2011-03-02
MASS SPECTROMETER

The present invention relates to a mass
spectrometer and a method of mass spectrometry.
Mass spectrometers are known which are suitable for
performing so called MS/MS experiments wherein in a
first step parent ions are mass analysed. In a second
step parent ions having a particular mass to charge
ratio are selected by a mass filter and are then
fragmented in a gas collision cell. The resulting
fragment ions are then mass analysed. The mass spectrum
of an analyte ion and the mass spectrum of the fragment
products of the analyte ion reveal useful information
about the structure of the analyte ion and this
information may then be used to identify the ion.
It is known to perform MS/MS experiments on triple
quadrupole mass spectrometers. Triple quadrupole mass
spectrometers comprise a first quadrupole mass filter
Ql, followed by a quadrupole ion guide arranged in a gas
collision cell Q2. Downstream of the gas collision cell
Q2 is provided a second quadrupole mass analyser, Q3.
A parent ion mass spectrum may be obtained by
setting Q1 to operate in a wide band pass mode (i.e. RF
only mode) so that the first quadrupole Q1 operates in
non-filtering ion guide mode. The ions then pass
through the gas collision cell Q2 but either collision
gas is not provided in the collision cell or the energy
of the ions passing through the collision cell is
arranged to be sufficiently low so.that ions are not
substantially fragmented within the collision cell. The
parent ions are then mass analysed by the second
quadrupole mass analyser Q3.
A fragment ion or MS/MS mass spectrum may be
obtained by setting the first quadrupole Q1 to operate
as a mass filter so that only parent ions having a
specific mass to charge ratio are onwardly transmitted
by the mass filter. Parent ions transmitted by the mass
filter Ql then enter the collision cell Q2 and are


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arranged to have an energy such that they fragment upon
colliding with gas molecules in the collision cell. The
resultant fragment ions are then mass analysed by the
second quadrupole mass analyser Q3.
Hybrid mass spectrometers wherein the second
quadrupole mass analyser Q3 is replaced with a Time of
Flight mass analyser are also known.
It is a feature of both the known triple quadrupole
mass spectrometer and hybrid quadrupole-Time of Flight
mass spectrometers that two mass filters/analysers are
required in order to perform MS/MS experiments.
It is desired to provide an improved mass
spectrometer for performing MS/MS experiments.
According to an aspect of the present invention
there is provided a mass spectrometer comprising:
an ion source;.
a mass filter/analyser arranged downstream of the
ion source;
an upstream ion detector arranged upstream of the
mass filter/mass analyser; and
a downstream ion trap arranged downstream of the
mass filter/analyser.
According to a particularly preferred feature MS/MS
experiments may be performed using a mass spectrometer
which comprises only a single mass filter/analyser.
This represents a considerable simplification and cost
saving over conventional arrangements such as triple
quadrupole mass spectrometers and quadrupole-Time of
Flight mass spectrometers wherein two mass
filters/analysers are required. The present invention
therefore constitutes an important advance in the art.
In order to use only one mass filter/analyser
rather than two mass filters/analysers as is
conventional, ions are preferably stored in an ion trap
downstream of a mass filter/analyser and are then sent
back upstream through the mass filter/analyser. The
ions, which may comprise parent ions, fragment ions or


CA 02733436 2011-03-02
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second (or further) generation fragment ions may be mass
filtered or mass analysed as they pass upstream through
the mass filter/analyser. Alternatively/additionally,
once the ions have been passed back upstream through the
mass filter/analyser and stored in an upstream ion trap,
the ions may then be passed back downstream through the
mass filter/analyser to be mass filtered/analysed for a
second, third or further time.
A number of distinct embodiments of the present
invention are contemplated.
According to a first embodiment in a first mode of
operation the mass filter is operated in a wide band
pass mode so as to transmit substantially all ions and
the downstream ion trap is arranged to accumulate parent
ions. The ion source remains ON during this mode of
operation.
In a second mode of operation the downstream ion
trap releases the parent ions and at least some of the
parent ions are passed back upstream through the mass
filter/analyser which is arranged to mass analyse the
parent ions. The ions are then detected by the upstream
ion detector. In this mode of operation the ion source
is switched OFF.
In a third mode of operation the mass
filter/analyser is arranged to mass filter parent ions
emitted from the ion source so that only parent ions
having a specific mass to charge ratio are onwardly
transmitted and ions having other mass to charge ratios
are substantially attenuated by the mass filter. Ions
onwardly transmitted by the mass filter are then
arranged to be substantially fragmented. The resulting
fragment ions are arranged to be accumulated in the
downstream ion trap. The ion source in this mode of
operation remains ON and the ions are preferably
fragmented within the downstream ion trap.
In a fourth mode of operation the downstream ion
trap releases the fragment ions and at least some of the


CA 02733436 2011-03-02
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fragment ions are passed back upstream through the mass
filter/analyser which is arranged to mass analyse the
fragment ions. The fragment ions are then detected by
the upstream ion detector. In this mode of operation
the ion source is switched OFF.
According to an alternative Single (or Selected)
Reaction Monitoring ("SRM") embodiment the mass
spectrometer may initially be operated in the second
mode of operation described above so that selected
parent ions are fragmented and the resultant fragment
ions are stored in the downstream ion trap. Then, the
downstream ion trap is arranged to release the fragment
ions and at least some of the fragment ions are passed
back upstream through the mass filter/analyser which is
arranged to mass filter the fragment ions so that
fragment ions having a specific mass to charge ratio are
onwardly transmitted and fragment ions having other mass
to charge ratios are attenuated by the mass filter. The
fragment ions transmitted by the mass filter are
detected by the upstream ion detector. When the
fragment ions are released from the downstream ion trap
the ion source is switched OFF. A Multiple Reaction
Monitoring ("MRM") embodiment is also contemplated
wherein either the transmission window of the mass
filter when filtering parent ions and/or when filtering
fragment ions is changed so that a different reaction is
monitored for.
A second embodiment of the present invention is
contemplated and further comprises a downstream ion
detector arranged downstream of the downstream ion trap.
According to a first mode of operation of the
second embodiment, the mass filter/analyser is arranged
to mass analyse ions emitted from the ion source and the
parent ions are detected by the downstream ion detector.
The ion source is ON and the downstream ion trap is
preferably arranged to be operated in a non-trapping ion
guide mode of operation.


CA 02733436 2011-03-02
-

In a second mode of operation the mass
filter/analyser is arranged to mass filter parent ions
emitted from the ion source so that parent ions having a
specific mass to charge ratio are onwardly transmitted
5 and ions having other mass to charge ratios are
attenuated by the mass filter. The ions onwardly
transmitted by the mass filter are arranged to be
substantially fragmented and fragment ions are arranged
to be accumulated in the downstream ion trap. The ion
source remains ON and ions are preferably fragmented
within the downstream ion trap.
In a third mode of operation the downstream ion
trap releases the fragment ions and at least some of the
fragment ions are passed back upstream through the mass
filter/analyser which is arranged to mass analyse the
fragment ions. The fragment ions are then detected by
the upstream ion detector. In this mode the ion source
is switched OFF and the downstream ion trap is
preferably operated in a non-trapping ion guide mode.
Single Reaction Monitoring and Multiple Reaction
Monitoring embodiments are also contemplated wherein the
mass filter/analyser mass filters the fragment ions
rather than mass analysing them i.e. the mass
filter/analyser is set to transmit ions having a
specific mass to charge ratio rather than being scanned.
According to a third embodiment of the present
invention there is provided a mass spectrometer
comprising:
an ion source;
a mass filter/analyser;
an upstream ion trap arranged upstream of the mass
filter/analyser;
a downstream ion trap arranged downstream of the
mass filter/analyser; and
a downstream ion detector arranged downstream of
the downstream ion trap;


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wherein the mass filter/analyser is arranged to
mass filter ions emitted from the ion source so that
ions having a specific mass to charge ratio are onwardly
transmitted and ions having other mass to charge ratios
are attenuated by the mass filter and wherein ions
onwardly transmitted by the mass filter are arranged to
be substantially fragmented and wherein the fragment
ions are arranged to be accumulated in the downstream
ion trap, wherein the downstream ion trap then releases
the fragment ions and at least some of the fragment ions
are passed back upstream through the mass
filter/analyser which is operated in a wide band pass
mode so as to transmit substantially all the fragment
ions wherein the fragment ions are arranged to be
accumulated in the upstream ion trap, wherein the
upstream ion trap then releases the fragment ions and at
least some of the fragment ions are passed through the
mass filter/analyser which is arranged to mass analyse
or mass filter the fragment ions and wherein the
fragment ions are transmitted by the downstream ion trap
without the ions being substantially fragmented and are
then detected by the downstream ion detector.
Single Reaction Monitoring and Multiple Reaction
Monitoring embodiments are contemplated wherein the mass
filter/analyser mass filters the fragment ions rather
than mass analysing them i.e. the mass filter/analyser
is set to transmit ions having a specific mass to charge
ratio rather than being scanned.
A fourth embodiment is contemplated which is
similar to the second embodiment except that an upstream
ion trap is arranged upstream of the mass
filter/analyser.
According to a first mode of operation of the
fourth embodiment the mass filter/analyser is arranged
to mass analyse parent ions emitted from the ion source
and wherein the ions are detected by the downstream ion
detector. The ion source is ON and preferably both the


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upstream ion trap and the downstream ion trap are
operated in non-trapping ion guide modes.
In a second mode of operation the mass
filter/analyser is arranged to mass filter ions emitted
from the ion source so that ions having a specific mass
to charge ratio are onwardly transmitted and ions having
other mass to charge ratios are attenuated by the mass
filter. The ions onwardly transmitted by the mass
filter are arranged to be substantially fragmented and
fragment ions are arranged to be accumulated in the
downstream ion trap. In this mode the ion source
remains ON and the upstream ion trap is operated in a
non-trapping ion guide mode.
In a third mode of operation the downstream ion
trap releases the fragment ions and wherein at least
some of the fragment ions are passed back upstream
through the mass filter/analyser which is arranged to
mass analyse the fragment ions. The fragment ions are
then detected by the upstream ion detector. In this
mode the ion source preferably remains ON and the
downstream ion trap is preferably operated in a non-
trapping ion guide mode. Preferably, ions emitted from
the ion source are substantially simultaneously
accumulated in the upstream ion trap whilst the fragment
ions are being mass analysed.
Single Reaction Monitoring and Multiple Reaction
Monitoring embodiments are also contemplated wherein the
mass filter/analyser mass filters the fragment ions
rather than mass analysing them i.e. the mass
filter/analyser is set to transmit ions having a
specific mass to charge ratio rather than being scanned.
In a fourth mode of operation the mass
filter/analyser is arranged to mass filter ions emitted
from the ion source so that ions having a specific mass
to charge ratio are onwardly transmitted and ions having
other mass to charge ratios are attenuated by the mass
filter. Ions onwardly transmitted by the mass filter


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are arranged to be substantially fragmented and fragment
ions are arranged to be accumulated in the downstream
ion trap. In this mode the ion source remains ON and
the upstream ion trap is operated in a non-trapping ion
guide mode. Preferably, the mass filter/analyser also
mass filters ions which have been accumulated in the
upstream ion trap during the third mode of operation
i.e. ions are released from the upstream ion trap.
In a fifth mode of operation the downstream ion
trap releases the fragment ions and wherein at least
some of the fragment ions are passed back upstream
through the mass filter/analyser which is arranged to
mass.filter the fragment ions so that fragment ions
having a specific mass to charge ratio are onwardly
transmitted and fragment ions having other mass to
charge ratios are attenuated by the mass filter.
Fragment ions onwardly transmitted by the mass filter
are arranged to be substantially further fragmented to
form second generation fragment ions and the second
generation fragment ions are arranged to be accumulated
in the upstream ion trap. In this mode of operation the
ion source is switched OFF and the downstream ion trap
is operated in a non-trapping ion guide mode. The
second generation fragment ions are preferably formed in
the upstream.
In a sixth mode of operation the upstream ion trap
is arranged to release the second generation fragment
ions and the mass filter/analyser is arranged to mass
analyse the second generation fragment. ions. The second
generation fragment ions are then detected by the
downstream ion detector. In this mode of operation the
ion source remains OFF and preferably both the upstream
ion trap and the downstream ion trap are operated in
non-trapping ion guide modes.
Single Reaction Monitoring and Multiple Reaction
Monitoring embodiments are also contemplated wherein the
mass filter/analyser mass filters the second generation


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fragment ions rather than mass analysing them i.e. the
mass filter/analyser is set to transmit second
generation fragment ions having a specific mass to
charge ratio rather than being scanned.
A fifth embodiment of the present invention is
contemplated. This embodiment is similar to the fourth
embodiment except that a second upstream ion trap is
arranged upstream of the (first) upstream ion trap.
According to the fifth embodiment the ion source
preferably remains permanently ON so that ions are
trapped within the second upstream ion trap whilst the
equivalent of the fifth and sixth modes of operation of
the fourth embodiment are performed. Accordingly,
according to a mode of operation the downstream ion trap
may release fragment ions and at least some of the
fragment ions are passed back upstream through the mass
filter/analyser which is arranged to mass filter the
fragment ions so that fragment ions having a specific
mass to charge ratio are onwardly transmitted and
fragment ions having other mass to charge ratios are
attenuated by the mass filter. Fragment ions onwardly
transmitted by the mass filter are arranged to be
substantially further fragmented to form second
generation fragment ions and wherein the second
generation fragment ions are arranged to be accumulated
in the upstream ion trap. Ions emitted from the ion
source are substantially simultaneously accumulated in
the second upstream ion trap whilst the fragment ions
are being mass filtered by the mass filter.
Similarly, in another mode of operation, the
upstream ion trap is arranged to release the second
generation fragment ions and the mass filter/analyser is
arranged to mass analyse the second generation fragment
ions. The second generation fragment ions are detected
by the downstream ion detector and ions emitted from the
ion source are substantially simultaneously accumulated
in the second upstream ion trap whilst the second


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generation fragment ions are being mass analysed by the
mass analyser.
Single Reaction Monitoring and Multiple Reaction
Monitoring embodiments are also contemplated wherein the
mass filter/analyser mass filters the second generation
fragment ions rather than mass analysing them i.e. the
mass filter/analyser is set to transmit second
generation fragment ions having a specific mass to
charge ratio rather than being scanned.
The following preferred features relate to all five
embodiments detailed above.
The ion source may comprise an Electrospray ("ESI")
ion source, an Atmospheric Pressure Chemical Ionisation
("APCI") ion source, an Atmospheric Pressure Photo
Ionisation ("APPI") ion source, a Matrix Assisted Laser
Desorption Ionisation ("MALDI") ion source, a Laser
Desorption Ionisation ("LDI") ion source, an Inductively
Coupled Plasma ("ICP") ion source, an Electron Impact
("EI") ion source, a Chemical Ionisation ("CI") ion
source, a Fast Atom Bombardment ("FAB") ion source, or a
Liquid Secondary Ions Mass Spectrometry ("LSIMS") ion
source.
When ions are arranged to be fragmented in either
the downstream ion trap and/or the upstream ion trap
preferably at least 500, 600, 70%, 800, 90% or 95% of
the ions enter either the downstream ion trap and/or the
upstream ion trap with an energy greater than or equal
to 10 eV for a singly charged ion or greater than or
equal to 20 eV for a doubly charged ion so that the ions
are caused to fragment.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap
are maintained in use at a pressure selected from the
group consisting of: (1) greater than or equal to 0.0001
mbar; (ii) greater than or equal to 0.0005 mbar; (iii)
greater than or equal to 0.001 mbar; (iv) greater than
or equal to 0.005 mbar; (v) greater than or equal to


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0.01 mbar; (vi) greater than or equal to 0.05 mbar;
(vii) greater than or equal to 0.1 mbar; (viii) greater
than or equal to 0.5 mbar; (ix) greater than or equal to
1 mbar; (x) greater than or equal to 5 mbar; and (xi)
greater than or equal to 10 mbar.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap is
maintained in use at a pressure selected from the group
consisting of: (i) less than or equal to 10 mbar; (ii)
less than or equal to 5 mbar; (iii) less than or equal
to 1 mbar; (iv) less than or equal to 0.5 mbar; (v) less
than or equal to 0..1 mbar; (vi) less than or equal to
0.05 mbar; (vii) less than or equal to 0.01 mbar; (viii)
less than or equal to 0.005 mbar; (ix) less than or
equal to 0.001 mbar; (x) less than or equal to 0.0005
mbar; and (xi) less than or equal to 0.0001 mbar.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap is
maintained in use at a pressure selected from the group
consisting of: (i) between 0.0001 and 10 mbar; (ii)
between 0.0001 and 1 mbar; (iii) between 0..0001 and 0.1
mbar; (iv) between 0.0001 and 0.01 mbar; (v) between
0.0001 and 0.001 mbar; (vi) between 0.001 and 10 mbar;
(vii) between 0.001 and 1 mbar; (viii) between 0.001 and
0.1 mbar; (ix) between 0.001 and 0.01 mbar; (x) between
0.01 and 10 mbar; (xi) between 0.01 and 1 mbar; (xii)
between 0.01 and 0.1 mbar; (xiii) between 0.1 and .10
mbar; (xiv) between 0.1 and 1 mbar; and (xv) between 1
and 10 mbar.
The upstream and downstream ion traps preferably
comprise ion tunnel devices consisting of a set of rings
having alternating polarities of RF voltage applied to
them. The ion tunnel ion traps may in one mode of
operation act as ion guides (i.e. do not actually trap
ions) and offer various advantages compared to
conventional multipole rod set ion guides. Each ring
within the ion tunnel device may be connected


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independently allowing these devices to be operated as
ion traps, ion mobility separators, collisionless drift
tubes and collision cells for fragmenting ions. In
addition, they may also act as continuous ion guides
between areas of differing pressures since one of the
rings of the ion tunnel may act as a differential
pumping aperture thereby improving ion transmission from
one region to another.
. The downstream ion trap and/or the upstream ion
trap and/or the second upstream ion.trap may comprise an
ion funnel comprising a plurality of electrodes having
apertures therein through which ions are transmitted,
wherein the diameter of the apertures becomes
progressively smaller or larger. Alternatively, they
may comprise an ion tunnel comprising a plurality of
electrodes having apertures therein through which ions
are transmitted, wherein the diameter of the apertures
remains substantially constant. They may also comprise
a stack of plate, ring or wire loop electrodes.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap
comprise a plurality of electrodes, each electrode
having an aperture through which ions are transmitted in
use. Each electrode preferably has a substantially
circular aperture although the apertures may take on
other shapes according to less preferred embodiments.
Preferably, the diameter of the apertures of at
least 500, 600, 700, 80%, 90% or 950 of the electrodes
forming the downstream ion trap and/or the upstream ion
trap and/or the second upstream ion trap are.selected
from the group consisting of: (i) less than or equal to
10 mm; (ii) less than or equal to 9 mm; (iii) less than
or equal to 8 mm; (iv) less than or equal to 7 mm; (v)
less than or equal to 6 mm; (vi) less than or equal to 5
mm; (vii) less than or equal to 4 mm; (viii) less than
or equal to 3 mm; (ix) less than or equal to 2 mm; and
(x) less than or equal to 1 mm.


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Preferably, at least 50%, 60%, 70%, 80%, 90% or 95%
of the electrodes forming the downstream ion trap and/or
the upstream ion trap and/or the second upstream ion
trap have apertures which are substantially the same
size or area.
Preferably, the thickness of at least 50%, 60%,
70%, 800,90% or 95% of the electrodes are selected from
the group consisting of: (i) less than or equal to 3 mm;
(ii) less than or equal to 2.5 mm; (iii) less than or
equal to 2.0 mm; (iv) less than or equal to 1.5 mm; (v)
less than or equal to 1.0 mm; and (vi) less than or
equal to 0.5 mm.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap
consist of: (i) 10-20 electrodes; (ii) 20-30 electrodes;
(iii) 30-40 electrodes; (iv) 40-50 electrodes; (v) 50-60
electrodes; (vi) 60-70 electrodes; (vii) 70-80
electrodes; (viii) 80-90 electrodes; (ix) 90-100
electrodes; (x) 100-110 electrodes; (xi) 110-120
electrodes; (xii) 120-130 electrodes; (xiii) 130-140
electrodes; (xiv) 140-150 electrodes; or (xv) more than
150 electrodes.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap
has a length selected from the group consisting of: (i)
less than 5 cm; (ii) 5-10 cm; (iii) 10-15 cm; (iv) 15-20
cm; (v) 20-25 cm; (vi) 25-30 cm; and (vii) greater than
cm. Preferably, at least 10%, 20%, 300, 40%, 50%,
60%, 70%, 80%, 90%, or 95% of the electrodes are
30 connected to both a DC and an AC or RF voltage supply.
Preferably, axially adjacent electrodes are supplied
with AC or RF voltages having a phase difference of 180 .
According to an alternative embodiment the
downstream ion trap and/or the upstream ion trap and/or
the second upstream ion trap may comprise a segmented
rod set. Embodiments are also contemplated wherein, for
example, one ion trap may comprise a plurality of


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electrodes having apertures and another ion trap may
comprise a segmented rod set.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap
comprise a housing having an upstream opening for
allowing ions to enter the ion trap and a downstream
opening for allowing ions to exit the ion trap.
Preferably, the downstream ion trap and/or the
upstream ion trap and/or the second upstream ion trap
further comprise an inlet port through which a collision
gas is introduced. A collision gas such as air and/or
one or more inert gases and/or one or more non-inert
gases is preferably introduced into the housing via the
inlet port.
The upstream ion detector and/or the downstream ion
detector preferably comprise a single detector or a
detector array providing spatial information. The
detector may comprise a Micro Channel Plate detector, an
electron-multiplier detector or a phosphor or
scintillator in conjunction with a photo-multiplier
detector.
The downstream ion detector and/or the upstream ion
detector may, less preferably, form part of a further
mass analyser such as a Time of Flight mass analyser, a
quadrupole mass analyser, a Penning or Fourier Transform
Ion Cyclotron Resonance ("FTICR") mass analyser, a 2D or
linear quadrupole ion trap or a Paul or 3D quadrupole
ion trap.
According to the preferred embodiment the
downstream ion trap and/or the upstream ion trap and/or
the second upstream ion trap may be operated in one of
more of the following modes: (i) an ion trapping mode
wherein one or more trapping voltages are applied to
prevent ions from exiting from one or more ends of the
ion trap; (ii) an ion guide mode wherein no trapping
voltages are applied and hence all ions received by the
ion trap are substantially onwardly transmitted by the


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ion trap; (iii) a fragmentation mode wherein the ion
trap is arranged to be maintained at a pressure and/or
ions are arranged to enter the ion trap with an energy
such that the ions are substantially fragmented within
the ion trap; and (iv) an ion trapping and fragmentation
mode wherein one or more trapping voltages are applied
to prevent ions from exiting from one or more ends of
the ion trap and wherein the ion trap is arranged to be
maintained at a pressure and/or ions are arranged to
enter the ion trap with an energy such that the ions are
substantially fragmented within the ion trap. In the
ion guide mode an axial DC voltage gradient may be
applied or maintained along at least a portion of the
ion trap so that ions are accelerated out or through the
ion trap.
The mass filter/analyser preferably comprises a
quadrupole rod set mass filter/analyser. According to
less preferred embodiments the mass filter/analyser may
comprise a magnetic sector mass analyser, or a Time. of
Flight mass analyser.
According to another aspect of the present
invention there is provided a method of mass
spectrometry, comprising:
providing an ion source, a mass filter/analyser
arranged downstream. of the ion source, an upstream ion
detector arranged upstream of the mass filter/mass
analyser and a downstream ion trap arranged downstream
of the mass filter/analyser;
trapping parent or fragment ions in the downstream
ion trap;
ejecting the parent or fragment ions from the
downstream ion trap and passing the parent or fragment
ions through the mass filter/analyser;
mass analysing or mass filtering the parent or
fragment ions; and
detecting the ions with the upstream ion detector.


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Preferably, the method further comprises trapping
ions generated from the ion source in an upstream ion
trap whilst fragment ions are being mass analysed.
According to another aspect of the present
invention there is provided a method of mass
spectrometry, comprising:
providing an ion source, a mass filter/analyser
arranged downstream of the ion source, an upstream ion
detector arranged upstream of the mass filter/mass
analyser, an upstream ion trap .arranged upstream of the
mass filter/analyser, a second upstream ion trap
arranged upstream of the upstream. ion trap and a
downstream ion trap arranged downstream of the mass
filter/analyser;
trapping fragment ions in the downstream ion trap;
ejecting the fragment ions from the downstream ion
trap and passing the fragment ions through the mass
filter/analyser;
mass filtering the fragment ions. so that fragment
ions having a specific mass to charge ratio are onwardly
transmitted and ions having other mass to charge ratios
are attenuated by the mass filter;
further fragmenting the fragment ions onwardly
transmitted by the mass filter to form second generation
fragment ions; and
accumulating the second generation fragment ions in
the upstream ion trap.
Preferably,, the method further comprises trapping
ions generated from the ion source in the second
upstream ion trap whilst fragment ions are being mass
filtered.
Preferably, the method further comprises:.
ejecting the second generation fragment ions from
the upstream ion trap and passing the second generation
fragment ions through the mass filter/analyser;
mass analysing or mass filtering the second
generation fragment ions; and


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detecting the ions with the downstream ion
detector.
Preferably, the method further comprises trapping
ions generated from the ion source in the second
upstream ion trap whilst the second generation fragment
ions are being mass analysed.
According to another aspect of the present
invention there is provided a method of mass
spectrometry, comprising:
providing an ion source, a mass filter/analyser
arranged downstream of the ion source, an upstream ion
detector arranged upstream of the mass filter/mass
analyser and a downstream ion trap arranged downstream
of the mass filter/analyser;
trapping fragment ions in the downstream ion trap;
ejecting the fragment ions from the downstream ion
trap and passing the fragment ions through the mass
filter/analyser;
mass filtering the fragment ions so that fragment
ions having a specific mass to charge ratio are onwardly
transmitted and ions having other mass to charge ratios
are attenuated by the mass filter; and
detecting the ions with the upstream ion detector.
According to another aspect of the present
invention there is provided a method of mass
spectrometry, comprising:
providing an ion source, a mass filter/analyser
arranged downstream of the ion source, an upstream ion
trap arranged upstream of the mass filter/mass analyser,
a downstream ion trap arranged downstream of the mass
filter/analyser, and a downstream ion detector arranged
downstream of the downstream ion trap;
arranging the mass filter/analyser to mass filter
ions emitted from the ion source so that ions having a
specific mass to charge ratio are onwardly transmitted
and ions having other mass to charge ratios are
attenuated by the mass filter;


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fragmenting the ions onwardly transmitted by the
mass filter;
accumulating the fragment ions in the downstream
ion trap;
releasing the fragment ions from the downstream ion
trap;
passing at least some of the fragment ions back
upstream through the mass filter/analyser which is
operated in a wide band pass mode so as to transmit
substantially all the fragment ions wherein the fragment
ions are arranged to be accumulated in the upstream ion
trap;
releasing the fragment ions from the upstream ion
trap;
passing at least some of the fragment ions through
the mass filter/analyser which is arranged to mass
analyse or mass filter the fragment ions;
transmitting the fragment ions through the
downstream ion trap without the fragment ions being
substantially further fragmented; and
detecting the ions with the downstream ion
detector.
In the above embodiments various modes of operation
are described as being first, second, third ... etc.
modes of operation. However, it should be understood
that not all of the modes of operation have to be
performed and at least some of the modes of operation
may be performed in different orders.
Reference is also made in the claims to various
components of the mass spectrometer being either
"upstream" or "downstream" from one another. For the
avoidance of any doubt it should be understood that such
terms should be construed to mean that components are
either physically located and/or functionally provided
upstream or downstream of one another. For example,
when reference is made to an ion detector arranged
upstream of a mass filter/analyser then it should be


CA 02733436 2011-03-02
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understood that ions pass back through the mass
filter/analyser and exit the mass filter/analyser from
what would normally be regarded as the entrance region
of the mass filter/analyser. In a conventional triple
quadrupole mass spectrometer or a hybrid quadrupole-Time
of Flight mass spectrometer the second mass analyser Q3
or the Time of Flight mass analyser and the ion detector
associated with such mass analyser is provided
downstream not upstream of the first mass
filter/analyser Q1.
According to another aspect of the present
invention there is provided a method of mass
spectrometry comprising sending ions an even number of
times through the same mass filter/analyser before said
ions are detected by an ion detector.
Ions are preferably passed twice, four times, six
times, eight times or ten times through the same mass
filter/analyser and are not passed an odd number of
times through the mass filter/analyser before said ions
are detected by an ion detector.
This embodiment is in contrast to arrangements
wherein ions pass an odd number of times through the
same mass filter/analyser.
Various embodiments of the present invention will
now be described, by way of example only, and with
reference to the accompanying drawings in which:
Fig. 1A illustrates a first embodiment of the
present invention for performing MS/MS and'SRM
experiments, Fig. 1B illustrates a second embodiment of
the present invention for performing MS/MS experiments,
Fig. 1C illustrates a third embodiment of the present
invention for performing MS/MS experiments, Fig. 1D
illustrates a fourth embodiment of the present invention
for performing MS3 experiments and Fig. 1E illustrates a
fifth embodiment of the present invention;
Fig. 2A illustrates a first mode.of the first
embodiment wherein parent ions are accumulated in an ion


CA 02733436 2011-03-02
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trap, Fig. 2B illustrates a second mode wherein parent
ions are released from the ion trap and are passed back
through the mass analyser for mass analysis, Fig. 2C
illustrates a third mode wherein particular parent ions
are selected, fragmented and stored in the ion trap and
Fig. 2D illustrates a fourth mode wherein the fragment
ions are passed back through the mass analyser for mass
analysis;
Fig. 3A illustrates a first mode of an alternative
embodiment wherein particular parent ions are selected,
fragmented and stored in an ion trap and Fig. 3B
illustrates a second mode wherein the fragment ions are
passed back through the mass filter;
Fig. 4A illustrates a first mode of the second
embodiment wherein parent ions are mass analysed, Fig.
4B illustrates a second mode wherein particular parent
ions are selected, fragmented and stored in an ion trap,
and Fig.-4C illustrates a third mode wherein the
fragment ions are passed back through the mass analyser
for mass analysis;
Fig. 5A illustrates a first mode of the third
embodiment wherein parent ions are mass analysed, Fig.
5B illustrates a second mode wherein particular parent
ions are selected, fragmented and stored in an ion trap,
Fig. 5C illustrates a third mode wherein the fragment
ions are passed back through the mass filter/analyser
which is arranged to transmit all the fragment ions
which are then stored in an upstream ion trap, and Fig.
5D illustrates a fourth mode wherein the fragment ions
are passed back through the mass analyser for mass
analysis;
Fig. 6A illustrates a first mode of the fourth
embodiment wherein parent ions are mass analysed, Fig.
6B illustrates a second mode wherein particular parent
ion are selected, fragmented and stored in an ion trap,
Fig. 6C illustrates a third mode wherein the fragment
ions are passed back through the mass analyser for mass


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analysis whilst parent ions are accumulated in an
upstream ion trap, Fig. 6D illustrates a subsequent mode
of operation wherein after further fragment ions have
been stored in a downstream ion trap they are,then
passed through the mass filter to select particular
fragment ions which are then further fragmented and
stored in an upstream ion trap, and Fig. 6E illustrates
a yet further mode wherein second generation fragment
ions are passed back through the mass analyser for mass
analysis; and
Fig. 7 illustrates a fifth embodiment of the
present invention.
Various embodiments of the present invention will
now be discussed in relation to Figs.. 1A-1E.
Fig. 1A illustrates a first embodiment of the
present invention. According to this embodiment an ion
source 1 is provided. Downstream of the ion source 1 is
provided a mass filter/analyser 2 and downstream of the
mass filter/analyser 2 is provided a downstream ion trap
3. Upstream of the mass filter/analyser 2 is provided
an upstream ion detector 4. As shown in more detail in
Figs. 2A-2D this embodiment can advantageously perform a
MS/MS experiment using apparatus comprising only a
single mass filter/analyser 2 whereas conventional
triple quadrupole mass spectrometers comprise two mass
filters/analysers.
As shown in Figs. 2A-2D according to the first
embodiment four different modes of operation are cycled
through in order to complete a MS/MS experiment. In the
first mode shown in Fig. 2A the ion source 1 is ON, the
mass filter/analyser 2 is set to transmit all ions
irrespective of their mass to charge ratio (e.g. wide
band pass mode or RF ion guide mode) and parent ions are
trapped in the downstream ion trap 3. In the subsequent
MS mode shown in Fig. 2B the ion source 1 is switched
OFF, parent ions are released from the downstream ion
trap 3 and pass upstream back through the mass analyser


CA 02733436 2011-03-02
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2 which is scanned so that the parent ions are mass
analysed and detected by the upstream ion detector 4.
In the subsequent mode shown in Fig. 2C the ion source 1
is switched back ON, the mass filter 2 is arranged to
operate in a narrow bandpass mode so that only parent
ions falling within a specific narrow range of mass to
charge ratios are transmitted by the mass filter 2.
These. parent ions are then arranged to have an energy
and the downstream ion trap 3 is arranged to be
maintained at a pressure such that when the parent ions
enter the downstream ion trap 3 they are caused to
fragment into fragment ions which are also trapped,
accumulated or otherwise stored in downstream ion trap
3. In the final mode shown in Fig. 2D the ion source 1
is again switched OFF and the fragment ions are released
from the downstream ion trap 3 and are arranged to pass
back upstream through the mass analyser 2 which is
arranged to be scanned so as to mass analyse the
fragment ions which are then detected by upstream ion
detector 4.
Although not shown in Fig. 2D Single Reaction
Monitoring and Multiple Reaction Monitoring embodiments
are contemplated wherein the mass filter/analyser 2 mass
filters the fragment ions rather than mass analysing
them i.e. the mass filter/analyser 2 is set to transmit
ions having a specific mass to charge ratio rather than
being scanned.
It will be apparent from the above that in the
second and fourth modes shown respectively in Fig. 2B
and Fig. 2D the ion source 1 is turned OFF to allow the
mass analyser 2 to analyse the previously accumulated
ions. This prevents parent ions from the source which
have not passed through the mass analyser 2 from
appearing in the resulting mass spectra but has the
disadvantage of lowering the overall duty cycle of the
MS/MS experiment.


CA 02733436 2011-03-02
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According to a preferred embodiment the mass
filter/analyser 2 may comprise a quadrupole rod set mass
filter. In a scanning experiment such as described
above approximately equal times may be spent in each of
the four different modes. Accordingly, the ion source 1
would be OFF for about 500 of the time hence 50% of the
ions generated would be used.
Figs. 3A and 3B show a variation of the first
embodiment for performing a Selected Reaction Monitoring
(SRM) experiment. In a SRM experiment a known targeted
compound is monitored. As shown in Fig. 3A for the
majority of the time (e.g. 900 of the time) the ion
source 1 can be left ON. The mass filter 2 is set to
transmit only parent ions having a specific mass to
charge ratio which corresponds with the targeted
compound. Those parent ions transmitted by the mass
filter 2 are then fragmented in the downstream ion trap
3 and are stored in the downstream ion trap 3.
Accordingly, a majority of the time in any given
experimental run can be spent accumulating fragment ions
in the downstream ion trap3 (i.e. the first mode shown
in Fig. 3A). The ion source 1 is then switched OFF for
a relatively short period of time whilst the fragment
ions are caused to exit the downstream ion trap 3, pass
back upstream through the mass filter 2 to the upstream
ion detector 4. Advantageously, concentrating the
desired ion signal in a relatively short portion of an
experimental cycle enhances the signal to noise ratio
compared with conventional arrangements wherein an ion
detector is active for substantially the whole of an
.experimental run. It is contemplated that an amplifier
may be phase locked to the waveform of the experimental
cycle. Multiple Reaction Monitoring (MRM) experiments
can also be performed by cycling through different mass
to charge ratios and transitions.
Fig. 1B illustrates a second embodiment of the
present invention. The second embodiment is similar to


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the first embodiment except that a downstream ion
detector 5 is also provided downstream of the downstream
ion trap 3. As shown in more detail in Figs. 4A-4C the
addition of a downstream ion detector 5 reduces the
number of steps required for certain analyses. MS/MS
.experiments can be performed requiring one less step
than in the first embodiment i.e. three steps as opposed
to four. Furthermore, as is apparent from comparing
Figs. 4A-C with Figs. 2A-D, the ion source 1 is OFF for
only one out of the three modes of operation. The ion
usage according to the second embodiment is therefore
improved to 66% compared with 50% according to the first
embodiment.
As shown in Figs. 4A-4C according to the second
embodiment three different modes of operation are cycled
through in order to complete a MS/MS experiment. In the
first mode shown in Fig. 4A the ion source 1 is ON, the
mass filter/analyser 2 is arranged to be scanned so as
to mass analyse parent ions which are then detected by
the downstream ion detector 5. The downstream ion trap
3 is arranged to operate as an ion guide. In the second
mode shown in Fig. 4B the ion source is again ON, the
mass filter 2 is arranged to operated in a narrow
bandpass.mode so that only parent ions falling within a
specific narrow range of mass to charge ratios are
transmitted by the mass filter 2. These parent ions are
then arranged to have an energy and the downstream ion
trap 3 is arranged to be maintained at a pressure such
that when the parent ions enter the downstream ion trap
3 they are caused to fragment into fragment ions which
are also trapped, accumulated or otherwise stored in
downstream ion trap 3. In the third mode of operation
shown in Fig. 4C the ion source 1 is switched OFF and
the fragment ions are released from the downstream ion
trap 3 and are arranged to pass back upstream through
the mass analyser 2 which is arranged to be scanned so


CA 02733436 2011-03-02
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as to mass analyse the fragment ions which are then
detected by upstream ion detector 4.
Although not shown in Fig. 4C Single Reaction
Monitoring and Multiple Reaction Monitoring embodiments
are contemplated wherein the mass filter/analyser 2 mass
filters the fragment ions rather than mass analysing
them i.e. the mass filter/analyser 2 is set to transmit
ions having a specific mass to charge ratio rather than
being scanned.
Fig. 1C illustrates a third embodiment of the
present invention. The third embodiment is similar to
the second embodiment except that an upstream ion
detector 4 is not necessarily required and an upstream
ion trap 6 is provided upstream of the mass
filter/analyser 2. As shown in more detail in Figs. 5A-
5D the addition of an upstream ion trap 6 without an.
upstream ion detector 4 allows MS" experiments to be
performed wherein parent ions are selected, fragmented
and then specific fragment ions may be selected and
fragmented to form second generation fragment ions.
This is possible because ions may be passed back and
forth through the mass filter 2 as many times as
desired. With no upstream ion detector 4 the ions
preferably pass through the mass filter 2 an odd number
of times for a particular experimental cycle. A typical
experimental cycle for a MS/MS experiment is shown in
Figs. 5A-5D.
The downstream ion detector 5 may be replaced by an
orthogonal acceleration Time of Flight mass analyser
which can reduce the number of steps required for any
particular analysis in addition to improving the duty
cycle.
As shown in Figs. 5A-5D according to the third
embodiment four different modes of operation may be
cycled through in order to complete a MS/MS experiment.
In the first mode shown in Fig. 5A the ion source 1 is
ON, the upstream ion trap 6 acts as an ion guide and the


CA 02733436 2011-03-02
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mass filter/analyser 2 is arranged to be scanned. The
ions transmitted by the mass analyser 2 are transmitted
by the downstream ion trap 3 which is arranged to be
operated as an ion guide and the ions are detected by
downstream ion detector 5. In the second mode shown in
Fig. 5B the ion source 1 remains ON, the upstream ion
trap 6 is arranged to act as an ion guide and the mass
filter/analyser 2 is arranged to act as a mass filter 2
so that only parent ions falling with a specific narrow
range of mass to charge ratios are transmitted by the
mass filter 2. These parent ions are then arranged to
have an energy and the downstream ion trap 3 is arranged
to be maintained at a pressure such that when the parent
ions enter the downstream ion trap 3 they are caused to
fragment into fragment ions which are also trapped,
accumulated or otherwise stored in downstream ion trap
3. In the third mode shown in Fig. 5C the ion source 1
is switched OFF and the fragment ions are released from
the downstream ion trap 3 and are arranged to pass. back
upstream through the mass filter/analyser 2 which is
arranged to transmit all ions irrespective of their mass
to charge ratio (i.e. it is operated in a wide band pass
mode or RF ion guide mode). The fragment ions are then
trapped in upstream ion trap 6. In the fourth mode
shown in Fig. 5D the ion source 1 remains OFF and the
fragment ions are released from the upstream ion trap 6
and are arranged to pass through the mass
filter/analyser 2 which is arranged to be scanned so as
to mass analyse the fragment ions. The fragment ions
are then transmitted by the downstream ion trap 3 which
is arranged to be operated as an ion guide and are
detected by downstream ion detector 5.
Although not shown in Fig. 5D Single Reaction
Monitoring and Multiple Reaction Monitoring embodiments
are contemplated wherein the mass filter/analyser 2 mass
filters the fragment ions rather than mass analysing
them i.e. the mass filter/analyser 2 is set to transmit


CA 02733436 2011-03-02
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ions having a specific mass to charge ratio rather than
being scanned.
Fig. 1D illustrates a fourth embodiment of the
present invention. This embodiment is similar to the
third embodiment except that an upstream ion detector 4
is provided upstream of the mass filter 2 and downstream
of the upstream ion trap 6. The combination of an
upstream ion trap 6 and an upstream ion detector 4
enables the number of cycles required for an experiment
to be reduced. The mass filter 2 may be configured to
scan so that a full mass spectrum can be acquired.
Alternatively, the mass filter 2 may select ions having
a certain mass to charge ratio for monitoring or
fragmentation. The mass filter 2 may also be switched
to a wideband pass mode so that ions pass through the
mass filter and are stored in an ion trap.
As shown in Figs. 6A-6E according to the fourth
embodiment a number of different modes of operation may
be cycled through in order to complete a MS3 experiment.
In the first mode the ion source 1 is ON and the
upstream ion trap 6 is set to act as an ion guide. The
ions are pass through the mass filter/analyser 2 which
is arranged to be scanned so as to mass analyse ions.
The ions are then transmitted by a downstream ion trap 3
which is also arranged to act as an ion guide. The ions
are then detected by a downstream ion detector S. In
the second mode the ion source 1 remains ON and the
upstream ion trap 6 is again arranged to act as an ion
guide. The mass filter 2 is arranged to transmit ions
falling within a specific narrow range of mass to charge
ratios. These parent ions are then arranged to have an
energy and the downstream ion trap 3 is arranged to be
maintained at a pressure such that when the parent ions
enter the downstream ion trap 3 they are caused to
fragment into fragment ions which are also trapped,.
accumulated or otherwise sorted in downstream ion trap
3. In the third mode the ion source 1 remains ON and


CA 02733436 2011-03-02
28 -

ions generated by the ion source 1 are preferably
trapped in the upstream ion trap 6. Meanwhile, fragment
ions are caused to exit the downstream ion trap 3 and
pass back upstream through the mass analyser 2 to the
upstream ion detector 4. The mass analyser 2 is
arranged to be scanned so as to mass analyse the
fragment ions which are then detected by the upstream
ion detector 4. According to the next mode ions from
the upstream ion trap 6 are released and these ions
together with other parent ions generated by the ion
source 1 are transmitted by the upstream ion trap 6
which is set to operate as an ion guide. The mass
filter 2 is arranged to transmit ions falling within a
specific narrow range of mass to charge ratios. These
parent ions are then arranged to have an energy and the
downstream ion trap 3 is arranged to be maintained at a
pressure such that when the parent ions enter the
downstream ion trap 3 they are caused to fragment into
fragment ions which are also trapped, accumulated or
otherwise stored in downstream ion trap 3. According to
the next mode shown and described in relation to Fig 6D
the ion source 1 is switched OFF and fragment ions are
released from the downstream ion trap 3. The fragment
ions are arranged to be passed back upstream through the
mass filter 2 which is arranged to operate in a narrow
bandpass mode so that only parent ions falling within a
specific narrow range of mass to charge ratios are
transmitted by the mass filter 2. The fragment ions are
then arranged to have an energy and the upstream ion
trap 6 is arranged to be maintained at a pressure such
that when the fragment ions enter the upstream ion trap
6 they are caused to fragment into second generation
fragment ions which are also trapped, accumulated or
otherwise stored in upstream ion trap 6. In the final
mode shown in Fig. 6E the. ion source 1 remains OFF and
the second generation fragment ions are ejected from, the
upstream ion trap 6 which is arranged to operate as an


CA 02733436 2011-03-02
29 -

ion guide. The ions are then passed through the mass
filter/analyser 2 which is arranged to be scanned so as
to mass analyse the second generation fragment ions
which are then transmitted by downstream ion trap 3 and
detected by downstream ion detector 5.
Although not shown in Fig. 6C and 6E Single
Reaction Monitoring and Multiple Reaction Monitoring
embodiments are contemplated wherein the mass
filter/analyser 2 mass filters the fragment or second
generation fragment ions rather than mass analysing them
i.e. the mass filter/analyser 2 is set to transmit ions
having a specific mass to charge ratio rather than being
scanned.
The modes described above illustrate how a MS3
experiment may be performed. The first and second modes
are similar to the first and second modes of the MS/MS
experiment according to the second embodiment. However,
the third mode shows how ions are preferably accumulated
in the upstream ion trap 6 whilst the fragment ions are
being analysed by the scanning mass analyser 2 and off-
axis upstream ion detector 4. Accumulating ions from
the ion source 1 in the upstream ion trap 6 whilst the
fragment ions are being mass analysed allows the overall
duty cycle to be further improved. The fifth mode shown
and described in relation to Fig. 6D shows how a
fragment ion is selected by the mass filter 2 and
fragmented and accumulated in the upstream ion trap 6.
This is possible if the upstream ion trap 6 is operating
at the correct pressure to act as a collision cell
otherwise it may be used simply to accumulate fragment
ions and then send them back to the downstream ion trap
3 for further fragmentation.
It can be seen from Figs. 6D and 6E that during the
fifth and sixth modes of operation the ion source 1 is
switched OFF to prevent parent ions from the ion source
appearing in the MS3 mass spectrum. This embodiment does


CA 02733436 2011-03-02
30 -

not therefore fully utilise 1000 of the ions generated
by the ion source 1.
Fig. 1E illustrates a fifth and yet further
embodiment. of the present invention. The fifth
embodiment is similar to the fourth embodiment except
that an additional (second) upstream ion trap 7 is
provided either upstream or downstream of the first
upstream ion trap 6. The additional second upstream ion
trap 7 allows all the ions generated by the ion source 1
to be used i.e. the ion source 1 does not need to be and
preferably is not switched OFF whilst performing a MS3
experiment. A general mode of operation is shown in
Fig. 7 wherein ions are released from downstream ion
trap 3 and are arranged to pass back upstream through
the mass filter 2 which is arranged to operate in a
narrow bandpass mode so that only ions falling within a
specific narrow range of mass to charge ratios are
transmitted by the mass filter 2. The ions are then
arranged to have an energy and the upstream ion trap 6
is arranged to be maintained at a pressure such that the
ions enter the upstream ion trap 6 and are caused to
fragment into fragment ions which are also trapped,
accumulated or otherwise stored in the upstream ion trap
6. Meanwhile, ions generated from the ion source 1 are
accumulated in the further upstream ion trap 7.
According to a preferred embodiment the various
modes according to the fifth embodiment may correspond
with those according to the fourth embodiment except
that preferably instead of switching the ion source 1
OFF in the fifth and sixth modes of the fourth
embodiment (as shown in Figs. 6D and 6E), the ion source
1 is preferably left ON and ions generated by the ion
source 1 are trapped in the further upstream ion trap 7.
In the above described embodiments the upstream
and/or downstream ion detector 4,5 preferably comprise a
detector per se. However, other less preferred
embodiments are also contemplated wherein the upstream


CA 02733436 2011-03-02
- 31 -

and/or downstream ion detectors 4,5 may comprise the
detector of a Time of Flight, a quadrupole, a Penning or
Fourier Transform Ion Cyclotron Resonance mass analyser,
a 2D or linear quadrupole ion trap or a Paul or 3D
quadrupole ion trap i.e. an additional mass analyser may
be provided.
It will be appreciated that the ion traps 3,6,7 are
not necessarily ion tunnel ion traps/ion guides
comprising a plurality of electrodes having apertures
through which ions are transmitted and wherein
substantially all the electrodes forming the ion tunnel
ion trap/ion guide have substantially the same size
apertures. Other forms of ion traps such as 2D linear
quadrupole ion traps or Paul 3D quadrupole ion traps may
also be used according to less preferred embodiments.
Similarly, although the mass filter/analyser 2 is
preferably a quadrupole rod set mass filter/analyser,
the mass filter/analyser could according to less
preferred embodiment comprise an axial Time of Flight
mass filter/analyser, a magnetic sector mass analyser, a
Paul or 3D quadrupole type ion trap, a 2D linear
quadrupole ion trap, a Wien filter or another type of
mass filter/analyser.
Reference is made in the present application to the
mass filter/analyser being operated in different modes.
When the mass filter/analyser is the to be operated as a
mass filter then unless otherwise stated it is intended
that the mass filter transmits ions having a narrow
(e.g. 1 amu) range of mass to charge ratios. Ions
having other mass to charge ratios are substantially
attenuated by the mass filter. When the mass filter is
described as operating in a wide band pass mode then
this is intended to mean that the mass filter does not
substantially mass filter ions.i.e. ions are transmitted
by the mass filter irrespective of their mass to charge
ratio. Finally, when the mass filter/analyser is
described as operating as a mass analyser, this is


CA 02733436 2011-03-02
32 -

intended to mean that a narrow (e.g. 1 amu) mass to
charge ratio transmission window of the mass
filter/analyser is rapidly scanned.
In all the embodiments described above an axial DC
voltage gradient or other means for urging ions through
the mass spectrometer may or may not be provided. For
example, according to less preferred embodiments when an
ion trap is arranged to eject ions no axial DC voltage
gradient may be provided along the length of the ion
trap so that ions drift out of the ion trap but are not
substantially accelerated out of the ion trap.
Similarly, it will be appreciated that axial DC voltage
gradients applied to one or more of the ion traps may be
varied along the length of the'ion trap and may vary in
a time dependent manner.
Although the present invention has been described
with reference to preferred embodiments, it will be
understood by those skilled in the art that various
changes in form and detail may be made without departing
from the scope of the invention as set forth in the
accompanying claims.

A single figure which represents the drawing illustrating the invention.

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Title Date
Forecasted Issue Date 2014-12-23
(22) Filed 2003-05-16
(41) Open to Public Inspection 2003-11-17
Examination Requested 2011-03-02
(45) Issued 2014-12-23

Abandonment History

There is no abandonment history.

Maintenance Fee

Description Date Amount
Last Payment 2018-04-19 $450.00
Next Payment if small entity fee 2019-05-16 $225.00
Next Payment if standard fee 2019-05-16 $450.00

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Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $800.00 2011-03-02
Registration of Documents $100.00 2011-03-02
Registration of Documents $100.00 2011-03-02
Filing $400.00 2011-03-02
Maintenance Fee - Application - New Act 2 2005-05-16 $100.00 2011-03-02
Maintenance Fee - Application - New Act 3 2006-05-16 $100.00 2011-03-02
Maintenance Fee - Application - New Act 4 2007-05-16 $100.00 2011-03-02
Maintenance Fee - Application - New Act 5 2008-05-16 $200.00 2011-03-02
Maintenance Fee - Application - New Act 6 2009-05-19 $200.00 2011-03-02
Maintenance Fee - Application - New Act 7 2010-05-17 $200.00 2011-03-02
Maintenance Fee - Application - New Act 8 2011-05-16 $200.00 2011-03-02
Maintenance Fee - Application - New Act 9 2012-05-16 $200.00 2012-05-07
Maintenance Fee - Application - New Act 10 2013-05-16 $250.00 2013-05-01
Maintenance Fee - Application - New Act 11 2014-05-16 $250.00 2014-05-02
Final Fee $300.00 2014-09-29
Maintenance Fee - Patent - New Act 12 2015-05-19 $250.00 2015-05-11
Maintenance Fee - Patent - New Act 13 2016-05-16 $250.00 2016-05-09
Maintenance Fee - Patent - New Act 14 2017-05-16 $250.00 2017-05-15
Maintenance Fee - Patent - New Act 15 2018-05-16 $450.00 2018-04-19
Current owners on record shown in alphabetical order.
Current Owners on Record
MICROMASS UK LIMITED
Past owners on record shown in alphabetical order.
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.

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Representative Drawing 2011-04-14 1 2
Cover Page 2011-04-14 1 29
Abstract 2011-03-02 1 12
Description 2011-03-02 32 1,554
Claims 2011-03-02 9 310
Drawings 2011-03-02 5 39
Claims 2012-11-07 5 230
Claims 2013-02-27 5 217
Cover Page 2014-12-05 1 29
Correspondence 2011-03-24 1 38
Assignment 2011-03-02 4 133
Prosecution-Amendment 2011-03-02 2 84
Prosecution-Amendment 2013-02-27 8 294
Prosecution-Amendment 2012-06-11 2 68
Prosecution-Amendment 2012-11-07 8 311
Prosecution-Amendment 2013-01-14 2 42
Assignment 2014-04-02 7 191
Correspondence 2014-09-29 1 54