# US 12,009,194 B2 · Mass spectrometry data-independent analysis methods with improved efficiency

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- Number: US 12,009,194 B2
- Document ID: US12009194B2
- Status: Granted
- Kind: B2
- Application number: 17/550,845
- Filed: 2021-12-14
- Published: 2023-06-15
- Granted: 2024-06-11
- Earliest claimed: 2021-12-14
- Applicants: Thermo Finnigan LLC
- Inventors: Philip M. Remes
- Web page: https://patentgrep.com/patent/US12009194B2

## CPC

- H01J 49/0027: {Methods for using particle spectrometers}
- H01J 49/0036: {Step by step routines describing the handling of the data generated during a measurement}
- G01N 30/8631: {Peaks}
- H01J 49/0045: {characterised by the fragmentation or other specific reaction}
- H01J 49/421: {Mass filters, i.e. deviating unwanted ions without trapping}
- H01J: ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS (spark-gaps H01T; electric arc lamps H05B31/00; particle accelerators H05H)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

A method of data-independent mass spectrometric analysis of compounds of a compound class of interest comprises: determining or retrieving a distribution, over a mass-to-charge (m/z) ratio range of interest, of a number of primary ion species of members of said compound class having m/z ratios within each respective one of a plurality of m/z sub-ranges of the m/z ratio range of interest; defining m/z positions of a set consisting of a number, nsb, of finite-width bins, within the m/z ratio range of interest, the set of bins excluding m/z sub-ranges within the m/z ratio range of interest that encompass fewer than a threshold number, tsb, of the primary ion species, wherein the defining based on the determined or received distribution; and performing a plurality of tandem mass analyses, each tandem mass analysis pertaining to primary ion species within a respective one of the defined bins.

## Claims

### Claim 1

A method of data-independent mass spectrometric analysis of compounds of a compound class of interest, comprising:
determining or retrieving a distribution, over a mass-to-charge (m/z) ratio range of interest, of a number of primary ion species of members of said compound class having m/z ratios within each respective one of a plurality of m/z sub-ranges of the m/z ratio range of interest, wherein the determined or retrieved distribution comprises a histogram of a number of primary ion species versus m/z;
defining m/z positions of a set consisting of a number, nsb, of finite-width bins, within the m/z ratio range of interest, the set of bins excluding m/z sub-ranges within the m/z ratio range of interest that encompass fewer than a threshold number, tsb, of the primary ion species, wherein the defining based on the determined or received distribution; and
performing one or more cycles of tandem mass spectral analyses of compounds of the class, wherein each cycle of tandem mass spectral analyses comprises one or more tandem mass analyses pertaining to primary ion species within a respective one of the defined bins, each tandem mass analysis of each cycle pertaining to a respective primary ion species,
wherein the defining of the m/z positions of the nsb finite-width bins comprises either defining a center of a bin within an m/z range encompassed by an isolated histogram bar or defining a center of a bin at an average m/z value of a cluster or an isolated cluster of histogram bars.

### Claim 2 (depends on 1)

A method as recited in claim 1, wherein the defining of the m/z positions of the nsb finite-width bins comprises:
dividing the m/z range of interest into n0 equal width partitions that encompass the entire m/z range of interest, where n0>nsb;
discarding partitions that encompass fewer than tsb of the compounds; and
defining each of the non-discarded partitions as a respective one of the finite-width bins.

### Claim 3 (depends on 2)

A method as recited in claim 2, wherein tsb=1.

### Claim 4 (depends on 1)

A method as recited in claim 1, wherein tsb=1.

### Claim 5 (depends on 1)

A method as recited in claim 1, wherein the number, nsb, of finite-width bins, is determined by dividing a known or estimated length of time, te, that is available for conducting a cycle of tandem mass spectral analyses by the tandem-mass-analysis repetition rate, re, of a mass spectrometer instrument that performs the tandem mass spectral analyses.

### Claim 6 (depends on 5)

A method as recited in claim 5, wherein the estimated length of time, te, is a known or expected width of a chromatographic elution peak.

### Claim 7 (depends on 1)

A method as recited in claim 1, further comprising defining a width, Δ(m/z) of at least one bin.

### Claim 8 (depends on 7)

A method as recited in claim 7, wherein the defining of the width of the at least one bin comprises expanding the width of a bin to increase a number of m/z values of primary ion species of the compounds encompassed by the bin.

### Claim 9 (depends on 7)

A method as recited in claim 7, wherein the defining of the width of the at least one bin comprises subdividing a bin so that a number of m/z values of primary ion species of the compounds encompassed by the bin is reduced to below a pre-determined maximum value, cmax.

### Claim 10

A mass spectrometer system comprising:
an ion source configured to receive portions of a sample comprising compounds that are members of a compound class of interest;
a mass filter configured to receive primary ion species generated by the ion source, the generated ions comprising a mass-to-charge (m/z) ratio range of interest;
an ion fragmentation cell configured to receive a plurality of isolated subsets of the primary ion species from the mass filter;
a mass analyzer configured to receive, from the fragmentation cell, product ions generated by fragmentation of the isolated subsets of the primary ion species;
a detector configured to detect ions outlet from the mass analyzer; and
one or more programmable processors electrically coupled to the mass filter, the ion fragmentation cell, the mass analyzer and the detector and comprising computer-readable instructions adapted to:
determine or retrieve, a distribution, over the m/z ratio range of interest, of a number of primary ion species of members of said compound class having m/z ratios within each respective one of a plurality of sub-ranges of the m/z range of interest, wherein the determined or retrieved distribution comprises a histogram of a number of primary ion species versus m/z;
define m/z positions of a set consisting of a number, nsb, of finite-width bins within the m/z ratio range of interest, the set of bins excluding m/z sub-ranges within the m/z ratio range of interest that encompass fewer than a threshold number, tsb, of the primary ion species, wherein the defining is based on the retrieved distribution; and
cause the mass filter, ion fragmentation cell and mass analyzer to perform one or more cycles of tandem mass spectral analyses of compounds of the class, wherein each cycle of tandem mass spectral analyses comprises one or more tandem mass analyses pertaining to primary ion species within a respective of the defined bins, each tandem mass analysis of each cycle pertaining to a respective primary ion species,
wherein the defining of the m/z positions of the non finite-width bins comprises either defining a center of a bin within an m/z range encompassed by an isolated histogram bar or defining a center of a bin at an average m/z value of a cluster or an isolated cluster of histogram bars.

### Claim 11 (depends on 10)

A mass spectrometer system as recited in claim 10, wherein the computer-readable instructions that are adapted to define the m/z positions of the set of nsb finite-width bins are adapted to:
divide the m/z range of interest into n0 equal width partitions that encompass the entire m/z range of interest, where n0>nsb;
discard partitions that encompass fewer than tsb of the primary ion species; and
define each of the non-discarded partitions as a respective one the finite-width bins.

### Claim 12 (depends on 10)

A mass spectrometer system as recited in claim 10, wherein the computer-readable instructions are further adapted to calculate the number, nsb, of finite-width bins by dividing a known or estimated length of time, te, that is available for conducting a cycle of tandem mass spectral analyses by a tandem-mass-analysis repetition rate, re, of the mass spectrometer system.

### Claim 13 (depends on 10)

A mass spectrometer system as recited in claim 10, wherein the computer-readable instructions are further adapted to define a width, Δ(m/z) of at least one bin.

### Claim 14 (depends on 13)

A mass spectrometer system as recited in claim 13, wherein the computer-readable instructions that are adapted to define the width, Δ(m/z) of at least one bin are adapted to expand the width of a bin so that a number of m/z values of primary ion species encompassed by the bin is caused to increase to a value greater than the threshold, tsb.

### Claim 15 (depends on 1)

A method as recited in claim 1, wherein the compound class is one of the group consisting of: endogenous metabolites, therapeutics, prescription drugs, industrial chemicals, medicines, textile chemicals, dyes, pesticides, herbicides, drugs of abuse, illegal drugs, personal care products, cosmetics, excipients, colorants, steroids, vitamins, hormones, sports doping drugs, natural toxins and perfluorinated hydrocarbons.

### Claim 16 (depends on 10)

A mass spectrometer system as recited in claim 10, wherein tsb=1.

### Claim 17 (depends on 11)

A mass spectrometer system as recited in claim 11, wherein tsb=1.