2.22.2008

Patent Baristas » Some Caveat Emptor for Provisional Applications - Sent Using Google Toolbar

Patent Baristas » Some Caveat Emptor for Provisional Applications

If you haven't seen it, the USPTO offers a little guide on filing a provisional application for a patent. Besides giving a brief overview of the history, purpose and filing date requirements, it offers a nice list of cautions about their use.  As patent attorneys soon find out, inventors hear about provisional patent applications and then come to you asking for one of those $100 applications.

I'm thinking of keeping the list of cautions as a stock document to send to prospective patentees so that I ensure they are duly warned.  See below:

Cautions

Provisional applications are not examined on their merits.

The benefits of the provisional application cannot be claimed if the one-year deadline for filing a non-provisional application has expired.

Provisional applications cannot claim the benefit of a previously-filed application, either foreign or domestic.

It is recommended that the disclosure of the invention in the provisional application be as complete as possible. In order to obtain the benefit of the filing date of a provisional application the claimed subject matter in the later filed non-provisional application must have support in the provisional application.

If there are multiple inventors, each inventor must be named in the application.

The inventor(s) named in the provisional application must have made a contribution to the invention as described.  If multiple inventors are named, each inventor named must have made a contribution individually or jointly to the subject matter disclosed in the application.

The non-provisional application must have one inventor in common with the inventor(s) named in the provisional application to claim benefit of the provisional application filing date.

A provisional application must be entitled to a filing date and include the basic filing fee in order for a non-provisional application to claim benefit of that provisional application.

There is a surcharge for filing the basic filing fee or the cover sheet on a date later than filing the provisional application.

Provisional applications for patent may not be filed for design inventions.

Amendments are not permitted in provisional applications after filing, other than those to make the provisional application comply with applicable regulations.

No information disclosure statement may be filed in a provisional application.

A provisional application cannot result in a U. S. patent unless one of the following two events occur within 12 months of the provisional application filing date:

  1. a corresponding non-provisional application for patent entitled to a filing date is filed that claims the benefit of the earlier filed provisional application; or
  2. a grantable petition under 37 CFR 1.53(c)(3) to convert the provisional application into a non-provisional application is filed.

Warnings

A provisional application automatically becomes abandoned when its pendency expires 12 months after the provisional application filing date by operation of law. Applicants must file a non-provisional application claiming benefit of the earlier provisional application filing date in the USPTO before the provisional application pendency period expires in order to preserve any benefit from the provisional-application filing.

Beware that an applicant whose invention is "in use" or "on sale" (see 35 U.S.C. ?102(b)) in the United States during the one-year provisional-application pendency period may lose more than the benefit of the provisional application filing date if the one-year provisional-application pendency period expires before a corresponding non-provisional application is filed. Such an applicant may also lose the right to ever patent the invention (see 35 U.S.C. ?102(b)).

Effective November 29, 2000, a claim under 35 U.S.C. 119(e) for the benefit of a prior provisional application must be filed during the pendency of the non-provisional application, and within four months of the non-provisional application filing date or within sixteen months of the provisional application filing date (whichever is later). See 37 CFR 1.78 as amended effective November 29, 2000.

Independent inventors should fully understand that a provisional application will not mature into a granted patent without further submissions by the inventor.  Some invention promotion firms misuse the provisional application process leaving the inventor with no patent.

I would just add that "you get what you pay for" still applies.

Posted December 1st, 2004 by Stephen Albainy-Jenei in USPTO
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America's Inventor[tm] Online: Patents, Trademarks & Copyrights - Sent Using Google Toolbar

America's Inventor[tm] Online: Patents, Trademarks & Copyrights

What Kind of Patent Application Should I File?
By Mark David Torche

Should you file a provisional patent application? Although Patwrite is a full service Intellectual Property Law Firm with corporate clients, we specialize in helping private inventors get legal protection for their intellectual property. Because of this, we hear this question on a daily basis. Most clients want us to tell them what they should do. We really can't make the decision for you, but we can give you the information you need to make an informed decision.

First let's look at the history of the provisional patent and just exactly what it is. The provisional patent application (PPA) is a fairly new innovation in the US patent system. It has only been around for about 10 years. Part of the problem that the PPA addresses, is that the US awards patents to the "first to invent" rather than the "first to file" used by the rest of the world. It is beyond the scope of this paper to get involved in that debate, but the need to quickly establish a priority date is needed and the provisional application fills this need.

A provisional patent NEVER matures into a utility patent and automatically becomes abandoned after one year. Before abandonment, it must be replaced with a utility patent application or priority is lost which could under some circumstances lead to a total loss of patent rights. It is possible to get an extension past the year, but only for unintentional or unavoidable circumstances, not just because an extension of time is desired.

What exactly is a provisional patent application? It is an unexamined application that must contain enough information to disclose the invention, but it does not contain any claims. It should contain drawings if they are needed to understand the invention in the same way a utility application needs drawings.

The only time a provisional application is examined, is after the fact when a utility application claims priority from the provisional application. In this case, the PPA is examined to be sure that the invention was sufficiently disclosed to ensure that the utility patent application does not introduce new subject matter. In this way, a PPA allows an inventor extra time to get a formal application together and postpones some of the cost associated with a utility application.

Are there any down sides to the PPA? There are two areas of concern to the inventor regarding the PPA. First is the very real danger that the PPA will not include enough disclosure. Because the PPA is unexamined, as long as the application meets the formal requirements of having a cover page identifying the application, etc. it will be given a filing date and the inventor is entitled to use the patent pending notification with respect to the invention. Therein lies the problem; an inventor can feel protected as to their invention, yet when the PPA is eventually replaced with a utility application, the patent office can find that the invention was not sufficiently disclosed and a new application without the benefit of the PPA priority date must be filed. This can be disastrous depending on the circumstances.

I have personally had clients with horror stories who filed a few pages and a drawing or two as their PPA and then lost all rights to the invention. I cringe when I read some of the "self-help" articles explaining that inventors can get "patent pending" status in one day at a fraction of the cost of a patent attorney. While this statement is true, it is highly unlikely that a significant and sufficient PPA can be prepared in a few hours and when the inventor goes to file the utility application, it may be impossible to claim priority to the PPA.

The second disadvantage to the PPA is that while it postpones some of the costs associated with a utility application, in the long run it costs more than if the inventor just filed the utility application. Since a utility application must be filed within a year of the PPA, the money spent on the PPA is an "extra" cost with respect to the utility application.

So what is the bottom line regarding PPA's? They are a valuable tool for an inventor on a tight budget or in a hurry to establish priority but they should be filed with care. You need to evaluate your long term goals and marketing strategy to see if a PPA makes sense for you. If you have the extra money to file the utility application, it will save you money, but if you are short on funds and looking for financing a PPA makes a great deal of sense.

If you decide to file a PPA on your own, you should carefully research all you can about filing utility applications and remember that eventually your PPA needs to serve as the basis for your utility application. Some attorneys and agents offer a fairly low cost review service for inventors filing on their own and I would minimally recommend this if you decide to file on your own.

If you have any specific questions not addressed in this newsletter, please feel free to call us at Patwrite and we will be glad to discuss it with you.

Mark David Torche is a Patent Attorney registered to practice before the United States Patent and Trademark Office. He has worked with many large corporate clients including Chase, Olympus, Fuji Electric, Mitsubishi Motors and International Rectifier, but specializes in working with independent inventors. Mr. Torche offers inventors a variety of affordable prices to fit their budget, in addition to payment plan options. He offers an initial "Free Consultation". For more information, call PatWrite at (866) 42-IPLAW (866-424-7529) or E-mail: mark@patwrite.com . His web site is www.patwrite.com

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2.19.2008

Throughput accounting - Wikipedia, the free encyclopedia - Sent Using Google Toolbar

Throughput accounting - Wikipedia, the free encyclopedia

Throughput accounting

From Wikipedia, the free encyclopedia

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Please help improve this article by adding citations to reliable sources. Unverifiable material may be challenged and removed.

Throughput accounting (TA) is an alternative to cost accounting proposed by Eliyahu M. Goldratt. It is not based on Standard Costing or Activity Based Costing (ABC). Throughput Accounting is not costing and it does not allocate costs to products and services. It can be viewed as business intelligence for profit maximization. Conceptually throughput accounting seeks to increase the velocity at which products move through an organization by eliminating bottlenecks within the organization.

Cost (or Management) accounting is an organization's internal method used to measure efficiency. Since no one outside the organization uses such internal accounts for investment or other decisions, any methods that an organization finds helpful can be used. Outside parties to a business depend on accounting reports prepared by financial (public) accountants who apply Generally Accepted Accounting Principles(GAAP) issued by the Financial Accounting Standards Board (FASB) and enforced by the U.S. Securities and Exchange Commission (SEC) and other regulatory agencies.

Throughput accounting improves profit performance with better management decisions by using measurements that more closely reflect the effect of decisions on three critical monetary variables (throughput, inventory, and operating expense — defined below).

[edit] History

When cost accounting was developed in the 1890's, labor was the largest fraction of product cost and workers might not know how many hours they would work in a week when they reported on Monday morning. Cost accountants, therefore, concentrated on how efficiently managers used labor since it was their most important variable resource. Now, however, workers who come to work on Monday morning almost always work 40 hours or more; their cost is fixed rather than variable. Many managers are still evaluated on their labor efficiencies, though, and many "downsizing," "rightsizing," and other labor reduction campaigns are based on them..

Goldratt argues that, under current conditions, labor efficiencies lead to decisions that harm rather than help organizations. Throughput accounting, therefore, removes standard cost accounting's reliance on efficiencies in general and labor efficiency in particular from management practice. Many cost and financial accountants agree with Goldratt's critique, but they have not agreed on a replacement of their own and there is enormous inertia in the installed base of people trained to work with existing practices.

The recent development of TA is constraints accounting, which focuses more strongly on the role of the constraint in decision making. (See Caspari & Caspari for details).

[edit] The concept of throughput accounting

Goldratt's alternative begins with the idea that each organization has a goal and that better decisions increase its value. The goal for a profit maximizing firm is easily stated, to increase profit, now and in the future. Throughput accounting applies to not-for-profit organizations too, but they have to develop a goal that makes sense in their individual cases.

Throughput Accounting also pays particular attention to the concept of bottlenecks in the manufacturing or servicing processes.

Throughput accounting uses three measures of income and expense:

  • Throughput (T) is the rate at which the system produces "goal units." When the goal units are money (in for-profit businesses), throughput is sales revenues less the cost of the raw materials (T = S - RM). Note that T only exists when there is a sale of the product or service. Producing materials that sit in a warehouse does not count. ("Throughput" is sometimes referred to as "Throughput Contribution" and has similarities to the concept of "Contribution" in Marginal Costing which is sales revenues less "variable" costs - "variable" being defined according to the Marginal Costing philosophy.)
  • Investment (I) is the money tied up in the system. This is money associated with inventory, machinery, buildings, and other assets and liabilities. In earlier Theory of Constraints (TOC) documentation, the "I" was interchanged between "Inventory" and "Investment." The preferred term is now only "investment." Note that TOC recommends inventory be valued strictly on totally variable cost associated with creating the inventory, not with additional cost allocations from overhead.
  • Operating expense (OE) is the money the system spends in generating "goal units." For physical products, OE is all expenses except the cost of the raw materials. OE includes maintenance, utilities, rent, taxes, payroll, etc.

Organizations that wish to increase their attainment of The Goal should therefore require managers to test proposed decisions against three questions. Will the proposed change:

  1. Increase Throughput? How?
  2. Reduce Investment (Inventory) (money that cannot be used)? How?
  3. Reduce Operating expense? How?

The answers to these questions determine the effect of proposed changes on system wide measurements:

  1. Net profit (NP) = Throughput - Operating Expense = T-OE
  2. Return on investment (ROI) = Net profit / Investment = NP/I
  3. Productivity (P) = Throughput / Operating expense = T/OE
  4. Investment turns (IT) = Throughput / Investment = T/I

These relationships between financial ratios as illustrated by Goldratt are very similar to a set of relationships defined by DuPont and General Motors financial executive Donaldson Brown about 1920. Brown did not advocate changes in management accounting methods, but instead used the ratios to evaluate traditional financial accounting data.

Throughput Accounting is an important development in modern accounting that allows managers to understand the contribution of constrained resources to the overall profitability of the enterprise. See Cost Accounting for practical examples and a detailed description of the evolution of throughput accounting.

[edit] External links

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Mass spectrometry - Wikipedia, the free encyclopedia - Sent Using Google Toolbar

Mass spectrometry - Wikipedia, the free encyclopedia

Mass spectrometry

From Wikipedia, the free encyclopedia

  (Redirected from Mass spec)
Jump to: navigation, search

Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of ions.[1] It is most generally used to find the composition of a physical sample by generating a mass spectrum representing the masses of sample components. The mass spectrum is measured by a mass spectrometer.

Main steps of measuring with a mass spectrometer
Main steps of measuring with a mass spectrometer

Mass spectrometers consist of three basic parts: an ion source, a mass analyzer, and a detector system. The stages within the mass spectrometer are:

  1. Production of ions from the sample
  2. Separation of ions with different masses
  3. Detection of the number of ions of each mass produced
  4. Collection of data to generate the mass spectrum

The technique is applicable in:

  • identifying unknown compounds by the mass of the compound molecules or their fragments
  • determining the isotopic composition of elements in a compound
  • determining the structure of a compound by observing its fragmentation
  • quantifying the amount of a compound in a sample using carefully designed methods (mass spectrometry is not inherently quantitative)
  • studying the fundamentals of gas phase ion chemistry (the chemistry of ions and neutrals in vacuum)
  • determining other physical, chemical, or even biological properties of compounds with a variety of other approaches

Contents

[hide]

[edit] Etymology

The earliest devices that measured the mass-to-charge ratio of ions were called mass spectrographs because they were instruments that recorded a spectrum of mass values on a photographic plate.[2][3] Removing several letters, such as the bound morphemes and free morphemes, and combining the lingustical roots of spectr-um and phot-ograph-ic plate creates the word spectrograph.[4] A mass spectroscope is similar to a mass spectrograph except that the beam of ions is directed onto a phosphor screen.[5] The suffix -scope here denotes the direct viewing of the spectra (range) of masses. A mass spectroscope configuration was used in early instruments when it was desired that the effects of adjustments be quickly observed. Once the instrument was properly adjusted, a photographic plate was inserted and exposed. The term mass spectroscope continued to be used even though the direct illumination of a phosphor screen was replaced by indirect measurements with an oscilloscope.[6] Mass spectroscopy has been used in the past, and is a strictly correct etymology, literally an instrument for the viewing of a range of masses, but is now discouraged due to the possibility of confusion with light spectroscopy.[1] The terms mass spectroscopy and mass spectrometry are currently used, although the latter is strongly preferred.[7][1] Mass spectrometry is often abbreviated as mass-spec or simply as MS.[1]

[edit] History

For more details on this topic, see History of mass spectrometry.
Francis William Aston won the 1922 Nobel Prize in Chemistry for his work in mass spectrometry
Francis William Aston won the 1922 Nobel Prize in Chemistry for his work in mass spectrometry

In 1886, Eugen Goldstein observed "rays" that travelled through the channels of a perforated cathode in a low pressure gas discharge and moved toward the anode, in the opposite direction to the negatively charged cathode rays. Goldstein called these positively charged anode rays "Kanalstrahlen" or canal rays. Wilhelm Wien found that strong electric or magnetic fields deflected the canal rays and, in 1899, constructed a device with parallel electric and magnetic fields that separated the positive rays according to their charge-to-mass ratio (e/m). Wien found that the charge-to-mass ratio depended on the nature of the gas in the discharge tube. English scientist J.J. Thomson later improved on the work of Wilhelm Wien by reducing the pressure to create a mass spectrograph. The processes that more directly gave rise to the modern version of the mass spectrometer were devised by Arthur Jeffrey Dempster and F.W. Aston in 1918 and 1919 respectively.

In 2002, the Nobel Prize in Chemistry was received by John Bennett Fenn for the development of electrospray ionization (ESI) and Koichi Tanaka for the development of soft laser desorption (SLD) in 1987. An improved SLD method, matrix-assisted laser desorption/ionization (MALDI), was developed in 1987 by Franz Hillenkamp and Michael Karas.[8]

[edit] Simplified working example

Schematics of a simple mass spectrometer
Schematics of a simple mass spectrometer

Different chemicals have different masses, and this fact is used in a mass spectrometer to determine what chemicals are present in a sample. For example, table salt (NaCl), may be vaporized (turned into gas) and ionized (broken down) into electrically charged particles (Na+ and Cl-), called ions, in the first phase of the mass spectrometry. The sodium ions are monoisotopic, with mass 23u. Chloride ions have two isotopes of mass 35u (~75%) and mass 37u (~25%). They also have a charge, which means that the speed and direction may be changed with an electric or magnetic field. An electric field accelarates the ions to a high speed. After this, they are directed into a magnetic field which applies a force to each ion perpendicular to the plane defined by the particles' direction of travel and the magnetic field lines. This force deflects the ions (makes them curve instead of traveling in a straight line) to varying degrees depending on their mass-to-charge (m/z) ratio. Lighter ions get deflected more than the heavier ions. This is due to Newton's second law of motion. The acceleration of a particle is inversely proportional to its mass. Therefore, the magnetic field deflects the lighter ions more than it does the heavier ions. The detector measures the deflection of each resulting ion beam. From this measurement, the mass-to-charge ratios of all the ions produced in the source can be determined. From this information, the chemical composition of the original sample (i.e. that both sodium and chlorine are present in the sample) and the isotopic compositions of its constituents (i.e. whether the ratio of 35Cl to 37Cl has been changed by some process) can de determined.

This example was of a sector instrument, however there are many types of mass spectrometers. All of these have in common that they possess an Ion Source, that produces ions, an Analyzer that sorts them in some way by their masses, and a Detector that measures the relative intensities of different masses. The underlying principle of all mass spectrometers is that the paths of gas phase ions in electric and magnetic fields are dependent on their mass-to-charge ratios which is used by the analyzer to distinguish the ions from one another.

[edit] Instrumentation

[edit] Ion source

The ion source is the part of the mass spectrometer that ionizes the material under analysis (the analyte). The ions are then transported by magnetic or electric fields to the mass analyzer.

Techniques for ionization have been key to determining what types of samples can be analyzed by mass spectrometry. Electron ionization and chemical ionization are used for gases and vapors. In chemical ionization sources, the analyte is ionized by chemical ion-molecule reactions during collisions in the source. Two techniques often used with liquid and solid biological samples include electrospray ionization (due to John Fenn ) and matrix-assisted laser desorption/ionization (MALDI, due to K. Tanaka and separately, M. Karas and F. Hillenkamp). Inductively coupled plasma sources are used primarily for metal analysis on a wide array of sample types. Others include glow discharge, field desorption (FD), fast atom bombardment (FAB), thermospray, desorption/ionization on silicon (DIOS), Direct Analysis in Real Time (DART), atmospheric pressure chemical ionization (APCI), secondary ion mass spectrometry (SIMS), spark ionization and thermal ionisation.[9] Ion Attachment Ionization is a newer soft ionization technique that allows for fragmentation free analysis.

[edit] Mass analyzer

Mass analyzers separate the ions according to their mass-to-charge ratio. All mass spectrometers are based on dynamics of charged particles in electric and magnetic fields in vacuum where the following two laws apply:

\mathbf{F} = q (\mathbf{E} + \mathbf{v} \times \mathbf{B}) (Lorentz force law)
\mathbf{F}=m\mathbf{a} (Newton's second law of motion)

where F is the force applied to the ion, m is the mass of the ion, a is the acceleration, q is the ionic charge, E is the electric field, and v x B is the vector cross product of the ion velocity and the magnetic field

Equating the above expressions for the force applied to the ion yields:

(m/q)\mathbf{a} = \mathbf{E}+ \mathbf{v} \times \mathbf{B}

This differential equation is the classic equation of motion of charged particles. Together with the particle's initial conditions it completely determines the particle's motion in space and time and therefore is the basis of every mass spectrometer. It immediately reveals that two particles with the same physical quantity m/q behave exactly the same. Thus all mass spectrometers actually measure m/q and strictly speaking should be called mass-to-charge spectrometers. When presenting data, it is common to use the (officially) dimensionless m/z (called mass-to-charge ratio, although (more accurately) it represents the ratio of the mass number and the charge number), where z is the number of elementary charges (e) on the ion (z=q/e).

There are many types of mass analyzers, using either static or dynamic fields, and magnetic or electric fields, but all operate according to this same law. Each analyzer type has its strengths and weaknesses. Many mass spectrometers use two or more mass analyzers for tandem mass spectrometry (MS/MS). In addition to the more common mass analyzers listed below, there are other less common ones designed for special situations.

[edit] Sector

For more details on this topic, see sector instrument.

A sector field mass analyzer uses an electric and/or magnetic field to affect the path and/or velocity of the charged particles in some way. As shown above, sector instruments change the direction of ions that are accelerated through the mass analyzer. The ions enter a magnetic or electric field which bends the ion paths depending on their mass-to-charge ratios, deflecting the more charged and faster-moving, lighter ions more. The ions eventually reach the detector and their relative abundances are measured. The analyzer can be used to select a narrow range of m/q or to scan through a range of m/q to catalog the ions present.[10]

[edit] Time-of-flight

For more details on this topic, see time-of-flight mass spectrometry.

Perhaps the easiest to understand is the time-of-flight (TOF) analyzer. It uses an electric field to accelerate the ions through the same potential, and then measures the time they take to reach the detector. If the particles all have the same charge, the kinetic energies will be identical, and their velocities will depend only on their masses. Lighter ions will reach the detector first.[11]

[edit] Quadrupole

For more details on this topic, see Quadrupole mass analyzer.

Quadrupole mass analyzers use oscillating electrical fields to selectively stabilize or destabilize ions passing through a radio frequency (RF) quadrupole field. A quadrupole mass analyzer acts as a mass selective filter and is closely related to the Quadrupole ion trap, particularly the linear quadrupole ion trap except that it operates without trapping the ions and is for that reason referred to as a transmission quadrupole. A common variation of the quadrupole is the triple quadrupole.

[edit] Quadrupole ion trap

For more details on this topic, see quadrupole ion trap.

The quadrupole ion trap works on the same physical principles as the QMS, but the ions are trapped and sequentially ejected. Ions are created and trapped in a mainly quadrupole RF potential and separated by m/q, non-destructively or destructively.

There are many mass/charge separation and isolation methods but most commonly used is the mass instability mode in which the RF potential is ramped so that the orbit of ions with a mass a > b are stable while ions with mass b become unstable and are ejected on the z-axis onto a detector.

Ions may also be ejected by the resonance excitation method, whereby a supplemental oscillatory excitation voltage is applied to the endcap electrodes, and the trapping voltage amplitude and/or excitation voltage frequency is varied to bring ions into a resonance condition in order of their mass/charge ratio.[12][13]

The cylindrical ion trap mass spectrometer is a derivative of the quadrupole ion trap mass spectrometer.

[edit] Linear quadrupole ion trap

A linear quadrupole ion trap is similar to a QIT, but traps ions in a 2D quadrupole field, instead of a 3D quadrupole field as in a QIT. Thermo Fisher's LTQ ("linear trap quadrupole") is an example of the Linear ion trap.[14]

[edit] Fourier transform ion cyclotron resonance

A FT-ICR mass spectrometer
A FT-ICR mass spectrometer
For more details on this topic, see Fourier transform mass spectrometry.

Fourier transform mass spectrometry, or more precisely Fourier transform ion cyclotron resonance MS, measures mass by detecting the image current produced by ions cyclotroning in the presence of a magnetic field. Instead of measuring the deflection of ions with a detector such as an electron multiplier, the ions are injected into a Penning trap (a static electric/magnetic ion trap) where they effectively form part of a circuit. Detectors at fixed positions in space measure the electrical signal of ions which pass near them over time producing cyclical signal. Since the frequency of an ion's cycling is determined by its mass to charge ratio, this can be deconvoluted by performing a Fourier transform on the signal. FTMS has the advantage of high sensitivity (since each ion is 'counted' more than once) and much high resolution and thus precision.[15][16]

Ion cyclotron resonance is an older mass analysis technique similar to FTMS except that ions are detected with a traditional detector. Ions trapped in a Penning trap are excited by an RF electric field until they impact the wall of the trap where the detector is located with ions of different mass being resolved in time.

[edit] Orbitrap

For more details on this topic, see Orbitrap.

The Orbitrap is the most recently introduced mass analyser. In the Orbitrap, ions are electrostatically trapped in an orbit around a central, spindle-shaped electrode. The electrode confines the ions so that they both orbit around the central electrode and oscillate back and forth along the central electrode's long axis. This oscillation generates an image current in the detector plates which is recorded by the instrument. The frequencies of these image currents depend on the mass to charge ratios of the ions in the Orbitrap. Mass spectra are obtained by Fourier transformation of the recorded image currents.

Similar to Fourier transform ion cyclotron resonance mass spectrometers, Orbitraps have a high mass accuracy, high sensitivity and a good dynamic range.[17]

[edit] Detector

A continuous dynode particle multiplier detector.
A continuous dynode particle multiplier detector.

The final element of the mass spectrometer is the detector. The detector records the charge induced or current produced when an ion passes by or hits a surface. In a scanning instrument the signal produced in the detector during the course of the scan versus where the instrument is in the scan (at what m/q) will produce a mass spectrum, a record of ions as a function of m/q.

Typically, some type of electron multiplier is used, though other detectors including Faraday cups and ion-to-photon detectors are also used. Because the number of ions leaving the mass analyzer at a particular instant is typically quite small, significant amplification is often necessary to get a signal. Microchannel Plate Detectors are commonly used in modern commercial instruments.[18] In FTMS and Orbitraps, the detector consists of a pair of metal surfaces within the mass analyzer/ion trap region which the ions only pass near as they oscillate. No DC current is produced, only a weak AC image current is produced in a circuit between the electrodes. Other inductive detectors have also been used. [19]

[edit] Tandem mass spectrometry

Tandem mass spectrometry (MS/MS) involves multiple steps of mass selection or analysis, usually separated by some form of fragmentation. A tandem mass spectrometer is one capable of multiple rounds of mass spectrometry. For example, one mass analyzer can isolate one peptide from many entering a mass spectrometer. A second mass analyzer then stabilizes the peptide ions while they collide with a gas, causing them to fragment by collision-induced dissociation (CID). A third mass analyzer then catalogs the fragments produced from the peptides. Tandem MS can also be done in a single mass analyzer over time as in a quadrupole ion trap. There are various methods for fragmenting molecules for tandem MS, including collision-induced dissociation (CID), electron capture dissociation (ECD), electron transfer dissociation (ETD), infrared multiphoton dissociation (IRMPD) and blackbody infrared radiative dissociation (BIRD). An important application using tandem mass spectrometry is in protein identification.[20]

Tandem mass spectrometry enables a variety of experiments. Although it allows for many uniquely designed experiments some types of experiments are commonly used and built into many commercial mass spectrometers. Examples of these include single reaction monitoring (SRM), multiple reaction monitoring (MRM) and precursor ion scan. In single reaction monitoring the first analyzer allows only a single mass through and the second analyzer monitors for a specifically defined fragment ion. MRM is nearly identical except the second analyzer monitors multiple user defined fragment ions. These monikers are most often used with scanning instruments where the second mass analysis event is duty cycle limited. These experiments are used to increase specificity of detection of known molecules such as in pharmacokinetic studies. Precursor ion scan refers to monitoring for a specific loss from the precursor ion. The first and second mass analyzers scan across the spectrum separated by a user defined m/z value. This experiment is used to detect specific motifs within unknown molecules.

[edit] Common Mass Spectrometer Configurations & Techniques

When all of the elements (source, analyzer and detector) of a mass spectrometer are combined to form a complete instrument and the specific configuration becomes common a new name, often an abbreviation of one or more of the internal components, becomes attached to the specific configuration and can become, within certain circles, more well known than the specific internal components. The most ubiquitous example of this is MALDI-TOF, which simply refers to combining a Matrix-assisted laser desorption/ionization source with a Time-of-flight mass analyzer. The MALDI-TOF moniker is, however, often more widely recognized by the non-mass spectrometrist scientist than MALDI or TOF individually as if inseparable. Other examples include inductively coupled plasma-mass spectrometry (ICP-MS), accelerator mass spectrometry (AMS), Thermal ionization-mass spectrometry (TIMS) and spark source mass spectrometry (SSMS). Sometimes the use of the generic "MS" actually implies a very specific mass analyzer and detection system as with AMS, which is always sector based. In other cases there are common configurations that may be implied but not necessarily.

Certain applications of mass spectrometry have developed monikers that although technically referring to a broad application also tend to indicate a specific or a limited number of instrument configurations. An example of this is isotope ratio mass spectrometry (IRMS). Despite only specifically indicating an application, the use of a limited number of sector based mass analyzers is implied and the name is used to refer to both the application and the instrument used for the application.

[edit] Other Separation Techniques Combined with Mass spectrometry

An important enhancement to the mass resolving and determining capacity of mass spectrometry is the combination of mass spectrometry with analysis techniques that resolve mixtures of compounds in a sample based on other characteristics before introduction into the mass spectrometer.

[edit] Gas chromatography

A gas chromatograph (right) directly coupled to a mass spectrometer (left)
A gas chromatograph (right) directly coupled to a mass spectrometer (left)
See also the main article on Gas chromatography-mass spectrometry

A common form of mass spectrometry is gas chromatography-mass spectrometry (GC/MS or GC-MS). In this technique, a gas chromatograph is used to separate different compounds. This stream of separated compounds is fed on-line into the ion source, a metallic filament to which voltage is applied. This filament emits electrons which ionize the compounds. The ions can then further fragment, yielding predictable patterns. Intact ions and fragments pass into the mass spectrometer's analyser and are eventually detected.[21]

[edit] Liquid chromatography

See also the main article on Liquid chromatography-mass spectrometry

Similar to gas chromatography MS (GC/MS), liquid chromatography mass spectrometry (LC/MS or LC-MS) separates compounds chromatographically before they are introduced to the ion source and mass spectrometer. It differs from GC/MS in that the mobile phase is liquid, usually a combination of water and organic solvents, instead of gas. Most commonly, an electrospray ionization source is used in LC/MS.

[edit] Ion mobility

Ion mobility spectrometry/mass spectrometry (IMS/MS or IMMS) is a technique where ions are first separated by drift time through some pressure of neutral gas given an electrical potential gradient before being introduced into a mass spectrometer.[22]

The drift time is a measure of the radius relative to the charge of the ion. The duty cycle of IMS (time over which the experiment takes place) is longer than most mass spectrometers such that the mass spectrometer can sample along the course of the IMS separation. This produces data about the IMS separation and the mass-to-charge ratio of the ions in a manner similar to LC/MS.[23]

The duty cycle of IMS is short relative to liquid chromatography or gas chromatography separations and can thus be coupled to such techniques producing triply hyphenated techniques such as LC/IMS/MS.[24]

[edit] Data and analysis

Mass spectrum of a peptide showing the isotopic distribution
Mass spectrum of a peptide showing the isotopic distribution

[edit] Data representations

Mass spectrometry produces various types of data. The most ubiquitous data representation is the mass spectrum.

Certain types of mass spectrometry data are best represented as a mass chromatogram. Types of chromatograms include selected ion monitoring (SIM), total ion current (TIC), and selected reaction monitoring chromatogram (SRM), among many others.

Other types of mass spectrometry data are well represented as a contour map. In this form, the mass-to-charge is on one axis, intensity on recorded on another axis, and an additional experimental parameter, such as time, is recorded on the third axis. This results in a three dimensional representation of the data.

[edit] Data analysis

Basics

Mass spectrometry data analysis is a complicated subject matter that is very specific to the type of experiment producing the data. There are general subdivisions of data that are fundamental to understand any data.

Many mass spectrometers work in either negative ion mode or positive ion mode. It is very important to know whether the observed ions are negatively or positively charged. This is often important in determining the neutral mass but it also indicates something about the nature of the molecules.

There are many different types of ion sources that behave very differently from each other. A source such as an electron ionization source produces many fragments and mostly odd electron species with one charge, whereas a source such as an electrospray source usually produces quasimolecular even electron species that may be multiply charged.

Tandem mass spectrometry purposely produces fragment ions post-source and can drastically change the sort of data achieved by an experiment.

By understanding the origin of a sample certain expectations can be assumed. For example, if the sample is coming from a synthesis/manufacturing process impurities are likely to be present that are related to the major component. If the sample is a relatively crude preparation of a biological sample, the sample likely contains a certain amount of salt that may form adducts with the analyte molecules in certain analyses.

Results can also depend heavily on how the sample was prepared and how it was run/introduced. An important example is which matrix was used for MALDI spotting, since much of the energetics of the desorption/ionization event is controlled by the matrix rather than the laser power. Sometimes samples are spiked with sodium or another ion-carrying species to produce adducts rather than a protonated species.

The most commonly overlooked basic question by non-mass spectrometrists trying to use mass spectrometry or interact with a mass spectrometrist is what is the over-arching goal of the project. To interpret data one must know the desired outcome (and have collected the right data in the first place). There are many bits of information that can be gleaned from mass spectrometry data, such as the masses of the molecules, the purity of the sample, and the structure of the molecules. Each of these questions requires a different approach. Simply asking for a "mass-spec" will most likely not answer the real question at hand.

[edit] Applications

[edit] Isotope ratio MS: isotope dating and tracking

Mass spectrometer to determine the 16O/18O and 12C/13C isotope ratio on biogenous carbonate
Mass spectrometer to determine the 16O/18O and 12C/13C isotope ratio on biogenous carbonate

Mass spectrometry is also used to determine the isotopic composition of elements within a sample. Differences in mass among isotopes of an element are very small, and the less abundant isotopes of an element are typically very rare, so a very sensitive instrument is required. These instruments, sometimes referred to as isotope ratio mass spectrometers (IR-MS), usually use a single magnet to bend a beam of ionized particles towards a series of Faraday cups which convert particle impacts to electric current. A fast on-line analysis of deuterium content of water can be done using Flowing afterglow mass spectrometry, FA-MS. Probably the most sensitive and accurate mass spectrometer for this purpose is the accelerator mass spectrometer (AMS). Isotope ratios are important markers of a variety of processes. Some isotope ratios are used to determine the age of materials for example as in carbon dating. Labelling with stable isotopes is also used for protein quantification. (see Protein quantitation below)

[edit] Trace gas analysis

Several techniques use ions created in a dedicated ion source injected into a flow tube or a drift tube: selected ion flow tube (SIFT-MS), and proton transfer reaction (PTR-MS), are variants of chemical ionization dedicated for trace gas analysis of air, breath or liquid headspace using well defined reaction time allowing calculations of analyte concentrations from the known reaction kinetics without the need for internal standard or calibration.

[edit] Atom Probe

Main article: Atom probe

An atom probe is an instrument that combines time-of-flight mass spectrometry and field ion microscopy (FIM) to map the location of individual atoms.

[edit] Pharmacokinetics

Main article: Pharmacokinetics

Pharmacokinetics is often studied using mass spectrometry because of the complex nature of the matrix (often blood or urine) and the need for high sensitivity to observe low dose and long time point data. The most common instrumentation used in this application is LC-MS with a triple quadrupole mass spectrometer. Tandem mass spectrometry is usually employed for added specificity. Standard curves and internal standards are used for quantitation of usually a single pharmaceutical in the samples. The samples represent different time points as a pharmaceutical is administered and then metabolized or cleared from the body. Blank or t=0 samples taken before administration are important in determining background and insuring data integrity with such complex sample matrices. Much attention is paid to the linearity of the standard curve; however it is not uncommon to use curve fitting with more complex functions such as quadratics since the response of most mass spectrometers is less than linear across large concentration ranges.[25][26][27]

There is currently considerable interest in the use of very high sensitivity mass spectrometry for microdosing studies, which are seen as a promising alternative to animal experimentation.

[edit] Protein characterization

Mass spectrometry is an important emerging method for the characterization of proteins. The two primary methods for ionization of whole proteins are electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). In keeping with the performance and mass range of available mass spectrometers, two approaches are used for characterizing proteins. In the first, intact proteins are ionized by either of the two techniques described above, and then introduced to a mass analyser. This approach is referred to as "top-down" strategy of protein analysis. In the second, proteins are enzymatically digested into smaller peptides using an agent such as trypsin or pepsin. Other proteolytic agents are also used. The collection of peptide products are then introduced to the mass analyser. This peptide mass fingerprinting (PMF) approach of protein analysis is also referred to as the "bottom-up" approach.

[edit] Space exploration

As a standard method for analysis, mass spectrometers have reached other planets and moons. Two were taken to Mars by the Viking program. In early 2005 the Cassini-Huygens mission delivered a specialized GC-MS instrument aboard the Huygens probe through the atmosphere of Titan, the largest moon of the planet Saturn. This instrument analyzed atmospheric samples along its descent trajectory and was able to vaporize and analyze samples of Titan's frozen, hydrocarbon covered surface once the probe had landed. These measurements compare the abundance of isotope(s) of each particle comparatively to earth's natural abundance.[28]

Mass spectrometers are also widely used in space missions to measure the composition of plasmas. For example, the Cassini spacecraft carries the Cassini Plasma Spectrometer (CAPS),[29] which measures the mass of ions in Saturn's magnetosphere.

[edit] Respired Gas Monitor

Mass spectrometers were used in hospitals for respiratory gas analysis beginning around 1975 through the end of the century, some are likely still in use but none are currently being manufactured.[30]

Found mostly in the operating room they were a part of a complex system in which respired gas samples from patients undergoing anesthesia were drawn into the instrument through a valve mechanism designed to sequentially connect up to 32 rooms to the mass spectrometer. A computer directed all operations of the system, the data collected from the mass spectrometer was delivered to the individual rooms for the anesthesiologist to use.

This magnetic sector mass spectrometer's uniqueness may have been the fact that a plane of detectors, each purposely positioned to collect all of the ion species expected to be in the samples, allowed the instrument to simultaneously report all of the patient respired gases. Although the mass range was limited to slightly over 120 u, fragmentation of some of the heavier molecules negated the need for a higher detection limit.[31]

[edit] See also

[edit] Manufacturers

[edit] References

  1. ^ a b c d Sparkman, O. David (2000). Mass spectrometry desk reference. Pittsburgh: Global View Pub. ISBN 0-9660813-2-3. 
  2. ^ Squires, Gordon (1998). "Francis Aston and the mass spectrograph". Dalton Transactions: 3893 - 3900. doi:10.1039/a804629h. Retrieved on 2007-12-06. 
  3. ^ KM Downard (2007). "Francis William Aston - the man behind the mass spectrograph". European Journal of Mass Spectrometry 13 (3): 177-190. doi:10.1255/ejms.878. 
  4. ^ Harper, Douglas. "Spectrum." Online Etymology Dictionary. Nov. 2001. Accessed 07-12-2007. Note: This part of the article only makes descriptive claims about the information found in the primary source, the accuracy and applicability of which is easily verifiable by any reasonable, educated person without specialist knowledge. (See WP:PSTS)
  5. ^ J.J., Thomson (1913). Rays Of Positive Electricity and Their Application to Chemical Analysis. London: Longman's Green and Company. 
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  7. ^ Price, Phil (1991). "Standard definitions of terms relating to mass spectrometry. A report from the Committee on Measurements and Standards of the American Society for Mass Spectrometry". Journal of the American Society for Mass Spectrometry 2 (4): 336-348. doi:10.1016/1044-0305(91)80025-3 . Retrieved on 2007-12-06. 
  8. ^ Measuring Mass: From Positive Rays to Proteins by Michael A. Grayson (Editor) (ISBN 0-941901-31-9)
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  10. ^ Extending the mass range of a sector mass spectrometer, John S Cottrell, Roger J Greathead, Mass Spectrometry Reviews Vol 5, 1986. pp 215-247
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  12. ^ Paul W., Steinwedel H. (1953). "Ein neues Massenspektrometer ohne Magnetfeld". RZeitschrift für Naturforschung A 8 (7): 448-450
  13. ^ R. E. March (2000). "Quadrupole ion trap mass spectrometry: a view at the turn of the century". International Journal of Mass Spectrometry 200 (1-3): 285-312. doi:10.1016/S1387-3806(00)00345-6. 
  14. ^ Schwartz, Jae C.; Michael W. Senko and John E. P. Syka (June 2002). "A two-dimensional quadrupole ion trap mass spectrometer". Journal of the American Society for Mass Spectrometry 13 (6): 659-669. Elsevier Science B.V.. doi:10.1016/S1044-0305(02)00384-7. 
  15. ^ M. B. Comisarow and A. G. Marshall (1974). "Fourier transform ion cyclotron resonance spectroscopy". Chemical Physics Letters 25 (2): 282-283. doi:10.1016/0009-2614(74)89137-2. 
  16. ^ Marshall, A. G.; Hendrickson, C. L.; Jackson, G. S. (1998). "Fourier transform ion cyclotron resonance mass spectrometry: a primer". Mass Spectrometry Reviews 17 (1): 1-34. doi:10.1002/(SICI)1098-2787(1998)17:1%3C1::AID-MAS1%3E3.0.CO;2-K. 
  17. ^ Q. Hu, R. J. Noll, H. Li, A. Makarov, M. Hardman and R. G. Cooks (2005). "The Orbitrap: a new mass spectrometer". Journal of Mass Spectrometry 40 (4): 430-443. doi:10.1002/jms.856. 
  18. ^ F. Dubois, R. Knochenmuss, R. Zenobi, A. Brunelle, C. Deprun and Y. L. Beyec (1999). "A comparison between ion-to-photon and microchannel plate detectors". Rapid Communications in Mass Spectrometry 13 (9): 786-791. doi:10.1002/(SICI)1097-0231(19990515)13:9%3C786::AID-RCM566%3E3.0.CO;2-3. 
  19. ^ M. A. Park, J. H. Callahan and A. Vertes (1994). "An inductive detector for time-of-flight mass spectrometry". Rapid Communications in Mass Spectrometry 8 (4): 317-322. doi:10.1002/rcm.1290080407. 
  20. ^ Robert K. Boyd (1994). "Linked-scan techniques for MS/MS using tandem-in-space instruments". Mass Spectrometry Reviews 13 (5-6): 359-410. doi:10.1002/mas.1280130502. 
  21. ^ Eiceman, G.A. (2000). Gas Chromatography. In R.A. Meyers (Ed.), Encyclopedia of Analytical Chemistry: Applications, Theory, and Instrumentation, pp. 10627. Chichester: Wiley. ISBN 0-471-97670-9
  22. ^ Verbeck, GF and Ruotolo, BT and Sawyer, HA and Gillig, KJ and Russell, DH (2002). "A fundamental introduction to ion mobility mass spectrometry applied to the analysis of biomolecules}" (http://jbt.highwire.org/cgi/content/abstract/13/2/56). J Biomol Tech 13 (2): 56-61. Retrieved on 2007-12-17. 
  23. ^ L. M. Matz, G. R. Asbury and H. H. Hill (2002). "Two-dimensional separations with electrospray ionization ambient pressure high-resolution ion mobility spectrometry/quadrupole mass spectrometry". Rapid Communications in Mass Spectrometry 16 (7): 670-675. doi:10.1002/rcm.623. 
  24. ^ Rena A. Sowell, Stormy L. Koeniger, Stephen J. Valentine, Myeong Hee Moon and David E. Clemmer (2004). "Nanoflow LC/IMS-MS and LC/IMS-CID/MS of Protein Mixtures". Journal of the American Society for Mass Spectrometry 15 (9): 1341-1353. doi:10.1016/j.jasms.2004.06.014. 
  25. ^ Increasing Speed and Throughput When Using HPLC-MS/MS Systems for Drug Metabolism and Pharmacokinetic Screening, Y. Hsieh and W.A. Korfmacher, Current Drug Metabolism Volume 7, Number 5, 2006, Pp. 479-489
  26. ^ Covey TR, Lee ED, Henion JD. 1986. High-speed liquid chromatography/tandem mass spectrometry for the determination of drugs in biological samples. Anal Chem 58:2453-2460.
  27. ^ Thermospray liquid chromatography/mass spectrometry determination of drugs and their metabolites in biological fluids. Covey TR et al. Anal Chem. 1985 Feb;57(2):474-81
  28. ^ S. Petrie and D. K. Bohme (2007). "Ions in space". Mass Spectrometry Reviews 26 (2): 258-280. doi:10.1002/mas.20114. 
  29. ^ Cassini Plasma Spectrometer. Southwest Research Institute. Retrieved on 2008-01-04.
  30. ^ Expired gas monitoring by mass spectrometry in a respiratory intensive care unit. Riker JB, Haberman B. Crit Care Med. 1976 Sep-Oct;4(5):223-9
  31. ^ J. W. W. Gothard, C. M. Busst, M. A. Branthwaite, N. J. H. Davies and D. M. Denison (1980). "Applications of respiratory mass spectrometry to intensive care". Anaesthesia 35 (9): 890-895. doi:10.1111/j.1365-2044.1980.tb03950.x. 

[edit] Bibliography

  • Tureček, František; McLafferty, Fred W. (1993). Interpretation of mass spectra. Sausalito, Calif: University Science Books. ISBN 0-935702-25-3. 
  • Edmond de Hoffman; Vincent Stroobant (2001). Mass Spectrometry: Principles and Applications, 2nd ed., John Wiley and Sons. ISBN 0-471-48566-7. 
  • Downard, Kevin (2004). Mass Spectrometry - A Foundation Course. Cambridge UK: Royal Society of Chemistry. ISBN 0-85404-609-6. 
  • Siuzdak, Gary (1996). Mass spectrometry for biotechnology. Boston: Academic Press. ISBN 0-12-647471-0. 
  • Dass, Chhabil (2001). Principles and practice of biological mass spectrometry. New York: John Wiley. ISBN 0-471-33053-1. 
  • Jnrgen H. Gross. Mass Spectrometry: A Textbook. Berlin: Springer-Verlag. ISBN 3-540-40739-1. 
  • Muzikar, P., et al., "Accelerator Mass Spectrometry in Geologic Research", Geological Society of America Bulletin v. 115 (2003) p. 643 - 654.
  • David O. Sparkman. Mass Spectrometry Desk Reference. Pittsburgh: Global View Pub. ISBN 0-9660813-9-0. 
  • Tuniz, C. (1998). Accelerator mass spectrometry: ultrasensitive analysis for global science. Boca Raton: CRC Press. ISBN 0-8493-4538-3. 

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