DETAILED ACTION
This Office action is in response to the amendment filed on May 13th, 2026. Claims 1-3, 5-10, 63-66, 71-73, and 79-82 are pending.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-3, 5-10, 63-66, 71-73, and 79-82 are is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0204219 (Stein) in view of “The nanopore mass spectrometer” (Bush et al.).
Regarding claim 1, Stein discloses a mass spectrometer, comprising:
an ion source comprising a nanopore (element 4) and an electrode proximate the nanopore (element 9), wherein the nanopore comprises an opening having a cross-sectional dimension of less than 125 nm (“In some cases, the pore may have a dimension less than about 500 nm, less than about 250 nm, or less than about 100 nm. In other cases, the pore may have a dimension less than about 50 nm, less than about 30 nm, less than about 15 nm, less than about 10 nm, less than about 5 nm, or less than about 2 nm.” P 20);
a fluid comprising water contained in the ion source (“In some embodiments, the sample chamber 6 contains an aqueous solution in which candidate molecules are dissolved.” P 26);
a biopolymer dissolved in the water (“In some instances where the species is a polymer, the polymer may be any polymer, including biopolymers or other organic polymers.” P 17);
a magnetic mass filter downstream of the ion source (element 10); and
an array of detectors downstream of the magnetic mass filter (element 11).
The nanopore of Stein is not a capillary, however Bush discloses a nanopore mass spectrometer where the nanopore comprises a capillary (“capillary nanotips”), wherein the capillary comprises an opening having a cross-sectional dimension of less than 125 nm (“Figures 5(c) and 5(d) show scanning electron micrographs of a nanotip with an inner diameter of 60 nm.”). It would have been obvious to a person having ordinary skill in the art at the time the application was filed to substitute the capillary based nanopores of Bush for the membrane based nanopores of Stein because the high aspect ratio tip concentrates the electric field for stronger electrospray with a lower voltage, as disclosed in Bush (“The high aspect ratio of the structure enhances the electric fields at the tip, thereby lowering the voltage required to generate an electrospray.”) which in turn makes them less prone to arcing and cracking (Bush “It is important to note that although we report our design for integrating a planar chip based nanopore into the nanopore mass spectrometer here, we were never able to obtain electrosprays from such planar devices. We found that strong electric fields would often develop at the corners and edges of the silicon chips which caused arcing to occur and the chip to crack before an electrospray from the nanopore could be observed. As a result, we chose to focus on nanopores made from the aforementioned pulled glass capillaries.”).
Regarding claim 2, Stein in view of Bush et al. discloses the mass spectrometer of claim 1, further comprising a vacuum chamber (fig. 8) housing the ion source (while Stein discloses the ion source as adjoining, rather than housed within, this only works because the membrane type nanopore forms an interface to a chamber, with the capillary based nanopore of Bush it would be housed within, as it is in Bush, see fig. 2).
Regarding claim 3, Stein in view of Bush et al. discloses the mass spectrometer of claim 2, wherein the vacuum chamber has a pressure of no more than 100 mPa (intended use, also “In some embodiments the vacuum is a pressure of less than about 760 mmHg, less than about 500 mmHg, less than about 100 mmHg, less than about 10 mmHg, less than about 1 mmHg, less than about 0.1 mmHg, less than about 0.001 mmHg, less than about 50 microns of Hg, less than about 10 microns of Hg, less than about 1 micron of Hg, or less than about 0.001 microns of Hg.” from Stein and “The pressure inside the chamber rises to about 10-6 mbar with the introduction of a nanopore containing liquid sample. The safe operation of the mass filter and the ion detector requires a chamber pressure in the lower part of the 10-6 mbar range.” From Bush).
Regarding claim 5, Stein in view of Bush et al. discloses the claimed invention except it is not specified whether the magnetic mass filter comprises a permanent magnet. The use of permanent magnets in magnetic mass filters is well-known in the art. It would have been obvious to a person having ordinary skill in the art to use a permanent magnet for the mass filter of Stein so that power would not be required to operate the mass filter.
Regarding claim 6, Stein in view of Bush et al. discloses the claimed invention except Stein does not disclose ion optics downstream of the ion source and upstream of the magnetic mass filter. Bush discloses such ion optics (fig. 2, ion lens 1 and ion lens 2). It would have been obvious to a person having ordinary skill in the art at the time the application was filed to modify the mass spectrometer of Stein to include the ion optics of Bush to improve ion transmission, as discussed in Bush (“A second einzel lens attached to the entrance of the quadrupole serves to improve the transmission of ions.”).
Regarding claim 7, Stein in view of Bush et al. discloses the claimed invention except Stein does not disclose an ion bender configured to deflect ions exiting the mass filter to the detector. Bush discloses such an ion bender (fig. 2, ion bender). It would have been obvious to a person having ordinary skill in the art at the time the application was filed to modify the mass spectrometer of Stein to include the ion bender of Bush et al. in order to allow for multiple detection paths as discloses in Bush (“Alternatively, the bender can be turned off to allow the ions to travel straight through it into a Faraday cup, or its voltages can be flipped to steer the ion beam in the opposite direction onto a microchannel plate detector that we use to adjust the ion optics while imaging the beam.”).
Regarding claim 8, Stein in view of Bush et al. discloses the mass spectrometer of claim 6, wherein the ion optics comprises at least one Einzel lens (Bush, “The ions travel through a circular hole in the center of the extractor and then through an electrostatic einzel lens that focuses their trajectories onto the main axis of the mass spectrometer.”).
Regarding claim 9, Stein in view of Bush et al. discloses the mass spectrometer of claim 1, wherein the mass spectrometer has a temporal resolution of less than or equal to 1 microsecond (as per MPEP 2112.01, when the structure recited in the reference is substantially identical to that the claims, claimed properties are presumed to be inherent, it is noted that at least the array of detectors is capable of this rate, “The detector array may comprise, for instance, a set of Channeltron (Burle Industries, Inc., Lancaster, Pa.) single ion detectors that are capable of counting ions with high efficiency, in some cases greater than 95% efficiency, and at a high rate, in some instances exceeding 100 million Hertz.”).
Regarding claim 10, Stein in view of Bush et al. discloses the mass spectrometer of claim 1, wherein the array of detectors comprises an electron multiplier (“The detector array may comprise, for instance, a set of Channeltron (Burle Industries, Inc., Lancaster, Pa.) single ion detectors” P 38).
Regarding claim 63, Stein in view of Bush et al. discloses the mass spectrometer of claim 1, wherein the detector is a single-ion detector (channeltrons are known to be single-ion detectors).
Regarding claim 64, Stein discloses a method of sequencing a biopolymer, comprising:
ionizing a biopolymer contained within a fluid from a nanopore (“In some embodiments, the sample chamber 6 contains an aqueous solution in which candidate molecules are dissolved.” P 26) into ions or ion clusters (“In one set of embodiments, the method includes acts of passing a polymer through a pore having a diameter of less than about 1 micrometer, sequentially cleaving the polymer as it passes through the pore to produce a plurality of fragments, and ionizing one or more of the fragments.” P 7), wherein the nanopore comprises an opening having a cross-sectional dimension of less than 125 nm (“In some cases, the pore may have a dimension less than about 500 nm, less than about 250 nm, or less than about 100 nm. In other cases, the pore may have a dimension less than about 50 nm, less than about 30 nm, less than about 15 nm, less than about 10 nm, less than about 5 nm, or less than about 2 nm.” P 20);
passing the ions or ion clusters through a magnetic mass filter (“In some embodiments, a property of at least one subunit of a polymer is determined using mass spectrometry.” P 16, wherein “Monomer 12 can be accelerated through mass spectrometer 19 using a magnetic field created by magnetic region 10, before impinging on a detector 11, from which an output can be recorded.”);
directing the ions or ion clusters to an array of detectors (“At the far end of the mass spectrometer, a single ion detector array 11 registers the location of each ion impingement.” P 38); and
determining a sequence of the biopolymer by determining the ions or ion clusters with the array of detectors (“For example, in the case of biopolymer sequencing, the mass of each monomer, or the mass of a fragment that corresponds to a monomer, and the order of detection of the monomers or fragments of monomers are sufficient to determine the sequence of the polymer.”).
The nanopore of Stein is not a capillary, however Bush discloses a method where the nanopore comprises a capillary (“capillary nanotips”), wherein the capillary comprises an opening having a cross-sectional dimension of less than 125 nm (“Figures 5(c) and 5(d) show scanning electron micrographs of a nanotip with an inner diameter of 60 nm.”). It would have been obvious to a person having ordinary skill in the art at the time the application was filed to substitute the capillary based nanopores of Bush for the membrane based nanopores of Stein because the high aspect ratio tip concentrates the electric field for stronger electrospray with a lower voltage, as disclosed in Bush (“The high aspect ratio of the structure enhances the electric fields at the tip, thereby lowering the voltage required to generate an electrospray.”) which in turn makes them less prone to arcing and cracking (Bush “It is important to note that although we report our design for integrating a planar chip based nanopore into the nanopore mass spectrometer here, we were never able to obtain electrosprays from such planar devices. We found that strong electric fields would often develop at the corners and edges of the silicon chips which caused arcing to occur and the chip to crack before an electrospray from the nanopore could be observed. As a result, we chose to focus on nanopores made from the aforementioned pulled glass capillaries.”).
Regarding claim 65, Stein in view of Bush et al. disclose the method of claim 64, wherein the biopolymer is a protein (“Non-limiting examples of biopolymers include a polynucleotide (e.g. DNA, RNA, etc.), a polypeptide (e.g. a protein, a hormone, etc.), a polysaccharide, (e.g. heparin, hyaluronic acid, glycogen, cellulose, chitin, etc.), or the like, as well as combinations of these.” P 17).
Regarding claim 66, Stein in view of Bush et al. disclose the claimed method except it is silent as to whether ionizing amino acids of the protein is done at a rate of at least 1 amino acid per microsecond. The process steps in Stein are the same as in the claimed method, and applicant has not shown that any particular settings, parameters, or additional steps are necessary to achieve the claimed ionization rate. Therefore, this appears to be merely a rate found to be achievable through routine experimentation. It would have been obvious to a person having ordinary skill in the art at the time the application was filed to ionize the amino acids at as high rate is reasonably achievable to improve efficiency.
Regarding claim 71, Stein in view of Bush et al. disclose the method of claim 64, wherein the ions or ion clusters have at an overall ion transmission efficiency of greater than or equal to about 0.8 (“In some instances, efficiency may be defined as the number of molecules detected by a mass spectrometer divided by the number of molecules entering the mass spectrometer … the efficiency of the mass spectrometer may be … at least about 80%, at least about 90%, at least about 95%, at least about 98%, or even at least about 99%.” P 39).
Regarding claim 72, Stein in view of Bush et al. disclose the claimed method except it is silent as to whether the ions or ion clusters are produced at a rate of greater than or equal to 1 ion or ion cluster/microsecond to 100 ions or ion clusters/microsecond. The process steps in Stein are the same as in the claimed method, and applicant has not shown that any particular settings, parameters, or additional steps are necessary to achieve the claimed ionization rate. Therefore, this appears to be merely a rate found to be achievable through routine experimentation. It would have been obvious to a person having ordinary skill in the art at the time the application was filed to ionize the biopolymer at as high rate is reasonably achievable to improve efficiency.
Regarding claim 73, Stein in view of Bush et al. disclose the claimed method except it is silent as to whether he time interval between a molecule exiting as ions or ion clusters proximate the opening and detection of the ions or ion clusters at the array of detectors is greater than or equal to 10 microseconds and less than or equal to 100 microseconds. The time interval is dependent on the length of the travel path and the strength of the extraction voltage and any acceleration voltages applied. Therefore, a person having ordinary would now how to set the time interval as desired, and the particular range given appears to choose through routine optimization or experimentation, as applicant has not stated that the range solves any particular problem or has any unexpected effect.
Regarding claim 79, Stein in view of Bush et al. disclose the method of claim 64, wherein the ions or ion clusters may be detected at a time resolution of better than 100 nanoseconds (“detectors that are capable of counting ions with high efficiency, in some cases greater than 95% efficiency, and at a high rate, in some instances exceeding 100 million Hertz.” P 38).
Regarding claim 80, Stein in view of Bush et al. disclose the method of claim 64, wherein ionizing a biopolymer contained within a fluid into ions or ion clusters comprises ionizing the biopolymer into single ions (“In some embodiments, a single ion (which may be a subunit of a polymer, or an ion based on another species) can be isolated in a mass spectrometer and a signal generated from the single ion.” P 16).
Regarding claim 81, Stein in view of Bush et al. disclose the method of claim 64, wherein passing the ions or ion clusters through a magnetic mass filter comprises passing single ions through a magnetic mass filter (“In some embodiments, a single ion (which may be a subunit of a polymer, or an ion based on another species) can be isolated in a mass spectrometer and a signal generated from the single ion.” P 16).
Regarding claim 82, Stein in view of Bush et al. disclose the method of claim 64, wherein directing the ions or ion clusters to an array of detectors comprises directing the single ions to an array of detectors (“At the far end of the mass spectrometer, a single ion detector array 11 registers the location of each ion impingement.” P 38).
Response to Arguments
Applicant's arguments filed May 13th, 2026 have been fully considered but they are not persuasive.
Applicant argues that using a capillary, rather than a membrane as in Stein, provides unexpected advantages such as being less susceptible to degradation and having a different electric field distribution.
These advantages are not unexpected and are in the fact the same advantages discussed in Bush (see rejection above). Furthermore, recognizing an advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant argues one of ordinary skill in the art would not have looked to use a water-based fluid in a capillary ion source as they would have expected that charging of the fluid would be poor, because water is not particularly conductive, and the volatility of water would cool and freeze capillary ion sources when the water evaporates over time. Applicant also notes that the peaks observed with a water-based fluid in Bush are relatively broad.
In fact, Bush discloses that water-based fluids can be used in their capillary ion sources (“Notably, we have been able to obtain mass spectra from salt solutions in water.”). The peaks may be broader than the peaks obtained in the experiment with the formamide solvent (fig. 11), but they are still readily distinguishable. Also, Stein uses an aqueous solution and while it is not directed to capillaries the same issues of poor conductivity and evaporative cooling would apply to the nanopore of Stein. Clearly both Stein and Bush have overcome these difficulties.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZA W OSENBAUGH-STEWART/Primary Examiner, Art Unit 2881
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