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 .
Election/Restrictions
Applicant’s election without traverse of Invention I, claims 1-15, in the reply filed on 07/15/2026 is acknowledged.
Claims 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/15/2026.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 1 recites the limitations “determining whether a shift of the parameter occurred between the first measurement and the second measurement, wherein a shift of the parameter between the first measurement and the second measurement indicates that one of the first molecular probes attached to an amino acid at a free end of the peptide; and responsive to determining that the shift of the parameter between the first measurement and the second measurement occurred, determining a type of the amino acid at the free end of the peptide based on a type of the first molecular probes.”
In accordance with MPEP 2106, the claims are found to recite statutory subject matter (Step 1: YES) and are analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A: Prong 1).
In the instant application, the limitations of “determining whether a shift of the parameter occurred between the first measurement and the second measurement, wherein a shift of the parameter between the first measurement and the second measurement indicates that one of the first molecular probes attached to an amino acid at a free end of the peptide; and responsive to determining that the shift of the parameter between the first measurement and the second measurement occurred, determining a type of the amino acid at the free end of the peptide based on a type of the first molecular probes” could be performed mentally, i.e. mental processes. Accordingly, the claims recite abstract ideas (Step 2A: Prong 1: Yes).
This judicial exception is not integrated into a practical application because the claims do not recite any additional elements that reflects an improvement to technology or applies or uses the judicial exception in some other meaningful way (Step 2A, Prong 2: No). In claim 1, after the limitations of “determining whether a shift of the parameter occurred between the first measurement and the second measurement, wherein a shift of the parameter between the first measurement and the second measurement indicates that one of the first molecular probes attached to an amino acid at a free end of the peptide; and responsive to determining that the shift of the parameter between the first measurement and the second measurement occurred, determining a type of the amino acid at the free end of the peptide based on a type of the first molecular probes”, no further action is performed. Additionally, the preceding steps and limitations are used for data gathering in the abstract idea; wherein, data gathering to be used in the abstract idea is insignificant extra-solution activity, and not a particular practical application. See MPEP 2106.05(g). Additionally, the preceding steps and limitations generally link the judicial exception to a particular field of use (MPEP 2106.05(h)). Therefore, the claimed limitations do not integrate the abstract idea into a practical application because it does not impose any meaningful limits on practicing the abstract idea. Thus, the claims are directed to an abstract idea that is not integrated into a practical application (Step 2A, Prong 2: No).
The claims 1-15 do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Claim 1 and dependent claims 2-15 further recites limitations, however these limitations generally link the judicial exception to a particular field of use (MPEP 2106.05(h)) and are used for data gathering, wherein data gathering to be used in the abstract idea is an insignificant extra-solution activity, and not a practical application (see MPEP 2106.05(g)), which alone or in combination do not amount to significantly more. Additionally, the limitations of claims 1-15 are well-understood, routine and conventional activities as evidenced by the prior art of Callewaert et al. (US 20200231956 A1; cited in the IDS filed 12/27/2023), Webster et al. (US 20210318242 A1), Jarmillo-Botero et al. (US 20130069665 A1), Peterson et al. (US 20060246475 A1), Turner et al. (US 20170038333 A1), Mandell et al. (US 20200123193 A1), Esfandyarpour et al. (US 20190256903 A1), Huang et al. (US 20210116413 A1; cited in the IDS filed 12/27/2023), and Somekh et al. (WO 2021211631 A2; cited in the IDS filed 12/27/2023). See MPEP 2106.05(d). The additional elements of the claims 1-15 do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). The claims are not patent eligible.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 7 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Callewaert et al. (US 20200231956 A1; cited in the IDS filed 12/27/2023).
Regarding claim 1, Callewaert teaches a method for sequencing peptides (abstract and paragraph [0005], “single molecule peptide sequencing”), the method comprising:
attaching a base end of a peptide to a channel region surface of a biosensor field effect transistor (bio-FET) that has an electrolyte gate (Fig. 2 and [0082] teaches use of BioFET including an immobilized polypeptide that allows charged molecules to bind to the FET gate, i.e. a base end of the polypeptide is attached to a channel region surface of the BioFet that has an electrolyte gate; [0083] teaches BioFets are sensitive for charge or potential changes generated by molecular interactions at the gate insulator/electrolyte interface, i.e. electrolyte gate);
obtaining a first measurement of a parameter of the bio-FET, wherein the parameter depends on a threshold voltage of the bio-FET (Fig. 14 and [0082] teaches measuring change in conductance of the FET channel, wherein conductance is dependent on threshold voltage; Fig. 14 shows at least an initial baseline measurement, i.e. first measurement);
providing one or more first molecular probes into the electrolyte gate, wherein each first molecular probe is linked to a respective charge tag ([0082] teaches “when charged molecules, such as a SPITC labeled aminopeptidase, bind to the FET gate”, therefore aminopeptidase, i.e. molecular probe, is provided into the electrolyte gate, the aminopeptidase is linked to SPITC, i.e. charge tag);
obtaining a second measurement of the parameter of the bio-FET (Fig. 14 and [0082] teaches when charged molecules, such as a SPITC labeled aminopeptidase, bind to the FET gate, change in conductance of the FET channel occurs; therefore, a second measurement is obtained);
determining whether a shift of the parameter occurred between the first measurement and the second measurement, wherein a shift of the parameter between the first measurement and the second measurement indicates that one of the first molecular probes attached to an amino acid at a free end of the peptide ([0082] teaches when charged molecules, such as a SPITC labeled aminopeptidase, bind to the FET gate, change in conductance of the FET channel occurs; [0083] teaches recognizing aminopeptidase-polypeptide binding and by measuring changes in the drain current, of the FETs, conductance of the SiNW, capacitance of the EIS sensor or photocurrent of the LAPS, the aminopeptidase, ITC or ITC analogue “on-time” values can be determined quantitatively, and detection of aminopeptidase binding to the immobilized polypeptides is performed using BioFET); and
responsive to determining that the shift of the parameter between the first measurement and the second measurement occurred, determining a type of the amino acid at the free end of the peptide based on a type of the first molecular probes ([0005] teaches “Therefore, by measuring the time the engineered aminopeptidase resides upon addition on the peptide substrate before the N-terminal amino acid is cleaved off, N-terminal amino acid is identified”; therefore, the type of amino acid is identified based on the engineered aminopeptidase, i.e. based on the type of the first molecular probe, since the amino acid is identified with the particular aminopeptidase).
Regarding claim 7, Callewaert further teaches the method of claim 1, wherein providing the one or more first molecular probes into the electrolyte gate comprises providing the first molecular probes already linked to the charge tags ([0082] teaches SPITC labeled aminopeptidase bind to the FET gate, therefore the aminopeptidase, i.e. first molecular probe, provided to the electrolyte gate is already linked to the charge tags, i.e. SPITC).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Webster et al. (US 20210318242 A1).
Regarding claim 2, Callewaert fails to teach: the method of claim 1, further comprising:
providing one or more second molecular probes into the electrolyte gate, wherein each second molecular probe is linked to a respective charge tag;
obtaining a third measurement of the parameter of the bio-FET;
determining whether a shift of the parameter occurred between the first or second measurements and the third measurements, wherein a shift of the parameter between the first or second measurements and the third measurement indicates that one of the second molecular probes attached to the amino acid at the free end of the peptide; and
responsive to determining that the shift of the parameter between the first or second measurements and the third measurement did not occur, determining the type of the amino acid at the free end of the peptide based on a type of the second molecular probes.
Callewaert teaches 2, 3, 4, or more aminopeptidases are utilized that can then distinguish different groups of amino acids ([0056]). Callewaert teaches an engineered aminopeptidase for a series of different amino acids of a polypeptide is provided, which allows for identification of the amino acid ([0064]). Callewaert teaches when charged molecules, such as a SPITC labeled aminopeptidase, bind to the FET gate, they can change the charge distribution of the underlying semiconductor material resulting in a change in conductance of the FET channel ([0082]). Callewaert teaches BioFETs with different biological recognition elements or receptors ([0083]). Callewaert teaches the cycle is repeated to sequence and identify amino acids from each peptide on the slide ([0003],[0010]).
Webster teaches instruments for genetic sequencing ([0002]), wherein the instruments are capable of analyzing samples in parallel, including identification of single molecules and nucleic acid sequencing ([0052]). Webster teaches field effect transistors ([0083]; Figs. 1-3). Webster teaches the identity of a terminal amino is assessed, after which the terminal amino acid is removed and the identity of the next amino acid at the terminus is assessed, and this process is repeated until a plurality of successive amino acids in the polypeptide are assessed ([0198]). Webster teaches determining the type of amino acid by determining which of the naturally-occurring 20 amino acids is the terminal amino acid is (e.g., using a recognition molecule that is specific for an individual terminal amino acid) ([0198]). Webster teaches the one or more types of amino acids are identified by detecting binding of one or more amino acid recognition molecules that selectively bind the one or more types of amino acids ([0199]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified to the method of Callewaert to incorporate Callewaert’s teachings of using different biological recognition elements to distinguish and identify different amino acids ([0056],[0064],[0083]), using charged molecules to measure change in conductance when binding to the gate ([0082]), and repeating the cycle to sequence and identify amino acids of each peptide ([0003],[0010]) and Webster’s teachings of genetic sequencing including identifying each amino acid of a polypeptide using recognition molecules that are specific for an individual type of amino acid ([0198],[0199]) to provide: the method of claim 1, further comprising: providing one or more second molecular probes into the electrolyte gate, wherein each second molecular probe is linked to a respective charge tag; obtaining a third measurement of the parameter of the bio-FET; determining whether a shift of the parameter occurred between the first or second measurements and the third measurements, wherein a shift of the parameter between the first or second measurements and the third measurement indicates that one of the second molecular probes attached to the amino acid at the free end of the peptide; and responsive to determining that the shift of the parameter between the first or second measurements and the third measurement did not occur, determining the type of the amino acid at the free end of the peptide based on a type of the second molecular probes. Doing so would have a reasonable expectation of successfully utilizing known genetic sequencing methods and molecular probes to improve identification of the different amino acids when repeating the steps to sequence each amino acid of the peptide.
Regarding claim 3, Callewaert further teaches the method of claim 1, further comprising:
degrading the peptide to remove the amino acid at the free end of the peptide, exposing an additional amino acid at the free end of the peptide (Fig. 14 and [0005] teaches the N-terminal amino acid is cleaved off, therefore the peptide is degraded to remove amino acid at the free end to expose an additional amino acid at the free end);
obtaining a fourth measurement of the parameter of the bio-FET (Fig. 14 teaches measurements are obtained between the on-time, i.e. T-on).
Callewaert fails to teach:
providing a plurality of third molecular probes into the electrolyte gate, wherein each third molecular probe is linked to a respective charge tag;
obtaining a fifth measurement of the parameter of the bio-FET;
determining whether a shift of the parameter occurred between the fourth measurement and the fifth measurement, wherein a shift of the parameter between the fourth measurement and the fifth measurement indicates that one of the third molecular probes attached to the additional amino acid at the free end of the degraded peptide; and
responsive to determining that the shift of the parameter between the fourth measurement and the fifth measurement occurred, determining a type of the additional amino acid at the free end of the degraded peptide based on a type of the third molecular probes.
Callewaert teaches 2, 3, 4, or more aminopeptidases are utilized that can then distinguish different groups of amino acids ([0056]). Callewaert teaches an engineered aminopeptidase for a series of different amino acids of a polypeptide is provided, which allows for identification of the amino acid ([0064]). Callewaert teaches when charged molecules, such as a SPITC labeled aminopeptidase, bind to the FET gate, they can change the charge distribution of the underlying semiconductor material resulting in a change in conductance of the FET channel ([0082]). Callewaert teaches BioFETs with different biological recognition elements or receptors ([0083]). Callewaert teaches the cycle is repeated to sequence and identify amino acids from each peptide on the slide ([0003],[0010]).
Webster teaches instruments for genetic sequencing ([0002]), wherein the instruments are capable of analyzing samples in parallel, including identification of single molecules and nucleic acid sequencing ([0052]). Webster teaches field effect transistors ([0083]; Figs. 1-3). Webster teaches the identity of a terminal amino is assessed, after which the terminal amino acid is removed and the identity of the next amino acid at the terminus is assessed, and this process is repeated until a plurality of successive amino acids in the polypeptide are assessed ([0198]). Webster teaches determining the type of amino acid by determining which of the naturally-occurring 20 amino acids is the terminal amino acid is (e.g., using a recognition molecule that is specific for an individual terminal amino acid) ([0198]). Webster teaches the one or more types of amino acids are identified by detecting binding of one or more amino acid recognition molecules that selectively bind the one or more types of amino acids ([0199]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified to the method of Callewaert to incorporate Callewaert’s teachings of using different biological recognition elements to distinguish and identify different amino acids ([0056],[0064],[0083]), using charged molecules to measure change in conductance when binding to the gate ([0082]), and repeating the cycle to sequence and identify amino acids of each peptide ([0003],[0010]) and Webster’s teachings of genetic sequencing including identifying each amino acid of a polypeptide using recognition molecules that are specific for an individual type of amino acid ([0198],[0199]) to provide: the method of claim 1, further comprising: providing a plurality of third molecular probes into the electrolyte gate, wherein each third molecular probe is linked to a respective charge tag; obtaining a fifth measurement of the parameter of the bio-FET; determining whether a shift of the parameter occurred between the fourth measurement and the fifth measurement, wherein a shift of the parameter between the fourth measurement and the fifth measurement indicates that one of the third molecular probes attached to the additional amino acid at the free end of the degraded peptide; and responsive to determining that the shift of the parameter between the fourth measurement and the fifth measurement occurred, determining a type of the additional amino acid at the free end of the degraded peptide based on a type of the third molecular probes. Doing so would have a reasonable expectation of successfully utilizing known genetic sequencing methods and molecular probes to improve identification of the different amino acids when repeating the steps to sequence each amino acid of the peptide.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Jarmillo-Botero et al. (US 20130069665 A1).
Regarding claim 4, Callewaert fails to teach: the method of claim 1, wherein the first molecular probe attaching to the amino acid at the free end of the peptide results in the charge tag linked to the attached first molecular probe being less than 3 nm from the channel region surface of the bio-FET.
Jarmillo-Botero teaches detector apparatus including a field-effect transistor to detect a charge-tagged molecule (abstract). Jarmillo-Botero teaches the device is used for identification of nucleic acid sequences in charge-tagged DNA/RNA molecules ([0002]). Jarmillo-Botero teaches a charge-tag, and the distance between the charge-tag and a gate insulator surface is 1 nm ([0055]). Jarmillo-Botero teaches charge tag at a distance of 1 nm is sufficient to activate current change in the gate ([0038]).
Since Jarmillo-Botero teaches detection of charge-tagged molecules using a field-effect transistor, similar to Callewaert, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Callewaert to incorporate Jarmillo-Botero’s teachings of detecting current change when a charge-tag is at a distance of 1 nm from a surface of the FET ([0038],[0055]) to provide: the method of claim 1, wherein the first molecular probe attaching to the amino acid at the free end of the peptide results in the charge tag linked to the attached first molecular probe being less than 3 nm from the channel region surface of the bio-FET. Doing so would have a reasonable expectation of successfully utilizing known distances of between charged-tags and a FET surface to optimize and properly allow measurement of a shift in the parameter of the bio-FET due to the attaching of the molecular probe to the peptide.
Regarding claim 5, Callewaert fails to teach: the method of claim 4, wherein the first molecular probe attaching to the amino acid at the free end of the peptide results in the charge tag linked to the attached first molecular probe being less than 1 nm from the channel region surface of the bio-FET.
Jarmillo-Botero teaches detector apparatus including a field-effect transistor to detect a charge-tagged molecule (abstract). Jarmillo-Botero teaches the device is used for identification of nucleic acid sequences in charge-tagged DNA/RNA molecules ([0002]). Jarmillo-Botero teaches a charge-tag, and the distance between the charge-tag and a gate insulator surface is 1 nm ([0055]). Jarmillo-Botero teaches charge tag at a distance of 1 nm is sufficient to activate current change in the gate ([0038]).
Since Jarmillo-Botero teaches detection of charge-tagged molecules using a field-effect transistor, similar to Callewaert, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Callewaert to incorporate Jarmillo-Botero’s teachings of detecting current change when a charge-tag is at a distance of 1 nm from a surface of the FET ([0038],[0055]) to provide: the method of claim 4, wherein the first molecular probe attaching to the amino acid at the free end of the peptide results in the charge tag linked to the attached first molecular probe being less than 1 nm from the channel region surface of the bio-FET. Doing so would have a reasonable expectation of successfully utilizing known distances of between charged-tags and a FET surface to optimize and properly allow measurement of a shift in the parameter of the bio-FET due to the attaching of the molecular probe to the peptide.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above.
Regarding claim 6, Callewaert fails to explicitly teach: the method of claim 1, further comprising:
promoting a binding of the charge tag that is linked to the attached first molecular probe to the channel region surface of the bio-FET by at least one of:
controlling a pH of the electrolyte gate;
applying a reagent to modify the charge tag;
providing additives to the electrolyte gate to induce binding between the charge tag and the channel region surface; or
modifying a charge of the charge tag.
Callewaert teaches by changing the reaction conditions during the experiment (e.g. protein sequencing) the temperature, the pH, solvents ,… can be adjusted to differentiate more between the “on-time” value for different amino acids ([0042]). Callewaert teaches specificity towards N-terminal primary amines can be increased by carefully controlling the pH ([0133]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Callewaert to incorporate Callewaert’s teachings of controlling pH ([0042],[0133]) to provide: the method of claim 1, further comprising: promoting a binding of the charge tag that is linked to the attached first molecular probe to the channel region surface of the bio-FET by at least one of: controlling a pH of the electrolyte gate. Doing so would have a reasonable expectation of successfully optimizing reaction conditions for improving specificity of identification of amino acids as discussed by Callewaert ([0042],[0133]).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Peterson et al. (US 20060246475 A1).
Regarding claim 8, Callewaert fails to teach: the method of claim 1, further comprising: providing the charge tags into the electrolyte gate separately from the first molecular probes, wherein the charge tags are configured to link to the first molecular probes in the electrolyte gate.
Callewaert teaches one way of detecting the aminopeptidases of the application is by fusing it to a molecular label and subsequent detection of the molecular label ([0080]).
Peterson teaches systems and methods for increasing the dynamic range of detection of a target nucleic acid in a sample, including the use of one or more probe oligonucleotides (abstract). Peterson teaches the methods includes DNA sequencing ([0150]). Peterson teaches charge tags may be synthesized directly onto a nucleic molecule or may be synthesized, for example, in liquid phase and then attached to a nucleic acid molecule or any other desired molecule ([0191]). Peterson teaches embodiments including charge tags ([0193]), wherein charge tags may be assembled on the end of a nucleic acid molecule or may be synthesized separately and attached to a nucleic acid molecule ([0193]). Peterson teaches mixtures comprises an agent to increase or decrease hybridization efficiency, such as a charge tag ([0009]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and charge tags of Callewaert to incorporate Callewaert’s teachings of fusing a molecular probe with a label prior to detection ([0080]) and Peterson’s teachings of methods of attaching charge tags, such as directly on a nucleic molecule or separately in a liquid phase and then attached to the molecule ([0191],[0193]) to provide: the method of claim 1, further comprising: providing the charge tags into the electrolyte gate separately from the first molecular probes, wherein the charge tags are configured to link to the first molecular probes in the electrolyte gate. Doing so would have a reasonable expectation of successfully linking or attaching the charge tags with the first molecular probes.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Turner et al. (US 20170038333 A1).
Regarding claim 9, Callewaert fails to teach: the method of claim 1, wherein each charge tag has a characteristic size greater than 10 nm.
Turner teaches a method for nucleic acid sequencing including a field effect transistor capable of measuring electrical changes due to molecular interactions ([0006],[0007],[0077]). Turner teaches exposing a substrate to a plurality of types of nucleotide analogs each comprising a different charge label, and measuring change in the electrical signal at the gate based on the charge label, therefore determining a sequence of the nucleic acid ([0007]). Turner teaches charge labels can include beads that have a size between 2-50 nm, wherein the beads can be an effective shape for controlling the current at the gate of the FET ([0218]). Turner teaches an example of a charge label being 15 or 25 nm in diameter ([0249]). Turner teaches charge labels can provide differences in channel conductivity, where the size can be varied over a wide range, such as from 2-50 nm in diameter ([0251]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified each charge tag of Callewaert to incorporate Turner’s teachings of nucleic acid sequencing with charge labels with a range of 2-50 nm in size, such as 15 or 25 nm ([0007],[0218],[0249],[0251]) to provide: the method of claim 1, wherein each charge tag has a characteristic size greater than 10 nm. Doing so would have a reasonable expectation of successfully optimizing the shape of the charge tag for controlling the current at the gate, therefore improving detection of the shift of the parameter at the electrolyte gate of the bio-FET.
Claims 10 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Mandell et al. (US 20200123193 A1).
Regarding claim 10, Callewaert fails to teach: the method of claim 1, wherein each charge tag comprises more than 100 elementary charges.
Mandell teaches a method of detecting an incorporation of a labelled nucleotide into a nascent polynucleotide strand (abstract) for nucleic acid sequencing procedures ([0057]). Mandell teaches there is a need for improved detection systems which provide differential recognition of nucleotides on the basis of differences in charges, such as to permit long sequencing reads in high-throughput manner; and examples set forth herein may satisfy this need and provide other advantages as well ([0057]). Mandell teaches charge tags with enhanced charged density ([0005]). Mandell teaches one or more labeled nucleotides can comprise a unique charge tag for each type of nucleotide; wherein the charge tag can have a charge from -200e to +200e, i.e. more than 100 elementary charges ([0088]). Mandell teaches an increased charge density may increase a charge detected by a conductive channel during incorporation of a nucleotide analog in a growing strand, such that a given species of nucleotide can be determined ([0098]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified each charge tag of Callewaert to incorporate Mandell’s teachings of charge tags with enhanced charge density, such as from -200 to +200e ([0088]) to provide: the method of claim 1, wherein each charge tag comprises more than 100 elementary charges. Doing so would have a reasonable expectation of successfully improving determination of a shift in the parameter of the bio-FET, therefore improving identification of the amino acid as discussed by Mandell.
Regarding claim 15, Callewaert fails to teach: the method of claim 1, wherein a dimension of the channel region surface of the bio-FET is less than 50 nm.
Mandell teaches a method of detecting an incorporation of a labelled nucleotide into a nascent polynucleotide strand (abstract) for nucleic acid sequencing procedures ([0057]). Mandell teaches there is a need for improved detection systems which provide differential recognition of nucleotides on the basis of differences in charges, such as to permit long sequencing reads in high-throughput manner; and examples set forth herein may satisfy this need and provide other advantages as well ([0057]). Mandell teaches charge tags with enhanced charged density ([0005]). Mandell teaches one or more labeled nucleotides can comprise a unique charge tag for each type of nucleotide; wherein the charge tag can have a charge from -200e to +200e, i.e. more than 100 elementary charges ([0088]). Mandell teaches a conductive channel of the FET (Fig. 1, conductive channel 5) that has at least one dimension on the nanoscale, such as from 1nm to 1um ([0070]).
Since Mandell teaches a channel region of a FET having a dimension of 1nm-1um ([0070]), wherein the range of 1nm-1um overlaps with the claimed range of less than 50 nm, i.e. less than 50 nm, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and channel region surface of Callewaert to provide the method of claim 1, wherein a dimension of the channel region surface of the bio-FET is less than 50 nm. I.e., it would have been prima facia obvious to have selected the overlapping portion of the range (i.e. less than 50 nm) from the taught range of 1nm-1um (Mandell, [0070]) (In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); see MPEP 2144.05 (I)).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Esfandyarpour et al. (US 20190256903 A1).
Regarding claim 11, Callewaert fails to teach: the method of claim 1, further comprising: providing a buffer into the electrolyte gate, thereby removing from the electrolyte gate any of the first molecular probes that are not attached to the peptide prior to obtaining the second measurement of the parameter of the bio-FET.
Callewaert teaches 2, 3, 4, or more aminopeptidases are utilized that can then distinguish different groups of amino acids ([0056]). Callewaert teaches an engineered aminopeptidase for a series of different amino acids of a polypeptide is provided, which allows for identification of the amino acid ([0064]). Callewaert teaches when charged molecules, such as a SPITC labeled aminopeptidase, bind to the FET gate, they can change the charge distribution of the underlying semiconductor material resulting in a change in conductance of the FET channel ([0082]). Callewaert teaches BioFETs with different biological recognition elements or receptors ([0083]). Callewaert teaches the cycle is repeated to sequence and identify amino acids from each peptide on the slide ([0003],[0010]).
Esfandyarpour teaches methods for sequencing nucleic acid molecules (abstract). Esfandyarpour teaches the use of charge labels ([0076]). Esfandyarpour teaches the sensor array may then be washed and contacted with a fluid comprising one or more types of nucleotides, polymerizing enzymes, and/or any co-factors in a suitable buffer; the array may then be washed and the incorporated nucleotides may be detected; and the incorporate, wash, detect cycle may be repeated until sample nucleic acids bound to the bead or bound to a surface of the sensor have been sequenced ([0153]). Esfandyarpour teaches sequencing incorporation error may result from inadequate washing ([0142]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Callewaert to incorporate Callewaert’s teachings of using different biological recognition elements to distinguish and identify different amino acids ([0056],[0064],[0083]) and repeating the cycle to sequence and identify amino acids of each peptide ([0003],[0010]) and Esfandyarpour’s teachings of sequencing including washing prior to detection and repeating the steps for sequencing the nucleic acids ([0153]) to provide: the method of claim 1, further comprising: providing a buffer into the electrolyte gate, thereby removing from the electrolyte gate any of the first molecular probes that are not attached to the peptide prior to obtaining the second measurement of the parameter of the bio-FET. Doing so would have a reasonable expectation of successfully improving sequencing procedures and ensuring adequate removal of undesired elements prior to detection, therefore improving measurement of the parameter of the bio-FET.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Huang et al. (US 20210116413 A1; cited in the IDS filed 12/27/2023).
Regarding claim 12, Callewaert fails to teach: the method of claim 1, wherein the second, measurement of the parameter of the bio-FET is obtained with a measuring frequency in a range of 1-100 kHz.
Huang teaches a bioFET device including a gate formed on a surface (abstract). Huang teaches applying varying electric field across the electrodes of the BioFET, wherein the electric field is applied with a frequency of 1-100 kHz ([0134]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Callewaert to incorporate Huang’s teachings of measuring frequency of 1-100 kHz of a bioFET ([0134]) to provide: the method of claim 1, wherein the second, measurement of the parameter of the bio-FET is obtained with a measuring frequency in a range of 1-100 kHz. Doing so would have a reasonable expectation of utilizing known measuring frequency ranges of bio-FETs to successfully optimize the measuring frequency to properly measure the parameter of the bio-FET.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Callewaert as applied to claim 1 above, and further in view of Somekh et al. (WO 2021211631 A2; cited in the IDS filed 12/27/2023).
Regarding claim 13, Callewaert fails to teach: the method of claim 1, further comprising performing the method of claim 1 in parallel for a plurality of additional bio-FETs.
Somekh teaches methods and systems for polypeptide sequencing or identification using FET arrays (abstract). Somekh teaches an ongoing need for more effective, efficient, and accurate computational methods for protein identification; and advancements in high-throughput technologies have enabled rapid and parallel sequencing of genomes and transcriptomes ([0003]). Somekh teaches a FET array including a plurality of pixels, each pixel comprising a FET or plurality of FET ([0087]). Somekh teaches high pixel density enable highly parallelized and high throughput peptide analysis, such as an array including over 256000 pixels ([0088]). Somekh teaches an array of FET sensors, that can include 1000 or more FET sensors ([0092]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Callewaert to incorporate Somekh’s teachings of FET arrays for polypeptide sequencing that includes a plurality of FET to enable highly parallelized and high throughput peptide analysis ([0003],[0087]-[0088],[0092]) to provide: the method of claim 1, further comprising performing the method of claim 1 in parallel for a plurality of additional bio-FETs. Doing so would have a reasonable expectation of successfully improving throughput of peptide sequencing and identification as taught by Somekh.
Regarding claim 14, Callewaert fails to teach: the method of claim 13, wherein all of the bio-FETs of the plurality of additional bio-FETs are arranged in a sensor array, and wherein a number of the bio-FETs in the sensor array is at least 1000.
Somekh teaches methods and systems for polypeptide sequencing or identification using FET arrays (abstract). Somekh teaches an ongoing need for more effective, efficient, and accurate computational methods for protein identification; and advancements in high-throughput technologies have enabled rapid and parallel sequencing of genomes and transcriptomes ([0003]). Somekh teaches a FET array including a plurality of pixels, each pixel comprising a FET or plurality of FET ([0087]). Somekh teaches high pixel density enable highly parallelized and high throughput peptide analysis, such as an array including over 256000 pixels ([0088]). Somekh teaches an array of FET sensors, that can include 1000 or more FET sensors ([0092]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Callewaert to incorporate Somekh’s teachings of FET arrays for polypeptide sequencing that includes a plurality of FET, such as over 1000 FET sensors, to enable highly parallelized and high throughput peptide analysis ([0003],[0087]-[0088],[0092]) to provide: the method of claim 13, wherein all of the bio-FETs of the plurality of additional bio-FETs are arranged in a sensor array, and wherein a number of the bio-FETs in the sensor array is at least 1000. Doing so would have a reasonable expectation of successfully improving throughput of peptide sequencing and identification as taught by Somekh.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Nygren (US 20120264618 A1) teaches methods for determining nucleic acid in a sample (abstract). Nygren teaches an oligonucleotide can be modified to include a detectable label using any method known to one of skilled in the art; the label may be incorporated as part of the synthesis or added on prior to using the primer in any of the processes described ([0115]). Nygren teaches the detectable labels can include charge tags ([0115]).
Mandell et al. (US 20200157618 A1) teaches a labeled nucleotide includes a nucleotide and a charge tag, the charge tag to be oxidized or reduced by an electrically conductive channel when maintained in proximity of a sensing zone of the electrically conductive channel (abstract). Mandell teaches the electrically conductive channel is a channel of a field effect transistor ([0023]). Mandell teaches nucleic acid sequencing ([0102]).
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758
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