DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/24/25 has been entered.
Claim Status
Claims 1, 2, 4-10, 16, and 17-23 are pending and are examined. Claims 11-15 are withdrawn and are not examined.
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.
Claims 1, 2, 4, 5, 6, 16, 17, 18, 19, 20, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Pisharody (US Pub 2004/0146863; previously cited), in view of De Lumley-woodyear (US Pub 2002/0081588; previously cited).
Regarding Claim 1, Pisharody teaches a sensor circuit comprising:
a pair of ruthenium electrodes comprising a first ruthenium electrode and a second ruthenium electrode spaced-apart from the first ruthenium electrode by a nanogap ([0014] Particularly preferred electrodes comprise a material such as ruthenium. [0075] The electrodes are conveniently formed from essentially any conductive material. Preferred conductive materials have resistivities of less than about 10-3 ohm-meters, preferably less than about 10-4 ohm meters, more preferably less than about 10-6 ohm meters, and most preferably less than about 10-7 ohm meters. In preferred embodiments, the electrodes are formed from materials that include, but are not limited to ruthenium); and
a bridge molecule comprising a first reactive group RGA configured at or near a first end, and a second reactive group RGB configured at a second end ([0044] FIGS. 2A and 2B illustrate an embodiment of the biosensor comprising two binding agents, 14a and 14b, one on each electrode (FIG. 2B). The two binding agents are bound by the analyte forming a binding agent/analyte complex spanning the electrodes.),
the bridge molecule electrically wired to each of the first and second ruthenium electrodes and spanning the nanogap ([0044] FIGS. 2A and 2B illustrate an embodiment of the biosensor comprising two binding agents, 14a and 14b, one on each electrode (FIG. 2B). The two binding agents are bound by the analyte forming a binding agent/analyte complex spanning the electrodes.);
wherein the first reactive group RGA is conjugated to a first reactive group Z1 covalently bonded to the first ruthenium electrode through a first bivalent tether L, and the second reactive group RGB is conjugated to a second reactive group Z2 covalently bonded to the second ruthenium electrode through a second bivalent tether L' (The binding agent 14 can be directly bound to the electrodes or it can be coupled to the first electrode 10 and/or the second electrode 12 through one or more linkers or functional groups 18. The examiner notes one or more linkers or function groups would indicate that a first reaction group RGA can be conjugated to a first reactive group Z1 and the second reactive group RGB is conjugated to a second reactive group Z2).
and wherein the average distance between the reactive groups RGA and RGB is substantially similar to the distance between the reactive groups Z1 and Z2 groups (see Fig. 2B shows the distance of the reactive groups 14 and 18. Note the distance where 14a would be in contact with 18 and 14b would be in contact with 18).
Pisharody teaches [0064] the transition metals are complexed with a variety of ligands to form suitable transition metal complexes, as is well known in the art. Suitable ligands include, but are not limited to, --NH2, Pisharody is silent to wherein RGA and RGB are independently selected from -CO2H, -NH2, -OH, -SH, -CH=CH2, -C-CH, and -N3.
De Lumley-woodyear teaches in the related art of detection (See Abstract). [0050] The working electrodes 102 are typically thin films of conductive material disposed on an insulating substrate 114, as shown in FIG. 1. A variety of conductive materials can be used to form the working electrodes 102. Suitable materials include, for example, metals, carbon, conductive polymers, and metallic compounds. Examples of these materials include ruthenium dioxide. [0075] A variety of methods may be used to immobilize a redox polymer on an electrode surface. Examples of functions of cross-linking agents useful in the invention include epoxy, aldehyde, N-hydroxysuccinimide, halogen, imidate, thiol, and quinone functions.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected a thiol (-SH), as taught by De Lumley-woodyear, for the RGA and RGB, in the sensor circuit, as taught by Pisharody, to allow for functionalization of the electrode, as taught by De Lumley-woodyear, in [0075].
Regarding Claim 2, Pisharody teaches the sensor circuit of claim 1, wherein the bridge molecule comprises a polypeptide, a protein, a protein fragment, a protein alpha-helix, DNA, RNA, a single-stranded oligonucleotide, a double-stranded oligonucleotide, a peptide nucleic acid duplex, a peptide nucleic acid-DNA hybrid duplex, an antibody, an antibody Fab binding domain, a carbon nanotube, a graphene-like polycyclic aromatic nanoribbon, other natural polymers, or (poly)thiophene ([0060] The binding agent is not limited to a nucleic acid. Any number of other binding agents can also be used in such a biosensor. Generally, binding agents are selected that are capable of specifically binding to a particular target analyte. Such binding agents include, but are not limited to proteins, antibodies, lectins, sugars, polysaccharides, and the like.).
Regarding Claim 4, Pisharody teaches the sensor circuit of claim 1, wherein L and L' are independently selected from -CH-; -(CH2)y,-; or -(CH2CH2O)y,-, wherein y = 1 to 25 ( an air gap, however, in preferred embodiments, the electrodes are separated by a spacer 16 (e.g. an insulator, a dialectric, or a semiconductor). The binding agent 14 can be directly bound to the electrodes or it can be coupled to the first electrode 10 and/or the second electrode 12 through one or more linkers or functional groups 18. As discussed in [0149]. Linkers suitable for joining molecules are well known to those of skill in the art and include, but are not limited to any of a variety of, a straight or branched chain carbon linker, or a heterocyclic carbon linker, amino acid or peptide linkers, and the like. Particularly preferred linkers include, but are not limited to 4,4'-diphenylethyne, 4,4'-diphenylbutadiyne, 4,4'-biphenyl, 1,4-phenylene, 4,4'-stilbene, 1,4-bicyclooctane, 4,4'-azobenzene, 4,4'-benzylideneaniline, and 4,4"-terphenyl, oligophenylene vinylene, and the like (see, e.g., U.S. Pat. No. 6,208,553).
Straight or branched chain carbon linker would be -CH-.
Regarding Claim 5, Pisharody teaches the sensor circuit of claim 1, wherein L further comprises a phenyl ring or substituted phenyl ring covalently bonded to the first ruthenium electrode (Particularly preferred linkers include, but are not limited to 4,4'-diphenylethyne, 4,4'-diphenylbutadiyne, 4,4'-biphenyl, 1,4-phenylene, 4,4'-stilbene, 1,4-bicyclooctane, 4,4'-azobenzene, 4,4'-benzylideneaniline.).
Regarding Claim 6, Pisharody teaches the sensor circuit of claim 1, wherein L' further comprises a phenyl ring or substituted phenyl ring covalently bonded to the second ruthenium electrode (Particularly preferred linkers include, but are not limited to 4,4'-diphenylethyne, 4,4'-diphenylbutadiyne, 4,4'-biphenyl, 1,4-phenylene, 4,4'-stilbene, 1,4-bicyclooctane, 4,4'-azobenzene, 4,4'-benzylideneaniline.).
Regarding Claim 16, Pisharody teaches the circuit of claim 1, wherein the average distance between the reactive groups RGA and RGB is greater than the nanogap ([0058] One embodiment of a basic the biosensor (molecular sensing apparatus) of this invention is schematically illustrated in FIG. 1. The sensor comprises a first electrode 10, a second electrode 12, and a binding agent (e.g. biomolecule) 14 spanning the gap between the two electrodes. The two electrodes can be separated by an air gap, however, in preferred embodiments, the electrodes are separated by a spacer 16 (e.g. an insulator, a dialectric, or a semiconductor). Note in Fig. 2B, the reactive groups are separated by the gap and therefore the average distance between the reactive groups is greater than the nanogap).
Regarding Claim 17, Pisharody teaches a sensor circuit, comprising: a pair of ruthenium electrodes comprising a first ruthenium electrode and a second ruthenium electrode spaced-apart from the first ruthenium electrode by a nanogap ([0014] Particularly preferred electrodes comprise a material such as ruthenium. [0075] The electrodes are conveniently formed from essentially any conductive material. Preferred conductive materials have resistivities of less than about 10-3 ohm-meters, preferably less than about 10-4 ohm meters, more preferably less than about 10-6 ohm meters, and most preferably less than about 10-7 ohm meters. In preferred embodiments, the electrodes are formed from materials that include, but are not limited to ruthenium); and
a bridge molecule comprising a first reactive group RGA configured at or near a first end, and a second reactive group RGB configured at a second end, the bridge molecule electrically wired to each of the first and second ruthenium electrodes and spanning the nanogap ([0044] FIGS. 2A and 2B illustrate an embodiment of the biosensor comprising two binding agents, 14a and 14b, one on each electrode (FIG. 2B). The two binding agents are bound by the analyte forming a binding agent/analyte complex spanning the electrodes.);
wherein the first reactive group RGA is conjugated to a first reactive group Zl covalently bonded to the first ruthenium electrode through a first bivalent tether L, and the second reactive group RGB is conjugated to a second reactive group Z2 covalently bonded to the second ruthenium electrode through a second bivalent tether L' (The binding agent 14 can be directly bound to the electrodes or it can be coupled to the first electrode 10 and/or the second electrode 12 through one or more linkers or functional groups 18. The examiner notes one or more linkers or function groups would indicate that a first reaction group RGA can be conjugated to a first reactive group Z1 and the second reactive group RGB is conjugated to a second reactive group Z2); and
wherein the surfaces of each of the first ruthenium electrode and the second ruthenium electrode is functionalized with the first reactive group Zl and the second reactive group Z2 prior to the addition of bridge molecule; and wherein the structure of the bivalent tether L or L' includes at least one of an aromatic group or an R substituent group to tune electrical conductivity between the respective electrode and the bridge molecule (Particularly preferred linkers include, but are not limited to 4,4'-diphenylethyne, 4,4'-diphenylbutadiyne, 4,4'-biphenyl, 1,4-phenylene, 4,4'-stilbene, 1,4-bicyclooctane, 4,4'-azobenzene, 4,4'-benzylideneaniline. The binding agent 14 can be directly bound to the electrodes or it can be coupled to the first electrode 10 and/or the second electrode 12 through one or more linkers or functional groups 18.).
Regarding Claim 18, Pisharody teaches the sensor circuit of claim 17, wherein the bridge molecule comprises a polypeptide, a protein, a protein fragment, a protein alpha-helix, DNA, RNA, a single-stranded oligonucleotide, a double-stranded oligonucleotide, a peptide nucleic acid duplex, a peptide nucleic acid-DNA hybrid duplex, an antibody, an antibody Fab binding domain, a carbon nanotube, a graphene-like polycyclic aromatic nanoribbon, other natural polymers, or (poly)thiophene ([0060] The binding agent is not limited to a nucleic acid. Any number of other binding agents can also be used in such a biosensor. Generally, binding agents are selected that are capable of specifically binding to a particular target analyte. Such binding agents include, but are not limited to proteins, antibodies, lectins, sugars, polysaccharides, and the like.).
Regarding Claim 19, Pisharody teaches the sensor circuit of claim 17, wherein L and L' are independently selected from -CH-; -(CH2)y-; or -(CH2CH2O)y-, wherein y = 1 to 25 (an air gap, however, in preferred embodiments, the electrodes are separated by a spacer 16 (e.g. an insulator, a dialectric, or a semiconductor). The binding agent 14 can be directly bound to the electrodes or it can be coupled to the first electrode 10 and/or the second electrode 12 through one or more linkers or functional groups 18. As discussed in [0149]. Linkers suitable for joining molecules are well known to those of skill in the art and include, but are not limited to any of a variety of, a straight or branched chain carbon linker, or a heterocyclic carbon linker, amino acid or peptide linkers, and the like. Particularly preferred linkers include, but are not limited to 4,4'-diphenylethyne, 4,4'-diphenylbutadiyne, 4,4'-biphenyl, 1,4-phenylene, 4,4'-stilbene, 1,4-bicyclooctane, 4,4'-azobenzene, 4,4'-benzylideneaniline, and 4,4"-terphenyl, oligophenylene vinylene, and the like (see, e.g., U.S. Pat. No. 6,208,553).
Straight or branched chain carbon linker would be -CH-.).
Regarding Claim 20, Pisharody teaches the sensor circuit of claim 17, wherein L further comprises a phenyl ring or substituted phenyl ring covalently bonded to the first ruthenium electrode and wherein the L' further comprises a phenyl ring or substituted phenyl ring covalently bonded to the second ruthenium electrode to thereby increase electrical conductivity between the respective ruthenium electrodes and the bivalent tethers (Particularly preferred linkers include, but are not limited to 4,4'-diphenylethyne, 4,4'-diphenylbutadiyne, 4,4'-biphenyl, 1,4-phenylene, 4,4'-stilbene, 1,4-bicyclooctane, 4,4'-azobenzene, 4,4'-benzylideneaniline.). .
Regarding Claim 21, Pisharody teaches the sensor circuit of claim 17, wherein the average distance between the reactive groups RGA and RGB is substantially similar to the distance between the reactive groups Zl andZ2 groups (see Fig. 2B shows the distance of the reactive groups 14 and 18. Note the distance where 14a would be in contact with 18 and 14b would be in contact with 18).
Regarding Claim 22, Pisharody teaches the sensor circuit of claim 17, wherein the average distance between the reactive groups RGA and RGB is greater than the nanogap ([0058] One embodiment of a basic the biosensor (molecular sensing apparatus) of this invention is schematically illustrated in FIG. 1. The sensor comprises a first electrode 10, a second electrode 12, and a binding agent (e.g. biomolecule) 14 spanning the gap between the two electrodes. The two electrodes can be separated by an air gap, however, in preferred embodiments, the electrodes are separated by a spacer 16 (e.g. an insulator, a dialectric, or a semiconductor). Note in Fig. 2B, the reactive groups are separated by the gap and therefore the average distance between the reactive groups is greater than the nanogap).
Claims 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Pisharody (US Pub 2004/0146863; previously cited), in view of De Lumley-woodyear (US Pub 2002/0081588; previously cited), and further in view of Wagner (US Pub 2002/0013003; previously cited).
Regarding Claim 7, modified Pisharody teaches the sensor circuit of claim 1.
Modified Pisharody is silent to further comprising a bifunctional linker configured to covalently bond a molecule to a ruthenium surface, the bifunctional linker molecule having a structure, A-L-Z, wherein: A=
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X=Cl-, Br-, I-, BF4-, ClO4-, or (SO4-)
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Z= -CO2H, -NH2, -OH, -OC(O)C(CH3)2
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-CH=CH2, -SH, -C-CH or N3; L is a bivalent tether selected from -G-CH-; -G-(CH2),-; or -G-(CH2CH2O),-, wherein y = 1 to 25 and G is an optional aryl linkage -Ar-; M=N or S, and E is a heterocycle selected from imidazole, imidazoline, thiazole, or triazole; and R1 and R2 are independently selected from an electron pair, H, an aliphatic substituent, or an aryl substituent.
Wagner teaches in the related art of bioconjugation. [0159] Still another class of photoactivatable groups are the diazo compounds, such as the diazoalkanes (e.g., diazomethane and diphenyldiazomethane), diazo ketones (e.g., diazoacetophenone and 1-trifluoromethyl-1-diazo-2-pentanone), and diazoacetates (e.g., t-butyl diazoacetate and phenyl diazoacetate).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added t-butyl diazoacetate, as taught by Wagner, to covalently bond a molecule to a ruthenium surface in the device of modified Pisharody, to allow for a photoactivatable group, as taught by Wagner in [0159].
Regarding Claim 9, modified Pisharody teaches the sensor circuit of claim 7, wherein A is a diazo group and Z is -CO2H, -NH2, -OH, -OC(O)C(CH3)2 -CH=CH2, -SH, -C-CH or N3 (Wagner teaches [0159] Still another class of photoactivatable groups are the diazo compounds, such as the diazoalkanes (e.g., diazomethane and diphenyldiazomethane), diazo ketones (e.g., diazoacetophenone and 1-trifluoromethyl-1-diazo-2-pentanone), and diazoacetates (e.g., t-butyl diazoacetate and phenyl diazoacetate).
Claims 8 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Pisharody (US Pub 2004/0146863; previously cited), in view of De Lumley-woodyear (US Pub 2002/0081588), Wagner (US Pub 2002/0013003; previously cited), and further in view of Hetemi (“Grafting of Diazonium Salts on Surfaces: Application to Biosensors”. Biosensors. 10(4). 2020. 1-32.; previously cited).
Regarding Claim 8, modified Pisharody teaches the sensor circuit of claim 7.
Modified Pisharody is silent to A is a diazonium salt and Z is -CO2H, -NH2, -OH, -OC(O)C(CH3)2-Br, -CH=CH2, -SH, -C-CH or N3.
Hetemi teaches in the related art of diazonium-based biosensors including small molecules of biological interest, proteins, and nucleic acid. See Abstract. Diazonium salts are easily synthesized. See pages 10 and 11. Paragraph 2 on page 11. The high reactivity of the diazonium function allows a fast and extremely dense grafting on a wide range of substrates. See Table 1. Reviews on biosensors built with the help of diazonium chemistry. See Tables 3 and 4. Column 2 Diazonium salt + Attached Recognizing Group.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the bifunctional linker molecule in the device of modified Pisharody, with a diazonium salt, as taught by Hetemi, to allow for more reliable and stable detection systems, as taught by Hetemi, in Concluding Remarks on page 25.
Regarding Claim 23, Pisharody teaches the sensor circuit of claim 17.
Pisharody is silent to the surfaces of each of the first and the second ruthenium electrodes are functionalized by exposing each electrode to a linker having a reactive diazonium, diazo or carbene group.
Hetemi teaches in the related art of diazonium-based biosensors including small molecules of biological interest, proteins, and nucleic acid. See Abstract. Diazonium salts are easily synthesized. See pages 10 and 11. Paragraph 2 on page 11. The high reactivity of the diazonium function allows a fast and extremely dense grafting on a wide range of substrates. See Table 1. Reviews on biosensors built with the help of diazonium chemistry. See Tables 3 and 4. Column 2 Diazonium salt + Attached Recognizing Group.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the bifunctional linker molecule in the device of modified Pisharody, with a diazonium salt, as taught by Hetemi, to allow for more reliable and stable detection systems, as taught by Hetemi, in Concluding Remarks on page 25.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Pisharody (US Pub 2004/0146863; previously cited), in view of De Lumley-woodyear (US Pub 2002/0081588), Wagner (US Pub 2002/0013003; previously cited), and further in view of Mao (US Pub 2011/0017595; previously cited).
Regarding Claim 10, modified Pisharody teaches the sensor circuit of claim 7. Pisharody teaches [0064] The transition metals are complexed with a variety of ligands to form suitable transition metal complexes, as is well known in the art. Suitable ligands include, but are not limited to, --NH.sub.2; imidazole.
However, modified Pisharody is silent to A is an imidazolium ring and Z is -CO2H, -NH2, -OH, -OC(O)C(CH3)2-Br -CH=CH2, -SH, -C-CH or N3.
Mao teaches in the related art of biosensors. See Table 1 for examples of reactive groups and resulting linkages. Imidazolium (see column 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the bifunctional linker molecule in the device of modified Pisharody with imidazolium, as taught by Mao, to form a suitable transition metal complex, as taught by Mao in order to have alternative reactive group that can couple with a biomolecule, as taught by Mao, in [0030].
Additional Reference
The prior art of Bertin (US Pub 2013/0112572) teaches in [0014] and [0015] ruthenium electrodes and biosensors.
Response to Arguments
Applicant's arguments, see pages 9 and 10, filed 11/24/25, have been fully considered but they are not persuasive.
First, Applicant argues on page 9 that independent claim 1 was amended with a new limitation about the average distance between the different reactive groups being substantially similar.
In response, the examiner notes the prior art of Pisharody (US Pub 2004/0146863) teaches in Fig. 2b that the average distance between the different groups would be substantially similar. See where the portion of 14a is near 18 and where the portion of 14b is near 18 and the average distance between the groups would be substantially similar. Therefore, the rejection is maintained.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACQUELINE BRAZIN whose telephone number is (571)270-1457. The examiner can normally be reached M-F 8-6.
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/JB/
/JILL A WARDEN/Supervisory Patent Examiner, Art Unit 1798