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 .
2. This action is in response to the papers filed September 16, 2025. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Claims 1, 2, 4-15 and 21-25 are currently pending.
Claims 21-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on March 20, 2025.
Claim Rejections - 35 USC § 112(b)
3. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-5 and 7-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2 and 4-5 are indefinite over the recitation of “wherein the reading step (f)” in claim 2. This limitation is confusing because claim 2 depends from claim 1, which has been amended and the “reading” now occurs in step g.
Claims 7-12 are indefinite over the recitation of “wherein the reading step (f)” in claim 7. This limitation is confusing because claim 7 depends from claim 1, which has been amended and the “reading” now occurs in step g.
Claims 8-12 are indefinite over the recitation of “after step (f): (g) chemically removing the label that is associated with the sample in step (d) by cleaving a cleavable linker in the tyramide-fluorophore conjugate, thereby leaving the plurality of binding agents of (b) and their associated oligonucleotides still bound to the sample; and (h) repeating steps (c), (d), (e) and (f) multiple times, each repeat using a different peroxidase- linked oligonucleotide and each repeat followed by step (g) except for the final repeat, to produce a plurality of images of the sample, each image corresponding to a peroxidase-linked oligonucleotide used in (c)”. First of all it unclear if step (g) is supposed to occur after the reading step (step f in claim 7) OR after the repeating step (step f in claim 1). Additionally step g is confusing because it requires “chemically removing the label”, but step f in claim 1 recites “without removing or inactivating the label”. Further step g is confusing because if the label is in fact removed it is not clear if it is removed before or after the reading takes place. Finally step h is confusing because it requires repeating steps c-f, yet claim 1 step f already requires repeating steps c-e. So it is unclear if these steps are being repeated again. Clarification is required.
Claim 9 is indefinite over the recitation of the phrase “wherein step (h) comprises repeating steps (c), (d), (e) and (f) 5 to 100 times”. As discussed above step h is confusing because it requires repeating steps c-f 5 to 100 times, yet claim 1 step f already requires repeating steps c-e. So it is unclear if these steps are being repeated again. Clarification is required.
Claims 10-12 are indefinite over the recitation that in “step (g) the label is removed using a reducing agent”. As discussed above this recitation is confusing because the it requires removing the label, but step f in claim 1 recites “without removing or inactivating the label”. Further step g is confusing because if the label is being removed it’s not clear if the label is removed before or after the reading.
Claim 13 is indefinite over the recitation of “the reading step (f)” in claim 13. This limitation is confusing because claim 13 depends from claim 1, which has been amended and the “reading” now occurs in step g.
Claim Rejections - 35 USC § 103
4. 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.
5. Claims 1, 2, 6, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Campton US 2019/0317080 Filed 4/12/2019 with priority back to 62/657,517 Filed 4/13/2018) in view of Hong (US 2019/0004061 Pub 1/3/2019 and Filed 8/4/2018) and Miller (WO 2020/163397 Filed 2/4/2020 with priority back to 62/801,011 and 62/801,009 filed 2/4/2019).
Regarding Claim 1 Campton teaches kits and methods for labeling target materials or target analytes.
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FIG 1A shows one embodiment of a kit for labeling a target analyte with a detection moiety. The kit for making the composition includes an affinity molecule-first oligonucleotide conjugate 102, a horseradish peroxidase (“HRP”) molecule-second oligonucleotide conjugate 104, and a tyramide-first detection moiety conjugate 106. The affinity molecule-first oligonucleotide conjugate 102 can be added to the sample first, such that the affinity molecule portion binds or interacts with a desired biomarker. The HRP-second oligonucleotide conjugate 104 can then be added to the sample. The first oligonucleotide (A) of affinity molecule-first oligonucleotide conjugate 102 and the second oligonucleotide (A’) of the HRP-second oligonucleotide conjugate 104 are complementary, such that the first and second oligonucleotides hybridize with each other. The HRP molecule and the affinity molecule are, in effect, bound to each via hybridized complementary oligonucleotides. The tyramide-first detection moiety conjugate 106 is then added to the sample. The HRP molecule and the tyramide (of the respective conjugates) undergo a catalytic reaction, whereby the tyramide is activated and deposited at, nearby, or adjacent to the biomarker. The tyramide and the detection moiety of the tyramide-first detection moiety conjugate 106 are directly conjugated (para 0041). Campton discloses the following steps after labeling is complete: (4) (Optional) Wash with buffer; (5) Add coverslip on top of slide; (6) Image the sample; (7) (Optional) Reduce or eliminate the signal generated by the detection moiety; (8) (Optional) Repeat steps 3-7 at least one more time; (9) (Optional) Isolate target analyte; and (10) (Optional) Process target analyte (paras 0052-0081). Thus Campton teaches a method for analyzing a sample, comprising: (a) obtaining: i. a plurality of binding agents that are each linked to a different oligonucleotide (102); and ii. a corresponding plurality of peroxidase-linked oligonucleotides, wherein each of the peroxidase-linked oligonucleotide specifically hybridizes with only one of the oligonucleotides of (a)(i) (104); (b) labeling the sample with the plurality of binding agents of (a)(i); (c) specifically hybridizing a single peroxidase-linked oligonucleotide of the plurality of peroxidase-linked oligonucleotides of (a)(ii) with the sample, thereby producing complexes that comprise the peroxidase; (d) treating the sample with at least one tyramide-label conjugate (106), wherein the peroxidase in the complexes produced in (c) activate tyramide in the conjugate and cause covalent binding of the label to the sample near the complexes; and (g) reading the sample to obtain data on the binding of the label.
Campton does not teach a method further comprising step (e) inactivating the peroxidase and step (f) repeating steps c-e multiple times (clm 1). Campton does not teach a method wherein in step (c) the tyramide-label conjugate is a tyramide- mass tag conjugate and wherein the reading step is done by a mass spectrometry-based method capable of detecting mass tags (clm 2). Campton does not teach a method that comprises repeating steps (c), (d) and (e) 5 to 100 times (clm 6).
However Hong discloses mass tag precursors that are conjugated to a tyramine or a tyramine derivative (para 0269-0270). Hong teaches that mass codes produced by ionizing the mass tags are detected and/or quantified using mass spectrometry. Hong teaches that the method can be used for multiplexed detection of multiple targets in a particular sample (abstract, 0026). Hong teaches that with respect to multiplexing, samples having multiple targets can be treated in a manner so that each target is identified and detected using a different mass (para 0206). When multiplexing is desired, a first target may be detected by a first enzymatic reaction. Residual enzyme from the first aliquot then is deactivated. For example, horseradish peroxidase can be used, and after a first mass tag is deposited at a first target, residual horseradish peroxidase can be deactivated using excess hydrogen peroxide. The second target is then detected using a second mass tag deposited using a second horse radish peroxidase reaction. Particular embodiments of a multiplexing method concern using a mass tag precursor conjugate. One such multiplexed embodiment is illustrated in FIG. 11 for detecting a plurality of targets 114, 116, and 118. A mass tag precursor conjugate 120, comprising a tyramine or tyramine derivative, is bound to a target 114 proximal to the first enzyme-specific binding moiety conjugate 122, to form complex MT1. Once complex MT1 has been formed, deactivated enzyme 124 of the first enzyme-specific binding moiety is obtained by addition of an excess of a peroxide reagent, in this case hydrogen peroxide (H2O2) or a combination of peroxide and EDTA. After this deactivation step, the sample is washed to remove the excess peroxide reagent. A second enzyme-specific binding moiety conjugate 126 is then added and bound to the target 116. A second mass tag precursor conjugate 128 is deposited onto a second target site 116 to form complex MT2. Once complex MT2 has been formed, deactivated enzyme 130 of the second enzyme-specific binding moiety is obtained by addition of an excess of a peroxide reagent, in this case hydrogen peroxide (H2O2) or a combination of peroxide and EDTA. After this deactivation step, the sample is washed to remove the excess peroxide reagent. A third enzyme-specific binding moiety conjugate 132 is then added and bound to the target 118. A third mass tag precursor conjugate 134 is deposited onto a third target site 118 to form complex MT3. This sequence can be repeated any number of times to provide multiple mass tag-target complexes, 136, 138, 140 and 142. Upon ionization of the mass tags, a plurality of mass codes, 144, 146, 148, and 150 are produced, which can then be detected using mass spectrometry (para 0352, Fig 11).
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Accordingly, 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 Campton by inactivating the peroxidase with H2O2 as suggested by Hong. In the instant case Hong teaches that plural enzymes do not need to be used. Instead a single enzyme (HRP) with plural intervening enzyme deactivation steps can be used (para 0352). One of skill in the art would have been motivated to inactivate the HRP for the benefit of not having to use plural enzymes for each TSA detection procedure. Also it would have been obvious to modify the method of Campton by using a tyramide-mass tag conjugate and detecting the mass tag by a mass spectrometry based method as suggested by Hong. The claim would have been obvious because the substitution of one type of label (the dyes/fluorophores of Campton) for another type of label (the mass tags of Hong) would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Additionally one of skill in the art would have been motivated to use the mass tags of Hong particularly since the reference teaches that with respect to multiplexing, samples having multiple targets can be treated in a manner so that each target is identified and detected using a different mass (para 0206). Further it would have been obvious to repeat steps (c), (d), and (e) 5-100 times using different peroxidase linked oligonucleotides and different tyramide mass tag conjugates for the benefit of being able to detect multiple targets in the sample. Hong teaches that the benefit of this multiplexing technique is that it provides detection of multiple targets of interest on the same tissue sample, which may be of significant medical value (para 0352).
The combination of references does not teach a method wherein step f is performed
without adding any further binding agents of (a) to the sample and without removing or inactivating the label that is associated with the sample in step (d). Further the combined references do not teach that each time steps c-e are repeated the method uses a different peroxidase-linked oligonucleotide that hybridizes with an oligonucleotide of (a)(i) that is already bound to the sample and (ii) a different tyramide label conjugate, thereby producing a sample that is covalently bound to multiple labels (clm 1).
However Miller teaches a method for analyzing N different target analytes in a sample. In general, N can be 2 or more (e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, 12 or more, 15 or more, or even more). In a first step 352, the sample is contacted with N different first agents. Each of the N different first agents includes a binding species that specifically binds to one of the N different target analytes, and a unique first oligonucleotide conjugated to the binding agent. In other words, the binding agent and conjugated first oligonucleotide of each of the N first agents are different from the binding agents and conjugated first oligonucleotide of the other first agents among the N first agents. Next, in step 354, one of the n target analytes is selected for analysis, and a second agent that includes a reactive species conjugated to a second oligonucleotide that is at least partially complementary to, and hybridizes to, the first oligonucleotide of the first agent that selectively binds the n-th target analysis is contacted to the sample. The second oligonucleotide is thus bound to the sample at locations corresponding to the n-th target analyte (and the corresponding n-th first agent). Then, in step 356, the sample is contact with an n-th labeling species that includes a labeling moiety that is different from the labeling moieties of the other (n−1) labeling species. The labeling species reacts with the reactive species of the n-th second agent, depositing the n-th labeling species in the sample in proximity to the n-th target analyte. Next, in step 360, the n-th second agent is removed from the sample by de-hybridization and washing as described previously. In step 362, if all N target analytes have been analyzed, the procedure terminates at step 366. If not, another n-th analyte among the N target analytes is selected for analysis, and the procedure returns to step 354 (page 22 line 12- page 23 line 2 and Fig 3A).
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This method is illustrated schematically in FIGS. 3A-3E for a sample that includes N=3 target analytes for analysis. It is noted that in Fig 3D, each of the different first agents remains bound to corresponding different target analytes 310a, and the labeling agent 318a deposited in proximity to target analyte 310a also remains bound to sample 302.
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Accordingly, 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 Campton and Hong by performing step f without adding any further binding agents of (a) to the sample and without removing or inactivating the label that is associated with the sample in step (d) as suggested by Miller. One of skill in the art would have been motivated to performing step f without adding any further binding agents of (a) to the sample in view of the teaching in Miller that the antibody binding agents can remain in between cycles and that removal of the antibodies between cycles is time consuming, aggressive, and can adversely affect the integrity of certain sample types (page 6, lines 21-25). Further the skilled artisan would have been motivated to not remove or inactivate the label for the benefit of being able to detect all the labels in a single reading step. Further it would have been obvious to have modified the method of Campton and Hong by using a different peroxidase-linked oligonucleotide that hybridizes with an oligonucleotide of (a)(i) that is already bound to the sample and (ii) a different tyramide label conjugate, thereby producing a sample that is covalently bound to multiple labels in view of the teachings of Miller. The skilled artisan would have been motivated to use different peroxidase linked oligonucleotides and different tyramide label conjugates for the benefit of being able to perform multiplex detection and visualize different targets in the sample.
Regarding Claim 14 Campton teaches a method wherein the sample is treated with a single tyramide-label conjugate in step (d), thereby labeling the sample with a single label in step (d) (para 0051).
Regarding Claim 15 Campton teaches a method wherein the sample is treated with multiple tyramide-label conjugates in step (d), thereby labeling the sample with a combination of labels in step (d) (para 0051).
6. Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Campton US 2019/0317080 Filed 4/12/2019 with priority back to 62/657,517 Filed 4/13/2018) in view of Hong (US 2019/0004061 Pub 1/3/2019 and Filed 8/4/2018) and Miller (WO 2020/163397 Filed 2/4/2020 with priority back to 62/801,011 and 62/801,009 filed 2/4/2019) as applied to claims 1-2 above and in further view of Bendall (US 2015/0080233 Pub 3/19/2015).
The teachings of Campton, Hong, and Miller are presented above.
The combined references do not teach a method wherein the reading is done by multiplexed ion beam imaging (MIBI) (clm 4).
However Bendall discloses reading mass tags by MIBI (para 0090).
Accordingly, 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 Campton, Hong, and Miller by reading the mass tags using MIBI as suggested by Bendall. One of skill in the art would have been motivated to read mass tags using MIBI particularly since Bendall teaches that MIBI has advantages over conventional IHC techniques. Background signal due to is autofluorescence is absent and the dynamic range presented here is already 105, exceeding immunofluorescence and chromogenic IHC by 100-fold and 1000-fold, respectively. Because the mass resolution is less than one hundredth of a dalton, no spectral overlap is observed between different metal-conjugated primary antibodies, obviating the need for channel compensation. Assay linearity is improved relative to both chromogenic IHC and IF because neither secondary labeling nor amplified detection are required. Meanwhile, relatively conventional methods are used for immunoreactions, and because mass tags do not degrade, samples are stable indefinitely, permitting remote preparation together with a centralized reading facility (para 0090).
The combined references do not teach a method wherein the reading is done by mass cytometry (clm 5).
However Bendall discloses reading mass tags by mass cytometry (para 0066).
Accordingly, 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 Campton, Hong, and Miller by reading the mass tags using mass cytometry as suggested by Bendall. One of skill in the art would have been motivated to read mass tags using mass cytometry since as demonstrated by Bendall this was conventional in the art at the time of the invention.
7. Claims 7-10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Campton US 2019/0317080 Filed 4/12/2019 with priority back to 62/657,517 Filed 4/13/2018) in view of Hong (US 2019/0004061 Pub 1/3/2019 and Filed 8/4/2018) and Miller (WO 2020/163397 Filed 2/4/2020 with priority back to 62/801,011 and 62/801,009 filed 2/4/2019) as applied to claim 1 above and in further view of Guo (US 2022/0026433 Filed 5/14/2021 with priority back to 62/767,630 Filed 11/15/2018).
The teachings of Campton, Hong, and Miller are presented above.
The combined references do not teach a method wherein the tyramide-label conjugate of step (c) is a tyramide- fluorophore conjugate that comprises a cleavable linker and wherein the reading of step (f) is done by fluorescence microscopy to produce an image showing the pattern of binding of the label to the sample (clm 7). The combined references do not teach a method further comprising after step (f): (g) chemically removing the label that is associated with the sample in step (d) by cleaving a cleavable linker in the tyramide-fluorophore conjugate, thereby leaving the plurality of binding agents of (b) and their associated oligonucleotides still bound to the sample; and (h) repeating steps (c), (d), (e) and (f) multiple times, each repeat using a different peroxidase- linked oligonucleotide and each repeat followed by step (g) except for the final repeat, to produce a plurality of images of the sample, each image corresponding to a peroxidase-linked oligonucleotide used in (c) (clm 8). The combined references do not teach a method wherein step (h) comprises repeating steps (c), (d), (e) and (f) 5 to 100 times (clm 9). The combined references do not teach a method wherein the cleavable linker is cleavable by a reducing agent; and in step (g) the label is removed using a reducing agent (clm 10). The combined references do not teach a method wherein the reducing agent is TCEP (tris(2-carboxyethyl)phosphine) (clm 12).
However Guo teaches a method for multiplexed in situ analysis of biomolecules in a tissue. Referring to FIG. 1A, the method comprises three steps in each analysis cycle. First, for analysis of a protein in a tissue, the tissue is contacted with a horseradish peroxidase (HRP)-conjugated antibody configured to bind specifically to the protein target. For analysis of nucleic acids in a tissue, the tissue is contacted with a HRP-conjugated oligonucleotide probe configured to hybridize to the nucleic acid target. The tissue is also contacted with a detectably-labeled, cleavable tyramide. HRP catalyzes the coupling reaction between the cleavable tyramide and tyrosine residues on an endogenous protein target in close proximity. In the second step, fluorescence images are captured to generate quantitative protein expression profiles. Finally, detectable labels attached to the cleavable tyramide are chemically cleaved in step that simultaneously deactivates HRP, which allows for initiation of the next analysis cycle. Through reiterative cycles of target staining, fluorescence imaging, fluorophore cleavage, and HRP deactivation, a large number of different target biomolecules with a wide range of expression levels can be quantified in single cells of intact tissues in situ (para 0040, Fig 1A). Guo teaches that the cleavable detectably labeled tyramide can be fluorescent tyramide (CFT). The detectable label can be a fluorophore. Guo teaches that detectable label can be removed from the detectably labeled tyramide using TCEP (pars 0005-0006).
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Accordingly, 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 Campton, Hong, and Miller by using a tyramide fluorophore conjugate that comprises a cleavable linker, detecting the label by fluorescence microscopy, and then removing the label by cleaving the linker as suggested by Guo. Further it would have been obvious to repeat steps (c), (d), (e), and (f) 5-100 times each repeat using a different peroxidase linked oligonucleotide for the benefit of being able to detect multiple targets in the sample. One of skill in the art would have been motivated to label a sample having multiple targets with cleavable fluorescent tyramides since Guo teaches that through reiterative staining cycles, this approach has the potential to sensitively detect greater than 50 different proteins in the same tissue at the optical resolution (para 0066). Finally it would have been obvious to cleave the linker and remove the label with a reducing agent such as TCEP since as demonstrated by Guo this was conventional in the art at the time of the invention.
8. Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Campton (US 2019/0317080 Filed 4/12/2019 with priority back to 62/657,517 Filed 4/13/2018) in view of Hong (US 2019/0004061 Pub 1/3/2019 and Filed 8/4/2018), Miller (WO 2020/163397 Filed 2/4/2020 with priority back to 62/801,011 and 62/801,009 filed 2/4/2019), and Guo (US 2022/0026433 Filed 5/14/2021 with priority back to 62/767,630 Filed 11/15/2018) as applied to claims 1, 7, 8, and 10 above and in further view of Gordon (US 2010/0323350 Pub 12/23/2010).
The teachings of Campton, Hong, Miller, and Guo are presented above.
The combined references do not teach a method wherein the cleavable linker is a disulphide bond (clm 11).
However Gordon discloses cleavable linkers that comprise disulfide bonds (para 0154).
Accordingly, 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 Campton, Hong, Miller and Guo by using a cleavable linker with a disulphide bond. Based on the teaching of Gordon many types of cleavable linkers including disulphide bonds were well known in the art at the time of the invention. The claim would have been obvious because the substitution of one type of cleavable linker (the azide-based linker of Guo) for another (the disulphide bond based linker of Gordon) would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
9. Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Campton US 2019/0317080 Filed 4/12/2019 with priority back to 62/657,517 Filed 4/13/2018) in view of Hong (US 2019/0004061 Pub 1/3/2019 and Filed 8/4/2018) and Miller (WO 2020/163397 Filed 2/4/2020 with priority back to 62/801,011 and 62/801,009 filed 2/4/2019), as applied to claim 1 above and in further view of Hilderbrand (WO 2010/051530 Pub 5/6/2010)
The teachings of Campton, Hong, and Miller are presented above.
The combined references do not teach a method wherein the tyramide-label conjugate comprises a heavy metal and the reading step (f) is done by electron microscopy.
However Hilderbrand discloses a gold nanoparticle-tyramide conjugate. Gold is considered to be a heavy metal. Hilderbrand further discloses electron microscopy (page 47, lines 25-27).
Accordingly, 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 Campton, Hong, and Miller by using a tyramide-heavy metal conjugate and reading the signal by electron microscopy as suggested by Hilderbrand. The claim would have been obvious because the substitution of one type of tyramide conjugate (the fluorophore tyramide conjugate of Campton) for another (the heavy metal tyramide conjugate of Hilderbrand) would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Further Hilderbrand specifically teaches that fluorophore tyramide conjugates can be replaced with gold nanoparticle tyramide conjugates (page 47, lines 25-28).
Response To Arguments
10. In the response the Applicants traversed the rejection under 35 USC 103. The Applicants argue that the combination of Campton and Hong does not teach or suggest the instantly claimed step (f) of: without adding any further binding agents of (a) to the sample and without removing or inactivating the label that is associated with the sample in step (d), repeating steps (c), (d), and (e) multiple times, each repeat using:
(i) a different peroxidase-linked oligonucleotide that hybridizes with an oligonucleotide of
(a)(i) that is already bound to the sample, and
(ii) a different tyramide label conjugate,
thereby producing a sample that is covalently bound to multiple labels.
The Applicants argue that contrary to the methods described in the cited references, pending claim 1 requires repeating steps (c), (d), and (e) multiple times without adding any further binding agents of (a). This avoids repeatedly adding a binding agent in each iteration of labeling an additional target and instead requires adding only the labeled secondary antibody and a different tyramide label conjugate.
This argument has been fully considered and it persuasive. It is noted that the rejection has been modified to address the claims as amended.
11. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682