DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election without traverse of Group I, claims 1-41, in the reply filed on 27 April 2026 is acknowledged.
Claim Objections
3. Claim 2 is objected to because of the following informalities: The claim does not end in a period (MPEP 608.01(m)). Appropriate correction is required.
4. Claims 19-23, 29-32 and 37 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claim Rejections - 35 USC § 112
5. 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.
6. Claims 2-40 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.
A. Claim 2 recites the phrase “generating a set of probes, wherein each probe comprises: (i) a targeting sequence; (ii) at least one initiator sequence; and (iii) at least two DNA amplifiers, wherein each DNA amplifier comprises an initiator complimentary sequence and a readout sequence…” Is the set of probes the encoding probe (comprising the targeting sequence and the at least one initiator sequence) and the at least two hairpin DNA amplifiers, as shown in FIG 1A of applicant’s drawings? If so, how does “each probe” (i.e., including the encoding probe) comprise “at least two DNA amplifiers”? Is “each probe” within the set of probes a complex of the encoding probe and the DNA amplifiers, as in step 4 of FIG 1A in applicant’s drawings? The language of this phrase, and how it is intended to limit the metes and bounds of the claim, is unclear.
Claim 2 additionally recites the phrase “and assigning them to a bacterium…” however the sample provided in line one of the claim does not specify that it comprises a bacterium, and it is unclear how this is intended to limit the metes and bounds of the claim in embodiments wherein the sample does not comprise a bacterium. For example, claim 3 provides additional embodiments such as urine samples, bone biopsies and plant biopsies, do these embodiments necessarily comprise bacterium? Claim 4 requires that the sample is a cell (i.e., a single cell) and claim 5, which depends from claim 4, comprises an embodiment wherein that cell is a eukaryotic cell (i.e., not a bacterium). It is unclear how these embodiments that do not comprise a bacterium are intended to be limited by this phrase.
Claim 2 recites the phrase “decoding the spectra into a single, targeted transcript through means of signal deconvolution, error correction, comparison to reference standards” and it is unclear as written how this list is intended to limit the claim. The list provides multiple options that would be useful for decoding a spectra of signal but provides no indication if these methods are intended to limit the claim in alternate (i.e., “…through means of signal deconvolution, error correction, or comparison to reference standards) or in combination (i.e., “…through means of signal convolution, error correction, and comparison to reference standards).
For the reasons outlined above, claim 2 is indefinite.
B. Claim 2 recites the limitation "the spectra" in lines 13 and 14 of the claim. There is insufficient antecedent basis for this limitation in the claim.
C. Claim 7 recites the phrase “wherein each cell comprises a specific targeting sequence.” However, claim 7 is dependent on claim 4, which recites “wherein the sample is a cell.” It is unclear how each cell comprises a specific targeting sequence when there is only a cell in the sample, therefore the claim is indefinite.
D. Claim 11 recites the phrase “wherein the target is mRNA and rRNA.” It is unclear how the target (i.e., a single target) can be two distinct types of RNA, therefore the claim is indefinite.
E. Claims 3-6, 8-10 and 12-40 are rejected for all embodiments in which they depend from claim 2 for being dependent on a previously rejected claim.
Claim Rejections - 35 USC § 102
7. 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.
8. Claims 1, 3, 6, 12, 24, 33, 34 and 40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fraser et al (United States Patent Application No. US 20200140921, published 07 May 2020).
Regarding claim 1, Fraser teaches a method to create dendritic biocompatible polymers from pairs of complementary nucleic acid molecules to “reveal the presence” of analytes such as specific nucleic acid molecules, small molecules, proteins and peptides (i.e., analyze a sample; abstract). Fraser teaches contacting an extended trigger probe that is specific for a polynucleotide with a sample ([0008], FIG 3B, and Example 10) and that the trigger probe comprises an extended nucleotide sequence that is specific for a polynucleotide (i.e., a targeting sequence that forms a first construct; [0008]) and a nucleic acid trigger (i.e., an initiator sequence; [0008], FIG 3B and FIG 4). Fraser teaches adding at least two different DNA amplifiers to the first complex to produce a second complex (FIG 1 A and B, FIG 2) and that each DNA amplifier comprises an initiator complimentary sequence (FIG 1A, sequence 1 is complementary to initiator sequence 1’ and comprises readout sequence 6, in FIG 1B sequence 3 is complementary to initiator sequence 3' and comprises readout sequence 5). Fraser additionally teaches adding emissive readout probes to the second complex, wherein each emissive readout probe comprises a label and a complementary sequence to the readout sequence of a corresponding DNA amplifier (FIG 4, [0233] and [0235]).
Regarding claims 3/1 and 6, Fraser teaches that the sample is a tissue sample ([0057] and [0349]). Tissue samples inherently comprise a plurality of cells.
Regarding claim 12/1, Fraser teaches a trigger having an extended nucleotide region (FIG 3B and [0008]). While the trigger region (i.e., the initiator sequence) orientation is not explicitly labeled, it is shown at one of the ends (i.e., on the 5' and/or 3' end) of the oligonucleotide and therefore meets the limitations of the instant claim.
Regarding claim 24/1, Fraser teaches a method comprising the addition of at least two additional molecules configure for self-assembled polymerization (i.e., two additional DNA amplifiers; FIG 6 and [0053]).
Regarding claims 33/1 and 34/1, Fraser teaches the use of dsDNA labels comprising fluorophores at each 5' and 3' end ([0233]).
Regarding claim 40/1, Fraser teaches a tissue sample on a microscope slide (Example 11, RNA in situ hybridization on Ffpe slides).
Claim Rejections - 35 USC § 103
9. 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.
10. 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.
11. Claims 1-15, 24, 33-35 and 38-41 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al (Highly multiplexed spatial mapping of microbial communities, Nature, 588, published 02 December 2020) in view of Fraser et al (United States Patent Application No. US 20200140921, published 07 May 2020).
Regarding claim 1, Shi teaches a method of analyzing the spatial ecology of environmental microbial communities at single-cell resolution (i.e., analyzing a sample; abstract). Shi teaches contacting rRNA with probes comprising an encoding sequence (i.e., encoding probes) to form a first complex (pg. 676 column 2 ¶ 2 and FIG 1a). Shi teaches adding emissive readout probes, wherein each readout probe comprises a label and a complementary sequence to a readout sequence (pg. 676 column 2 ¶ 2 and FIG 1a).
Shi does not teach adding at least two different DNA amplifiers to the first complex to produce a second complex, wherein each DNA amplifier comprises and initiator complementary sequence and a readout sequence, nor do they teach that the emissive readout probes are complementary to the readout sequence of a corresponding DNA amplifier.
However, Fraser teaches at least two different DNA amplifiers that are initiated by a trigger sequence (i.e., they comprise an initiator complementary sequence) and that each DNA amplifier comprises ‘extension dendrite’ domains that are complementary to fluorescently labeled readout sequences ([0006], FIG 1 and FIG 4).
It would have been obvious to one having ordinary skill in the art to have modified the sample analysis method taught by Shi to have incorporated the DNA amplifier probes taught by Fraser to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this modification because Fraser teaches that their ‘complementary dendritic monomers’ constitute a biologically compatible signal amplification technology ([0004]) and that signal amplification technologies are preferable to direct labeling methods as they enhance the signal to noise ratio, increasing the detection ease and accuracy ([0003]). In addition, the ordinary artisan would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the in situ labeling of samples with DNAs for the purpose of fluorescent-based detection.
Regarding claim 2, Shi teaches a method of analyzing the spatial ecology of environmental microbial communities at single-cell resolution (i.e., analyzing a sample; abstract). Shi teaches a set of probes wherein each probe comprises an encoding sequence (i.e., a targeting sequence) and at least one readout sequence (i.e., an initiator sequence) and contacting the sample with taxon-specific probes that hybridize to rRNA in the sample to form a complex (pg. 676 column 1 ¶ 2, pg. 676 column 2 ¶ 2 and FIG 1a). Shi teaches adding a set of emissive readout probes, wherein each readout probe comprises a label and a complementary sequence to a readout sequence (pg. 676 column 2 ¶ 2 and FIG 1a). Shi teaches imaging the sample (i.e., detecting the emissive readout probes; Methods – Spectral Imaging and FIG 1), determining the spectra of “signal” and assigning them to a bacterium (“species-specific detection” pg. 677 column 2 ¶ 1, “detected cells for the genera of…” pg. 678 column 2 ¶ 2, pg. 677 column 2 ¶ 1, and FIG 1). Shi additionally teaches that taxon-specific probes are flanked by different readout sequences (pg. 676 column 1 ¶ 2 and pg. 676 column 2 ¶ 2), and that probes with the same encoding sequence but different readout sequences stochastically bind individual rRNA molecules within the same cell to generate a spectral barcode based on the observed fluorescence emission spectra (i.e., a single rRNA transcript was decoded and represented by a barcode; pg. 676 column 2 ¶ 2 and FIG 1a). Shi teaches that this method is performed by signal deconvolution (Extended data FIG 8), reference spectra (pg. 677 column 1 ¶ 1) and utilizing Bonferroni correction (i.e., a method of error correction; Extended data FIG 9).
Shi does not teach that the probe set comprises at least two DNA amplifiers, wherein each DNA amplifier comprises an initiator complementary sequence and a readout sequence, nor do they teach that the emissive readout probes are complementary to the readout sequence of a corresponding DNA amplifier.
However, Fraser teaches at least two different DNA amplifiers that are initiated by a trigger sequence (i.e., they comprise an initiator complementary sequence) and that each DNA amplifier comprises ‘extension dendrite’ domains that are complementary to fluorescently labeled readout sequences ([0006], FIG 1 and FIG 4).
It would have been obvious to one having ordinary skill in the art to have modified the sample analysis method taught by Shi to have incorporated the DNA amplifier probes taught by Fraser (i.e., the readout sequences of Shi become the trigger/initiator sequences taught by Fraser, while the ‘dendritic extension’ sequences on the DNA amplifiers taught by Fraser because the readout sequences that bind the emissive probes taught by Shi) to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this modification because Fraser teaches that their ‘complementary dendritic monomers’ constitute a biologically compatible signal amplification technology ([0004]) and that signal amplification technologies are preferable to direct labeling methods as they enhance the signal to noise ratio, increasing the detection ease and accuracy ([0003]). In addition, the ordinary artisan would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the in situ labeling of samples with DNAs for the purpose of fluorescent-based detection.
Regarding claim 3, Shi teaches the analysis of environmental microbial communities at single-cell resolution from mouse tissue sections (i.e., the sample is a tissue specimen; abstract pg. 678 column 1 ¶ 2).
Regarding claims 4 and 7, Shi teaches that the sample is analyzed at single-cell resolution (abstract and FIG 1). Without further limitation to the claims, “the sample” being any one of the single bacterial cells observed is considered to read on this claim limitation. Shi teaches that the bacteria comprises an encoding probe targeting a specific rRNA segment (i.e., the cell comprises a specific targeting sequence; pg. 676 column 2 ¶ 2 and FIG 1).
Regarding claim 5, Shi teaches that the single cell is a bacterial cell (“barcoded E. coli isolates;” FIG 1).
Regarding claim 6, Shi teaches the classification of many individual bacterial cells simultaneously (i.e., the sample comprises a plurality of cells; FIG 1).
Regarding claims 8 and 10, Shi teaches that the target is rRNA (pg. 676 column 2 ¶ 2).
Regarding claims 8, 9 and 11, Shi does not specifically teach that the target is mRNA, however Shi teaches that the HiPR-FISH method uses a two-step hybridization scheme that was previously exploited to spatially map mRNA molecules in tissue (pg. 681 column 1 ¶ 2). It would have been obvious to one having ordinary skill in the art to have used the encoding probe and emissive probe design taught by Shi, and the amplification probe design taught by Fraser, to have detected mRNA targets, and to further have detected mRNA and rRNA targets together, based on the above teaching. In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited reference could have been combined with predictable results because the known techniques in the cited reference predictably result in the detection of RNA targets.
Regarding claims 12-14, Shi teaches that the encoding probe comprises readout sequences (i.e., initiator sequences) at the 5' and the 3' ends, and that the two initiator sequences are different sequences (FIG 1).
Regarding claim 15, Shi does not teach that the two initiator sequences on the coding probe have the same sequence.
However, Fraser teaches a trigger sequence that initiated DNA amplifier polymerization for the purpose of signal amplification.
It would have been obvious to one having ordinary skill in the art to have simply substituted both readout sequences taught by Shi with the same trigger sequence taught by Fraser to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this substitution in order to theoretically double the amount of signal generation from the encoding probe being able to initiate two DNA amplifier polymerization reactions, without needing to perform the additional steps of designing new DNA amplifiers for each different initiator sequence on the encoding probes taught by Shi. In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the generation of DNA complexes for the purposes of in situ sequencing.
Regarding claim 24, Fraser teaches a method comprising the addition of at least two additional molecules configured for self-assembled polymerization (i.e., two additional DNA amplifiers; FIG 6 and [0053]).
Regarding claims 33-35, Shi teaches readout probes comprising a label at the 5' and 3' ends, and that the labels are the same (Supplementary Information Table 1).
Regarding claims 38 and 39, Shi teaches that images are taken on a Zeiss 880 confocal microscope (i.e., point scanning confocal microscopy) and spectral imaging (i.e., a spectral detection strategy; Methods – Spectral Imaging).
Regarding claim 40, Shi teaches samples on UltraStick slides (i.e., microscope slides; Methods – HiPR-FISH on synthetic multi-species microbial communities).
Regarding claim 41, Shi teaches a method for analyzing a cell (abstract) comprising: contacting at least one encoding probe with the cell (FIG 1) wherein the encoding probe comprises an RNA targeting sequence and a readout sequence (FIG 1).
Shi teaches adding two emissive readout probes to the sample, wherein each emissive readout probe comprises a fluorophore and a complementary sequence to the readout sequence of the encoding probe (FIG 1).
Shi does not teach that the encoding probes comprise an mRNA target sequence, nor does Shi teach adding two different DNA amplifiers to the first complex to produce a second complex, wherein each DNA amplifier comprises an initiator complementary sequence and a readout sequence.
However, Shi teaches that the HiPR-FISH method uses a two-step hybridization scheme that was previously exploited to spatially map mRNA molecules in tissue (pg. 681 column 1 ¶ 2). Fraser teaches at least two different DNA amplifiers that are initiated by a trigger sequence (i.e., they comprise an initiator complementary sequence) and that each DNA amplifier comprises ‘extension dendrite’ domains that are complementary to fluorescently labeled readout sequences ([0006], FIG 1 and FIG 4).
It would have been obvious to one having ordinary skill in the art to have used the encoding probe and emissive probe design taught by Shi, and the amplification probe design taught by Fraser, to have detected mRNA targets based on Shi’s teaching that HiPR-FISH was previously used to detect mRNA molecules in tissue. The ordinary artisan would have been motivated to make the modification taught by Fraser because Fraser teaches that their ‘complementary dendritic monomers’ constitute a biologically compatible signal amplification technology ([0004]) and that signal amplification technologies are preferable to direct labeling methods as they enhance the signal to noise ratio, increasing the detection ease and accuracy ([0003]). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited reference could have been combined with predictable results because the known techniques in the cited reference predictably result in the detection of RNA targets.
12. Claims 17, 18 and 25-28 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al (Highly multiplexed spatial mapping of microbial communities, Nature, 588, published 02 December 2020) in view of Fraser et al (United States Patent Application No. US 20200140921, published 07 May 2020) as applied to claims 1 and 2 above, and further in view of Liu et al (Branched Hybridization Chain Reaction Circuit for Ultrasensitive Localizable Imaging of mRNA in Living Cells, Analytical Chemistry, 90, 1502-1505, published 04 January 2018).
Regarding claims 17 and 18, the methods of claims 1 and 2 are discussed fully above and incorporated here.
Shi in view of Fraser teaches two DNA amplifiers (Fraser; FIG 1A and 1B). Fraser teaches that one of the two DNA amplifiers (FIG 1A) comprises, from 5' to 3', a toehold sequence (1), a stem sequence (2), a loop sequence (3'), a complement stem sequence (2’) and a readout sequence (5). Fraser teaches that the other DNA amplifier (FIG 1B) comprises, from 5' to 3', a readout sequence (6), a stem sequence (2’), a loop sequence (1’), a complement stem sequence (2), and a toehold sequence (3).
The combination of Shi in view of Fraser does not teach an orientation wherein one of the DNA amplifiers comprises, from 5' to 3', a readout sequence, a toehold sequence, a stem sequence, a loop sequence, and a complement of the stem sequence while the other DNA amplifier comprises, from 5' to 3', a stem sequence, a loop sequence, a complement stem sequence, a toehold sequence, and a readout sequence.
However, Liu teaches a method of performing a branched HCR reaction wherein the branching sequence (analogous to the “extension dendrite” taught by Fraser; [0005]) is on the same side of the stem as the toehold and at the distal end (i.e., closer to the 5' or 3' end of the hairpin) than the toehold.
It would have been obvious to one having ordinary skill in the art to have modified the DNA amplifiers taught by Fraser to have moved the readout sequence (i.e., region 5 in FIG 1A and region 6 in FIG 1B) adjacent to the toehold (i.e., region 1 in FIG 1A and region 3 in FIG 1B) and at the distal end of the hairpin as taught by Fraser to arrive at the instantly claimed invention with a reasonable expectation of success. The resulting orientation of Fraser’s hairpins would be, from 5' to 3': readout region (5), toehold region (1), stem region (2), loop region (3), and stem complement (2’); and stem region (2’), loop region (1’), stem complement (2), toehold region (3), and readout region (6). The ordinary artisan would have been motivated to make this modification because it represents a simple substitution of known elements in the art to achieve predictable results.
Regarding claims 25-28, the method of claim 24 is discussed fully above and incorporated here.
Fraser teaches a method comprising the addition of at least two additional molecules configured for self-assembled polymerization (i.e., two additional DNA amplifiers; FIG 6 and [0053]).
As discussed above, Fraser in view of Liu teaches DNA amplifiers comprising, from 5' to 3': DNA amplifier 1 having a readout region (5), toehold region (1), stem region (2), loop region (3), and stem complement (2’); and DNA amplifier 2 having a stem region (2’), loop region (1’), stem complement (2), toehold region (3), and readout region (6). These orientations read on the limitations of instant claims 27 and 28. Similarly, Fraser teaches a method of quadratic amplification (FIG 6 and [0053]) and the embodiment wherein the initial two hairpin molecules taught by Fraser and in view of Liu are used to “seed additional polymers” ([0053]), wherein the “extension dendrites” taught by Fraser seed the polymerization of the second two molecules rather than bind readout probes reads on the limitations of claims 25 and 26.
13. Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Shi et al (Highly multiplexed spatial mapping of microbial communities, Nature, 588, published 02 December 2020) in view of Fraser et al (United States Patent Application No. US 20200140921, published 07 May 2020) as applied to claims 1 and 2 above, and further in view of Tsuneoka et al (Modified in situ hybridization chain reaction using short hairpin DNAs, Frontiers in Molecular Neuroscience, 13, 75, published 12 May 2020).
Regarding claim 16, the method of claims 1 and 2 are discussed fully above and incorporated here.
Neither Shi nor Fraser teach an encoding probe comprises two fractional initiator sequences.
However, Tsuneoka teaches a split initiator probe set wherein one probe has one part of the hairpin initiator sequence and another probe has the other part (FIG 1B).
It would have been obvious to one having ordinary skill in the art to have substituted the trigger/initiator sequences taught by Shi in view of Fraser with the fractional initiator sequences taught by Tsuneoka to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this substitution because Tsuneoka specifically teaches that the split probes are very robust for non-specific hybridization (pg. 12 column 1 ¶ 3) and that such split initiator probes reduce non-specific signal, provide high signal-to-noise ratio and high sensitivity (pg. 2 column 1 ¶ 3). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the in situ detection of RNA.
14. Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Shi et al (Highly multiplexed spatial mapping of microbial communities, Nature, 588, published 02 December 2020) in view of Fraser et al (United States Patent Application No. US 20200140921, published 07 May 2020) as applied to claim 34 above, and further in view of Behnam et al (A straightforward DOPE (Double Labeling of Oligonucleotide Probes)-FISH (Fluorescence In Situ Hybridization) Method for Simultaneous Multicolor Detection of Six Microbial Populations, Applied and Environmental Microbiology, 78, 15, 5138-5142, published 11 May 2012).
Regarding claim 36, the method of claim 34 is discussed fully above and incorporated here.
Neither Shi nor Fraser teach emissive readout probes comprising a label on the 5' end and a label on the 3' end wherein the labels are different.
However, Behnam teaches the method of DOPE-FISH (Double Labeling of Oligonucleotide Probes – FISH) using probes labeled at one end with one dye and the other end with a different dye (e.g., Cy3 and Cy5; FIG 2 and pg. 5140 column 1 ¶ 3).
It would have been obvious to one having ordinary skill in the art to have replaced the single-labeled emissive probes taught by Shi or the double-labeled emissive probes having the same fluorophore taught by Fraser, with the double-labeled probes having different dyes at each end taught by Behnam to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this modification because Behnam teaches that the dual-colored probes outperform two differentially labeled probes competing for the same site (pg. 5140 column 1 ¶ 4) and that the use of oligonucleotide probes labeled with different binary combinations of dyes will further enhance the potential of multicolor FISH (pg. 5142 column 1 ¶ 2). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the imaging and analysis of cellular RNAs by in situ fluorescence.
Conclusion
15. No claims are allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN ELLIS YOUNG whose telephone number is (703)756-5397. The examiner can normally be reached M-T 0800 - 1630.
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/BRIAN ELLIS YOUNG/Examiner, Art Unit 1684
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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