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 .
Response to Remarks
Applicants’ arguments, filed on 06/30/2025, have been approved and entered.
They have been fully considered. Rejections and/or objections not reiterated from
previous office actions are hereby withdrawn. The following rejections and/or objections
are either newly applied or reiterated. They constitute the complete set presently
being applied to the instant application.
Claim Rejections - 35 USC § 102/103
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.
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.
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.
Claim(s) 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, 36, and 73-74 is/are rejected under 35 U.S.C. 103 as being unpatentable over Desai et al. (WO 2018175779, The paragraphs in the rejection are based on its US 20200224243 equivalent).
Desai et al. discloses a method named PLISH whereby a sample containing target RNA molecules is contacted with a first probe hybridizing to the target RNA and having a section which does not hybridize to said RNA (HR probe). Thereto a second probe hybridizes (Circle) which also comprises reporter moieties (this is viewed to be inclusive of claim 10). Following extension of the first probe, an extended product is generated that comprises a plurality of label regions each comprising an oligonucleotide sequence. The label regions on the same circle may thereby be different (this is viewed to be inclusive of claim 12). Desai et al. further discloses a third and fourth probe being used to generate a circular nucleic acid for rolling circle amplification. (See Fig. 1 A; claims 1, 25-28).
Desai et al. discloses a target site is a complementary region of the target nucleic acid to which a probe binds. A pair of probes in a probe set bind to a pair of different target sites that are sufficiently close together to allow simultaneous hybridization to a bridge oligonucleotide [0078] (this is viewed to be inclusive of instant claim 2: “the second probe comprises a second probe binding region that is complementary to, and hybridizes to, a second portion of the secondary oligonucleotide region different from the first portion of the secondary oligonucleotide region”)
With regards to claims 3 and 6, Desai et al. discloses a circle oligonucleotide comprises a first portion that hybridizes to a complementary region at the 5′ end of the 5′ overhang region of the first probe of a probe set, and a second portion that hybridizes to a complementary region at the 3′ end of the 3′ overhang region of the second probe of the probe set. Circular DNA forms where any two probes of a probe set bind sufficiently close to each other on one of the target nucleic acids to allow ligation of a bridge oligonucleotide and circle oligonucleotide that are hybridized to the two probes to generate a closed circle [0081]-[0082].
With regards to claims 14 and 17, Desai et al.’s FIG. 1C shows that up to five distinct transcripts can be simultaneously detected using five different barcode sequences (one unique sequence for each RNA), and five complementary imager oligonucleotides that are conjugated to spectrally-distinct fluorophores. Desai et al. discloses “A target site is a complementary region of the target nucleic acid to which a probe binds. …. Target sites are typically present on the same strand of the target nucleic acid in the same orientation. Target sites are usually selected to provide a unique binding site not present in other nucleic acids in the sample. Each target site is generally from about 18 to about 30 nucleotides in length, or any length within this range such as 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.[0078] (see also [0144]:PLISH represents a practical technology for multiplexed expression profiling in tissues. It combines high performance in four key areas: specificity, detection efficiency, signal-to-noise, and speed. The specificity derives from coincidence detection, which requires two probes to hybridize next to one another for signal generation. Efficient detection of low-abundance transcripts is accomplished by targeting multiple sites along the RNA sequence. Enzymatic amplification produces extremely bright puncta and allows many different RNA transcripts to be marked with unique barcodes in one step. The different RNA transcripts can then be iteratively detected to rapidly generate high dimensional data).
With regards to claim 21-24, 28-30, 36, Desai et al. discloses:
g) contacting each concatemer with one or more imager oligonucleotides, wherein each imager oligonucleotide comprises a detectable label and a nucleotide sequence complementary to one or more sites in the circular DNA sequence, wherein the imager oligonucleotide binds to said sites in the multiple copies of the circular DNA sequence of the concatemer; (viewed as the instant plurality of optical labels in claim 21 (a) and (b)); and h) detecting the bound imager oligonucleotides (viewed as the instant claim 21 (d)) [0008]. See also [0021] teaching: In another embodiment, subsets of the target nucleic acids are detected sequentially by a method comprising: a) contacting the sample with a subset of the imager oligonucleotides; b) performing a cycle of fluorescence imaging; c) removing the imager oligonucleotides from the sample (this is viewed to be inclusive of claim 36); d) contacting the sample with another subset of the imager oligonucleotides; e) performing another cycle of fluorescence imaging; and f) removing the imager oligonucleotides from the sample. The method may further comprise repeating steps (a)-(f) until all of the imager oligonucleotides have been used for detection of the plurality of target nucleic acids (this is viewed to be inclusive of claims 28-30).
Desai et al. discloses the sample is optionally washed to remove excess imager oligonucleotides. The target nucleic acids are detected by measuring a signal from the bound imager oligonucleotides. The sample can be imaged to reveal the location of the detectably labeled imager oligonucleotides complexed with the target nucleic acids [0068] (viewed as the instant claim 21 (e) and claim 24).
Exemplary detectable labels include fluorescent labels, bioluminescent labels, chemiluminescent labels, isotopic labels, nanoparticles, and metals [0012] (this is viewed to be inclusive of claims 22-23).
With regards to claims 25-26, Desai et al. discloses: In another embodiment, a plurality of probe sets comprising probes capable of hybridizing at a plurality of target sites on multiple target nucleic acids are used for multiplexed detection of a plurality of target nucleic acids. The method may further comprise using a plurality of circle oligonucleotides, wherein each circle oligonucleotide binds to a different probe set; and a plurality of imager oligonucleotides, wherein each imager oligonucleotide comprises a different detectable label. For example, each circle oligonucleotide may comprise one or more binding sites for a different imager oligonucleotide, such that different circle oligonucleotides are bound by different imager oligonucleotides comprising different detectable labels to allow different target nucleic acids to be detectably distinguished from one another [0011].
With regards to claims 32-34, Desai et al. discloses: FIGS. 3A-3D show multiplexed PLISH: rapid label-image-erase cycles, automated data analysis, and unsupervised cell classification. FIG. 3A shows the multiplexed PLISH experimental workflow. Probes for many different RNAs are hybridized and amplified in a single reaction. The PLISH amplicons marking four RNA species are then labeled with four fluorescent imager oligonucleotides, imaged on a microscope, and ‘erased’ by elimination of the imager oligonucleotides. Amplicons marking a different subset of four RNAs are then labeled with four new imager oligonucleotides, imaged, and erased. This cycle is repeated until all of the RNA species have been visualized and photo-documented. The images are automatically aligned and processed, and the signal for each RNA species in each cell is summed to produce single-cell expression profiles. [0033] . For multiplex assays, each RNA species can be detectably labeled in a unique color by using imager oligonucleotides with spectrally-distinct fluorophores. Fluorescence micrographs can be interpreted by direct visual inspection. Typically, up to five distinct channels can be simultaneously detected and imaged by conventional fluorescence microscopy, as well as allowing a determination of RNA abundance. [0097]. In certain embodiments, RNA species are imaged in sets of 5, with differently colored fluorophores associated with different targets (most fluorescence microscopes can only accommodate 5 color channels). In order to overcome the limit of 5 color channels on a typical fluorescence microscope, iterative rounds of staining, imaging and erasing can be used to colocalize large numbers of distinct RNA species in sequential images.[0100]
With regards to claims 7 and 20, they merely cover embodiments that fall into the range of the conventional for the skilled person.
With regards to claim 7, Desai et al. discloses f) performing rolling circle amplification, wherein each circular DNA molecule formed serves as a template to produce a concatemer comprising multiple copies of the circular DNA nucleotide sequence (this is viewed to be inclusive of at least 10 copies); g) contacting each concatemer with one or more imager oligonucleotides, wherein each imager oligonucleotide comprises a detectable label and a nucleotide sequence complementary to one or more sites in the circular DNA sequence, wherein the imager oligonucleotide binds to said sites in the multiple copies of the circular DNA sequence of the concatemer; and h) detecting the bound imager oligonucleotides ([0008] and claim 1).
With regards to claim 20, Desai et al. discloses “The terms “polynucleotide,” “oligonucleotide,” “nucleic acid” and “nucleic acid molecule” are used herein to include a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides” [0047]; “As used herein, the term “probe” or “oligonucleotide probe” refers to a polynucleotide, as defined above, that contains a nucleic acid sequence complementary to a nucleic acid sequence present in the target nucleic acid analyte. The polynucleotide regions of probes may be composed of DNA, and/or RNA, and/or synthetic nucleotide analogs. Probes may be labeled in order to detect the target sequence. Such a label may be present at the 5′ end, at the 3′ end, at both the 5′ and 3′ ends, and/or internally” [0056].
With regards to claims 73-74, Desai et al. discloses the term “detectable label” refers to a molecule or substance capable of detection, including, but not limited to, fluorescers [0060].
Therefore, one of ordinary skill in the art seeking to solve the stated problem, according to the circumstances, would have been motivated to modify the primary reference in the manner of the claims, without exercising inventive skill, to achieve the expected benefits, optimizations and/or expanded applications as this is well known practice in the art.
MPEP states wherein the “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Alter, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Routine optimization is not considered inventive and no evidence has been presented that the selection for the number of copies of the reporter moiety or for the label regions comprising a same number of nucleotides, was other than routine, that the products resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
Response to Arguments
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicants argue that the methods described in Desai differ from the claims at least in that Desai does not teach or suggest the feature in independent claim 1 of “wherein the reporter moiety comprises a plurality of label regions each comprising an oligonucleotide sequence; and wherein one or more of the label regions of the reporter moiety are different from the other label regions of the reporter moiety”. This is not convincing because it is noted that the reporter moiety with its label regions are a simple nucleic acid sequence. The nucleic acid sequence (= reporter moiety) to which the labelled probes of Desai bind can be seen as being made up of different label regions by, for example, dividing the said nucleic acid sequence in the three parts, which, evidently, are different from each other.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEZIA RILEY whose telephone number is (571)272-0786. The examiner can normally be reached 7:30-6:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEZIA RILEY/Primary Examiner, Art Unit 1681 27 August 2026
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