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 .
Election/Restrictions
Applicant’s election of (1) 3' end (polyA tail of mRNA targets); (2) RNA (nucleic acid mRNA transcript targets); and (3) in the reply filed on 6/12/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 59, 66, 68-69, 73-77, 80-92 are being examined.
Priority
The instant application was filed 01/11/2024 and is a continuation of 16348071 filed 05/07/2019, which is a national stage entry of PCT/US2017/060558 with an international filing date: 11/08/2017 and claims priority from provisional application 62569127 , filed 10/06/2017 and claims priority from provisional application 62419033 , filed 11/08/2016.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/2/2024, 6/12/2026 are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 59, 66, 68-69, 73-77, 80-92 are objected to because of the following informalities:
Claim 59 recites, “a method.” Claim are more concise and clearer when the preamble sets for the intended outcome of the claim.
Claim 81 recites, “nucleic caid probes.” This appears to be a typographical error and should be amended to recite, “nucleic acid probes.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 59, 66, 68-69, 73-77, 80-92 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163 IB New or amended claims section II
With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04 which provides that a "simple statement such as ‘applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation ‘___’ in the application as filed’ may be sufficient where the claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported."); see also MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure."); and MPEP § 2163.04
Independent claim 59 has been amended to recite, “A method, comprising: exposing a sample comprising nucleic acid mRNA transcript targets to a plurality of primary nucleic acid probes comprising a target binding sequence; exposing a sample to a plurality of anchor nucleic acid probes, wherein the anchor probes comprise a poly-dT portion that is complementary and hybridizes to the nucleic acid mRNA transcript targets; immobilizing the anchor probes to an expandable materialprimary nucleic acid probes to the nucleic acid mRNA transcript targets by imaging labeled secondary nucleic acid probes that hybridize to the primary nucleic acid probes.” The recitation of “exposing” encompasses bringing in to view. The response asserts the claims as amended are supported by the specification and claims as originally filed. Review and searching of the specification did not reveal support for “exposing a sample comprising nucleic acid mRNA transcript targets to a plurality of primary nucleic acid probes comprising a target binding sequence.” Thus the amendment is new matter. This rejection can be overcome by amending the claims to require contacting instead of exposing.
Claim 75 has been amended to recite, “wherein the plurality of primary nucleic acid probes comprises a first portion comprising a target sequence and a second portion comprising one or more read sequences.” Review and searching of the did not reveal antecedent basis for portion comprising a target sequence and a second portion comprising one or more read sequences. Thus the amendment has introduced new matter.
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 59, 66, 68-69, 73-77, 80-92 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.
Claim 59 recites, “exposing a sample comprising nucleic acid mRNA transcript targets to a plurality of primary nucleic acid probes comprising a target binding sequence; exposing a sample to a plurality of anchor nucleic acid probes, wherein the anchor probes comprise a poly-dT portion that is complementary and hybridizes to the nucleic acid mRNA transcript targets.” The metes and bounds are unclear how exposing (i.e. opening in the near vicinity) allows for hybridizing nucleic acids. This rejection can be overcome by amending the claim to require contacting.
Claim 77 recites, “the secondary nucleic acid probe.” The metes and bounds are unclear as the claim does not previously recite, “secondary nucleic acid probe.” Thus it is unclear what this recitation is referencing. This rejection can easily overcome by amending the claim to provide an indefinite article instead of a definite article.
Claim 84 recites, “the gel.” The metes and bounds are unclear as the claim does not previously recite, “gel.” Thus it is unclear what this recitation is referencing. This rejection can easily overcome by amending the claim to provide an indefinite article instead of a definite article.
Claims 88-90 recites, “the acrydite portion.” The claims do not previously recite, “acrydite portion.” Thus the metes and bounds are unclear what the recitation is referencing. This rejection can easily overcome by amending the claim to provide an indefinite article instead of a definite article. Further it is unclear if “acrydite portion” is limited to the acrydite, acrydite linker, etc.
Claim 91 recites, “ the expandable matrix.” The claims do not previously recite, “expandable matrix.” Thus the metes and bounds are unclear what the recitation is referencing.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 59, 66, 68-69, 73-7481-92 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen (WO2015127183), Baeissa ( Applied and material interface(2010) volume 2, pages 3594-3600), Deissorth (USPGPUB 20150144490), Kuhn (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 284, NO. 34, pp. 22803–22814, August 21, 2009) and Thomsen (RNA (2005) volume 11, pages 1745-1748).
Chen teaches, “[0007] The present invention is a method for optical imaging of biological specimens with resolution better than the classical microscopy diffraction limit, based on physically expanding the specimen itself. In this method, cultured cells, fixed tissue, or in principle other types of samples of interest, including biological materials, are infused with a composition, or chemical cocktail, that results in it becoming embedded in the sample material, and then the composition can be expanded isotropically, preferably with nanoscale precision, in three dimensions.”
Chen teaches, “[0008] In an embodiment of this concept, the composition comprises a polyelectrolyte hydrogel ( or the components thereof), which can swell macroscopically, for example, in low-salt water. The composition can comprise a tag or other feature of interest (for example, fluorescent dye molecules that have been delivered to the biological sample via antibody staining) which can be anchored (e.g., chemically) into the hydrogel before expansion. Following anchoring, the specimen is subjected to an enzymatic digestion ( or other digestion) to disrupt the underlying network of biological molecules, leaving the tags of interest (e.g., the fluorescent dye molecules) intact and anchored to the gel. In this way, the mechanical properties of the gel-biomolecule hybrid material are rendered more spatially uniform, allowing isotropic expansion with minimal artifacts.”
Chen teaches, “[0025] As used herein, the term "sample of interest" generally refers to, but not limited to, a biological, chemical or biochemical sample, such as a cell, array of cells, tumor, tissue, cell isolate, biochemical assembly, or a distribution of molecules suitable for microscopic analysis.”
Chen teaches, “ [0026] In a preferred embodiment, the sample of interest can be labeled or tagged. Typically, the label or tag will bind chemically ( e.g., covalently, hydrogen bonding or ionic bonding) to the sample, or a component thereof. The tag can be selective for a specific target (e.g., a biomarker or class of molecule), as can be accomplished with an antibody or other target specific binder. The tag preferably comprises a visible component, as is typical of a dye or fluorescent molecule. Contacting the sample of interest with a label or tag results in a "labeled sample of interest." A fluorescently labeled sample of interest, fix example, is a sample of interest labeled through techniques such as, but not limited to, immunofiuorescence, immunohistocbemical or immunocytochemical staining to assist in microscopic analysis. Thus, the label or tag is preferably chemically attached to the sample of interest, or a targeted component thereof. In a preferred embodiment, the label or tag, e.g. the antibody and/or fluorescent dye, further comprises a physical, biological, or chemical anchor or moiety that attaches or crosslinks the sample to the composition, hydrogel or other swellable material. The labeled sample may furthermore include more than one label. For example, each label can have a particular or distinguishable fluorescent property, e.g., distinguishable excitation and emission wavelengths. Further, each label can have a different target specific binder that is selective for a specific and distinguishable target in, or component of the sample.”
Chen teaches, “[0038] Anchor-able dye system: DNA sequences were ordered with 5' amine modification (Integrated DNA Technologies) and conjugated to secondary antibodies (Jackson ImmunoResearch) using a commercial kit (Solulink, Antibody-Oligonucleotide All-in-One Conjugation Kit). For the tertiary DNA/dye staining molecule, the complementary oligonucleotides are ordered with a 3' amine modification and a 5' Acrydite modification (Integrated DNA Technologies) and conjugated to dyes (Life Technologies and Sigma Aldrich) modified with NHS-ester chemistry per the manufacturer's directions. Conjugated DNA molecules were purified via reverse-phase HPLC, lyophilized and re-suspended in ddH20.” Thus the anchor dye system immobilizes the nucleic acid in the expandable material.
Chen teaches, “Following anchoring, the specimen is subjected to an enzymatic
digestion (or other digestion) to disrupt the underlying network of biological molecules,
leaving the tags of interest (e.g., the fluorescent dye molecules) intact and anchored to the gel. ln this way, the mechanical properties of the gel-biomolecule hybrid material arc
rendered more spatially uniform, allowing isotropic expansion with minimal artifacts.” (00008).
With regards to claim 1, Chen teaches tissue preparation (0040)including Slices were incubated with DNA-labeled secondary antibodies in hybridization buffer at a concentration of approximately 10 ug/mL for 6-12 hours, then washed in slice blocking buffer as for primary. Specimens were incubated with dye-labeled DNA tertiaries in hybridization buffer at a concentration of l ng/uL for 6-1 hours, then washed in slice blocking buffer as for primary.” Chen further teaches hydrogel embedding to anchor the probes via the acrylate modified 5’ end of the probes (0041). Chen teaches digestion of cell by digestion with proteinase K and expansion (0042). Chen teachings imaging (0043).
Thus Chen teaches exposing cells sample to the oligonucleotide modified with 5’ acrylate moieties, anchoring the target and modified oligonucleotide in the gel by expansion, digesting with proteinase K and imaging.
While Chen teaches the sampled can be analyzed for a specific target molecule or other target specific binder, Chen does not specifically teach detection of nucleic acids or nucleic acids probes or clearing to remove proteins.
However, Baeissa teach acrydite DNA (table 1). Baeissa teaches, “One is modified with an acrydite on the 5′ end to achieve covalent attachment to the polyacrylamide hydrogel matrix “ (page 3596, 1st column design of hydrogel based colorimetric DNA)
However, Deisseroth teaches methods of microscopic analysis. (abstract). Deisseroth teaches, “detection macromolecules, e.g., antibodies, nucleic acid probes ( oligonucleotides, vectors, etc.), chemicals, etc.; buffers, e.g., buffer for fixing, washing, clearing, and/or staining specimens; mounting medium; embedding molds; etc. Systems in accordance with certain embodiments may also include a microscope and/or related imaging equipment, e.g., camera components, digital imaging components and/or image capturing equipment, computer processors configured to collect images according to one or more user inputs, and the like”.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to substitute nucleic acid probes for the detection of nucleic acids by hybridizing sequences to target nucleic acids that have an acrydite anchor moiety . The artisan would be motivated to determine location the target nucleic acid in the cell following polymerization and expansion. The artisan would be motivated as Chen teaches a target specific binder, which the skilled artisan would recognizes complementary nucleic acids. The artisan would be motivated as use the acrydite linked DNA to anchor the sequences to the gel. The artisan would have a reasonable expectation of success as the artisan is merely substituting one detection macromolecule for another.
Chen, Baeissa, and Deissorth do not specifically teach the use of oligo dT or locked dT or two or more probes to one region.
However, Chen teaches, “.[0026] In a preferred embodiment, the sample of interest can be labeled or tagged. Typically, the label or tag will bind chemically ( e.g., covalently, hydrogen bonding or ionic bonding) to the sample, or a component thereof. The tag can be selective for a specific target (e.g., a biomarker or class of molecule), as can be accomplished with an antibody or other target specific binder. The tag preferably comprises a visible component, as is typical of a dye or fluorescent molecule. Contacting the sample of interest with a label or tag results in a "labeled sample of interest." A fluorescently labeled sample of interest, fix example, is a sample of interest labeled through techniques such as, but not limited to, immunofiuorescence, immunohistochemical or immunocytochemical staining to assist in microscopic analysis. Thus, the label or tag is preferably chemically attached to the sample of interest, or a targeted component thereof. In a preferred embodiment, the label or tag, e.g. the antibody and/or fluorescent dye, further comprises a physical, biological, or chemical anchor or moiety that attaches or crosslinks the sample to the composition, hydrogel or other swellable material. The labeled sample may furthermore include more than one label. For example, each label can have a particular or distinguishable fluorescent property, e.g., distinguishable excitation and emission wavelengths. Further, each label can have a different target specific binder that is selective for a specific and distinguishable target in, or component of the sample.”
Kuhn teaches, “Because the length of the poly(A) tail is important for its function, it is not surprising that poly(A) tails are generally synthesized with a defined length, which is species-specific, 70–90 nucleotides in Saccharomyces cerevisiae (13, 14) and 250 nucleotides in mammalian cells (15) “(22803, 2nd column, 1st full paragraph).
Thomsen teaches, “The usage of locked nucleic acid (LNA)-modified oligonucleotide probes has been shown to significantly improve the sensitivity and specificity of microRNA detection (Valoczi et al. 2004; Wienholds et al. 2005). LNA oligonucleotides are a new class of bicyclic RNA analogs that exercise an unprecedented high affinity for their complementary DNA or RNA targets (Koshkin et al. 1998). By using a design in which several positions in a conventional DNA oligonucleotide were substituted by LNAs, the sensitivity in detecting mature miRNAs by Northern blotting was increased by at least one order of magnitude (Valoczi et al. 2004). More recently, LNA-modified DNA-oligonucleotides were also used as FISH-probes on whole-mount zebrafish embryos to detect the temporal and spatial expression pattern of 115 conserved vertebrate miRNAs (Wienholds et al. 2005)” (page 1745, 1st column-2nd column). Thomsen teaches in table 1 probes with LNA from 32% of the probe to 35 % of the probe including oligo-dT of 20 nucleotides.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use oligo dT anchored to the gel including locked dT of Thomsen in the art as the tag(or label) or alternative as a replacement for the antibody to hybridize up to mRNA. The artisan would be motivated to take advantage of the unprecedented affinity and/or sensitivity in the method of detecting nucleic acids. The artisan would further be motivated to determining the location of poly-adenylated transcripts. The artisan would have a reasonable expectation of success as the artisan is merely substituting one nucleic acid or detection reagent for known oligo dT with LNA. (claims 59, 87)
With regards to claim 66, Chen teaches, “0038] Anchor-able dye system: DNA sequences were ordered with 5' amine modification (Integrated DNA Technologies) and conjugated to secondary antibodies (Jackson ImmunoResearch) using a commercial kit (Solulink, Antibody-Oligonucleotide 25 All-in-One Conjugation Kit). For the tertiary DNA/dye staining molecule, the complementary oligonucleotides are ordered with a 3' amine modification and a 5' Acrydite modification (Integrated DNA Technologies) and conjugated to dyes (Life Technologies and Sigma Aldrich) modified with NHS-ester chemistry per the manufacturer's directions. Conjugated DNA molecules were purified via reverse-phase 30 HPLC, lyophilized and re-suspended in ddH20.”
With regards to claim 68, Baeissa teaches, “One is modified with an acrydite on the 5′ end to achieve covalent attachment to the polyacrylamide hydrogel matrix “ (page 3596, 1st column design of hydrogel based colorimetric DNA). Chen teaches “Monomers or oligomers can comprise one 10 or more substituted or unsubstituted methacrylates, acrylates, acrylamides, methacrylamides, vinylalcohols, vinylamines, allylamines, allylalcohols, including divinylic cross linkers thereof (e.g., N, N-alkylene bisacry !amides).” (0027)
With regards to claim 69, Chen teaches “Monomers or oligomers can comprise one 10 or more substituted or unsubstituted methacrylates, acrylates, acrylamides, methacrylamides, vinylalcohols, vinylamines, allylamines, allylalcohols, including divinylic cross linkers thereof (e.g., N, N-alkylene bisacry !amides).” (0027)
With regards to claim 73, Chen teaches swellable in water (0027)
With regards to claim 74, Chen teaches water which is hypotonic to cells, tissue, etc.
With regards to claim 81-86, It would have been further prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims the use of proteinase K allows for the degradation of proteins (non-target cellular components), while leaving the target nucleic acids. The artisan would be motivated as Chen teaches the use of proteinase K. Chen specifically teaches, “, the specimen is subjected to an enzymatic digestion (or other digestion) to disrupt the underlying network of biological molecules, leaving the tags of interest (e.g., the fluorescent dye molecules) intact and anchored to the gel. ln this way, the mechanical properties of the gel-biomolecule hybrid material arc rendered more spatially uniform, allowing isotropic expansion with minimal artifacts.” (00008). The artisan would have a reasonable expectation of success as the artisan is merely using known means to degrade proteins.
With regards to claim 88-89, 91, Chen teaches, “0038] Anchor-able dye system: DNA sequences were ordered with 5' amine modification (Integrated DNA Technologies) and conjugated to secondary antibodies (Jackson ImmunoResearch) using a commercial kit (Solulink, Antibody-Oligonucleotide 25 All-in-One Conjugation Kit). For the tertiary DNA/dye staining molecule, the complementary oligonucleotides are ordered with a 3' amine modification and a 5' Acrydite modification (Integrated DNA Technologies) and conjugated to dyes (Life Technologies and Sigma Aldrich) modified with NHS-ester chemistry per the manufacturer's directions. Conjugated DNA molecules were purified via reverse-phase 30 HPLC, lyophilized and re-suspended in ddH20.”
While Chen teaches the a 5’ acrydite moiety for anchoring the oligodT, Chen does not specifically teach a 3’ acrydite moiety for anchoring the oligodT.
However Chen teaches a 3’ and 5’ amine linkage. Therefore it would have been prima facie3 obvious to one of ordinary skill in the art prior to the effective fling date of the claims to substitute a 3’ acrydite linkage for the 5’ linkage. The artisan would be motivated to use a 3’ acrydite moiety for anchoring the oligodT to replace 5’ acrydite moiety for anchoring the oligodT in order to determine if the location of the anchor acrydite altered hybridization, sensitivity or localization. The artisan would have a reasonable expectation of success as the artisan is merely linking the acrydite to the 3’ end instead of the 5’ end.
With regards to claim 92, Chen teaches, “spinning disk confocal post-ExM.” (0050)
Claim(s) 75-77, 80 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen (WO2015127183), Baeissa ( Applied and material interface(2010) volume 2, pages 3594-3600), Deissorth (USPGPUB 20150144490), Kuhn (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 284, NO. 34, pp. 22803–22814, August 21, 2009) and Thomsen (RNA (2005) volume 11, pages 1745-1748) as applied to claims 59, 66, 68-69, 73-7481-92 above, and further in view of Chen (Science (2015) volume 348, pages 412-)
The teachings of Chen, Baeissa, Deissort), Kuhn and Thomsen are set forth above. While Chen, Baeissa, Deissort), Kuhn and Thomsen detection of analytes by hybridization, they do not specifically teach the probes comprise a first portion and second portion, such a MerFISH.
However, Chen (science ) teaches, “Here, we report multiplexed error-robust FISH(MERFISH), a highly multiplexed smFISH imaging method that substantially increases the number of RNA species that can be simultaneously imaged in single cells by using combinatorial labeling and sequential imaging with error-robust encoding schemes. We demonstrated this transcriptome imaging approach by simultaneously measuring 140 RNA species with an encoding scheme that can both detect and correct errors and 1001 RNA species with an encoding scheme that can detect but not correct errors. Correlation analyses of the copy number variations and spatial distributions of these genes allowed us to identify groups of genes that are coregulated and groups of genes that share similar spatial distribution patterns inside the cell.: (page 1, middle column). Chen (science) teaches, “First, we label cellular RNAs with a set of encoding probes, each probe comprising a RNA targeting sequence and two flanking readout sequences. Four of the N distinct readout sequences were assigned to each RNA species base on the N-bit MHD4 code word of the RNA. Second, we identified these N readout sequence with complementary FISH probes (the readout probes) via N rounds of hybridization and imaging, each round using a different readout probe. To increase the signal-to-background ratio, we labeled every cellular RNA with ~192 encoding probes. Because each encoding probe contained two of the four readout sequences associated with that RNA (Fig. 1E), a maximum of ~96 readout probes can bind to each cellular RNA per hybridization round. To generate the massive number of encoding probes required, we amplified them from array-derived oligonucleotide pools containing tens of thousands of custom sequences using a modified form of the oligo paint protocol comprising in vitro transcription followed by reverse transcription (fig. S3 and supplementary mate-rials, materials and methods, “Probe Synthesis”)(22, 23). This two-step labeling approach dramatically diminished the total hybridization time for an experiment; we found that efficient hybridization to the readout sequences took only 15 min, whereas efficient direct hybridization to cellular RNA required more than 10 hours.” (aaa6090-2)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to substitute the MERFISH method of Chen (science) for the detection method of Chen, Baeissa, Deissort), Kuhn and Thomsen. The artisan would be motivated as Chen science teaches, “we report multiplexed error-robust fluorescence in situ hybridization (MERFISH), a single-molecule imaging approach that allows the copy numbers and spatial localizations of thousands of RNA species to be determined in single cells. Using error-robust encoding schemes to combat single-molecule labeling and detection errors, we demonstrated the imaging of 100 to 1000 distinct RNA species in hundreds of individual cells. Correlation analysis of the ~104 to 10 6 pairs of genes allowed us to constrain gene regulatory networks, predict novel functions for many unannotated genes, and identify distinct spatial distribution patterns of RNAs that correlate with properties of the encoded proteins.” The artisan would be motivated as the artisan is substituting one method of labeling and detection for another method of labeling and detection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 59, 66, 68-69, 73-77, 80-92 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 119-124, 126, 129-130, 132-134, 136-137, 146, 170-173 of copending Application No. 18/391,977. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to A method, comprising: exposing a sample comprising nucleic acid mRNA transcript targets to a plurality of primary nucleic acid probes comprising a target binding sequence; exposing a sample to a plurality of anchor nucleic acid probes, wherein the anchor probes comprise a poly-dT portion that is complementary and hybridizes to the nucleic acid mRNA transcript targets; immobilizing the anchor probes to an expandable materialprimary nucleic acid probes to the nucleic acid mRNA transcript targets by imaging labeled secondary nucleic acid probes that hybridize to the primary nucleic acid probes
The claims of 977 are drawn to A method, comprising: exposing a sample comprising nucleic acid targets to a plurality of MERFISH nucleic acid probes comprising a target binding sequence and one or more read sequences; exposing a sample to a plurality of anchor nucleic acid probes, wherein the anchor probes specifically hybridize to the nucleic acid targets; embedding at least a portion of the sample within a polyacrylamide gel; immobilizing at least some of the anchor nucleic acid probes to the polyacrylamide gel; clearing proteins and/or lipids and/or DNA and/or extracellular matrix and/or RNA molecules from the sample; and determining binding of the MERFISH nucleic acid probes to the nucleic acid targets by imaging the polyacrylamide gel wherein the MERFISH probes are contacted with a plurality of secondary nucleic acid probes comprising a fluorescent dye and a recognition sequence that hybridizes to the one or more read sequence of the MERFISH probe.
Thus it is prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims the claims of 977 are a species encompassed by the claims. Thus the claims of 977 at least render the instant claims obvious.
Dependent claims are obvious as they are commensurate in scope.
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683
Prosecution Insights