Patent Application 18310477 - MATRIX IMPRINTING AND CLEARING - Rejection

Patent Application 18310477 - MATRIX IMPRINTING AND CLEARING

Title: MATRIX IMPRINTING AND CLEARING

Application Information

• Invention Title: MATRIX IMPRINTING AND CLEARING
• Application Number: 18310477
• Submission Date: 2025-05-23T00:00:00.000Z
• Effective Filing Date: 2023-05-01T00:00:00.000Z
• Filing Date: 2023-05-01T00:00:00.000Z
• National Class: 435
• National Sub-Class: 006110
• Examiner Employee Number: 82354
• Art Unit: 1683
• Tech Center: 1600

Rejection Summary

• 102 Rejections: 0
• 103 Rejections: 4

Cited Patents

No patents were cited in this rejection.

Office Action Text

    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 without traverse of Group I, wherein clearing proteins and/or lipids from the sample comprises "degrading proteins";  * wherein clearing RNA and/or DNA and/or the extracellular matrix comprises "degrading extracellular matrix";  * wherein the acrydite portion is bound to the "5' end";  * wherein clearing comprises exposing the gel to a "proteinase";  * wherein imaging comprises using "epi-fluorescence microscopy"  in the reply filed on 4/14/2025is acknowledged.
Claims 172, 174, 181, 186-188 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/14/2025.
Claims 170-171, 173, 175-180, 182-185, and 189 are being examined.
Priority
	The instant application was filed 05/01/2023  and is a continuation of 16347874 , filed 05/07/2019, which is a national stage entry of PCT/US2017/060570 with an international filing date: 11/08/2017 and claims priority from provisional application 62419033 , filed 11/08/2016.  
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/22/2024 and 4/14/2025 are being considered by the examiner.
Drawings
The specification teaches, FIGS. 3A-3E illustrate a reduction of background in multiple color imaging, in yet another embodiment of the invention;.”  Thus the drawings appear to be in color.  “Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES

Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification (table 1) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).  Applicant should review the rest of the application and provide SEQ ID NO with any nucleotide or amino acid sequences.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); 
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter.  See 37 CFR 1.75(d)(1) and MPEP § 608.01(o).  Correction of the following is required: Claim 170 has been added by amendment and recites, “specifically hybridizes.”  Review and searching of the specification did not reveal antecedent basis for this limitation..
Claim Objections
Claims 170-171, 173, 175-180, 182-185, and 189 objected to because of the following informalities: 
The preamble of claim 170 recites, “method.”  Claims are more clear and concise when the preamble provides for the intended outcome of the intended claim.
Claim 170 is objected to as it recites “MERFISH” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented.  Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
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 170-171, 173, 175-180, 182-185, and 189  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

Claim 170 has been added by amendment and recites, “the anchor probes specifically hybridize to the nucleic acid targets.”  Review and searching of the specification did not reveal antecedent basis for the limitation.  Thus it appears to be 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 170-171, 173, 175-180, 182-185, and 189 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 170 recites, “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.”  The metes and bounds unclear what “MERFISH nucleic acid probes” require as the specification provides no definition of what is required.  MERFISH is generally considered an assay in which secondary probes hybridize to and allow identification or decoding of sequences.  Thus it is unclear what is required of “MERFISH nucleic acid probes.”  
Claim 170 recites, “exposing a sample to a plurality of anchor nucleic acid probes, wherein the anchor probes specifically hybridize to the nucleic acid targets;.”  The metes and bounds are unclear of what condition or step  exposing requires as  the wherein clause provides an intended outcome of exposing, but does not explicitly require hybridization to be performed.  Further the recitation of “specifically hybridizes” suggests there is non-specifically hybridizes.  The specification provides no specific guidance on how to differentiate “specifically hybridizes” from non-specifically hybridizes.  Thus the metes and bounds are unclear.
Claim 170 concludes with, “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.”  The metes and bounds are unclear as the wherein clause is not a positive active step.  Thus is unclear how or when and under what conditions the secondary nucleic acids probes are contacted with the MERFISh probes.
Claim 175 recites, “degrading DNA and/or RNA and/or extracellular matrix.”  The multiple and/or make the claim confusing and unclear what is required of the claim.
Claim 182 recites, “Triton X-100 (polyethylene glycol p-(1,,1,3,3- 13720367 tetramethylbutyl)-phenyl ether).  Triton X-2100 is a tradename or trademark.  MPEP 2173.05 (u) states, “trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. In fact, the value of a trademark would be lost to the extent that it became descriptive of a product, rather than used as an identification of a source or origin of a product. Thus, the use of a trademark or trade name in a claim to identify or describe a material or product would not only render a claim indefinite, but would also constitute an improper use of the trademark or trade name.”  Further it is unclear if the language in parenthesis is a limitation of the claim, preferred embodiment, or something else.
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) 170-171173, 175-176, 182-185 is/are rejected under 35 U.S.C. 103 as being unpatentable over  Chen (WO2015127183), and Zhuang (WO2016018960)
Chen teaches, “The present invention relates to an enlarged sample of interest for microscopy and methods for enlarging a sample of interest and the optical imaging of a sample of interest with resolution better than the classical microscopy diffraction limit, by synthesizing a swellable polymer network within a sample, it can be physically expanded, resulting in physical magnification.”
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, “ [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 a 20 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, immunobistocbemical 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 30 labeled sample may furthermore include more than one label. For example, each label can have a particular or distin1:,ruishable fluorescent property, e.g., distin1:,ruishable 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 an anchor moiety.
With regards to claim 170, Chen teaches tissue preparation (0040)including Slices were incubated with DNA-labeled secondary antibodies in hybridization buffer at a concentration of approximately lOug/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 lng/uL for 6-1 hours, then washed in slice blocking buffer as for primary.”  Chen further teaches hydrogel embedding  (polymerization) to anchor the probes via the acrylate modified 5’ end of the probes (0041).  Chen teaches digestion of DNA by digestion with proteinase K and expansion (0042).  Chen teachings imaging (0043).
Thus Chen anticipates the active steps of the claims by exposing ta fixed sample to the oligonucleotide modified with 5’ acryalate moieties, anchoring the target and modified oligonucleotide in the gel by polymerization, expanding, clearing the gel by use of a proteinase K and imaging. 
Chen teaches polymerization is a separate step followed by swelling or expansion (0027-0032) and (0041-0042). Chen (wo)  states, “[0035] In one embodiment, the addition of water allows for the embedded sample to expand 4x to 5x (e.g., 4.5x) or more its original size in 3-dimensions. Thus, the sample can be increased 100-fold or more in volume. This is because the polymer is embedded throughout the sample, therefore, as the polymer swells (grows) it expands the tissue as well. Thus, the tissue sample itself becomes bigger. Surprisingly, as the material swells isotropically, the anchored tags maintain their relative spatial relationship. [0036] The swollen material with the embedded sample of interest can be imaged on any optical microscope, allowing effective imaging of features below the classical diffraction limit. Since the resultant specimen is preferably transparent, custom microscopes capable of large volume, wide field of view, 3-D scanning may also be used in conjunction with the expanded sample.”
Chen does not specifically teach the use of MERFISH probes.
However, Zhaung teaches , “The following examples reports various techniques directed to single molecule imaging approaches that allow the copy numbers and spatial localizations of thousands of RNA species to be determined in single cells. Some of these techniques are called Multiplexed Error-Robust Fluorescence in Situ Hybridization or "MERFISH.”  
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 MERFISH probes in the methods of Chen.  The artisan would be motivated to be able to image and examine multiple up to thousands of RNA in a single sample.  The artisan would have a reasonable expectation of success as artisan is merely combining known techniques.   
With regards to claim 171, Chen teaches anchor to polyacrylamide gel (0026-0027). 
With regards to claim 173 and 175 , Chen teaches proteinase K digestion with degrades proteins which encompasses the extracellular matrix.  (0042) 
With regards to claim 176, Zhaung teaches detection of RNA (example 4)
With regards to claim 182-183, Chen teaches, “Proteinase K (New England Biolabs) was diluted to 200ug/mL in digestion buffer (50mM Tris pH8, lmM EDTA, 0.5% TritonXlO0, IM NaCl, 0.8M guanidine HCl)” (0042)
With regards to claim 184, Chen teaches, “[0032] In a preferred embodiment, the sample (e.g., a labeled sample) is anchored or crosslinked to the swellable material before expansion. This can preferably be accomplished by chemically crosslinking a tag or label with the swellable material, such as during or after the polymerization or in situ formation of the swellable material. ” 
With regards to claim 185, Chen teaches epifluorescence (0052).
Claim(s) 177-178 is/are rejected under 35 U.S.C. 103 as being unpatentable over  Chen (WO2015127183), and Zhuang (WO2016018960) as applied to claims 170-171173, 175-176, 182-185  above, and further in view of Thomsen (RNA (2005) volume 11, pages 1745-1748).
The teachings of Chen and Zhuang are set forth above.
Chen and Zhuang do not specifically teach the use of oligo dT or alternating oligo dT with locked dT.
However, 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.  
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 the oligo dT including locked dT of Thomsen in the art of as either the tag(or label) or alternative as a replacement for the antibody and in anchor probe in a gel.  The artisan would be motivated to take advantage of the unprecedented affinity and/or sensitivity in the method and determine if gel expansion alters specificity or distortion.  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.
Claim(s) 179-181 is/are rejected under 35 U.S.C. 103 as being unpatentable over  Chen (WO2015127183), and Zhuang (WO2016018960) as applied to claims 170-171173, 175-176, 182-185  above, and further in view of Schiboleth (US20150211023).
The teachings of Chen and Zhuang are set forth above.
Chen and Zhuang do not  specifically teach the acrydite modification of the 3’ or 5’ end.  
However, Shiboleth teaches methods of modify nucleic acid sequences (abstract).  Shiboleth suggests in paragraph 0036 that nucleic acids can be modified at the 5’ end, the 3’ end or at an internal location.  Shiboleth continues in paragraph 0034 to identify modifications including acrydite.
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 3’ end acrydite modified nucleic acids or internally acrydite modified nucleic acids in the method of Chen and Zhuang.  The artisan would be motivated to determine if the location of the acrydite  and or/ the level of expansion altered the specificity, sensitivity or location the target in the image following polymerization.  The artisan would have a reasonable expectation of success the artisan is merely using art accepted and known reagents, conditions, and methods. 
Claim(s) 189 is/are rejected under 35 U.S.C. 103 as being unpatentable over  Chen (WO2015127183), and Zhuang (WO2016018960) as applied to claims 170-171173, 175-176, 182-185  above, and further in view of Goldenberger (PCR Methods andAppllcotions (1995) volume 4, pages 368-370)).
The teachings of Chen and Zhuang are set forth above.
While Chen teaches, “Proteinase K (New England Biolabs) was diluted to 200ug/mL in digestion buffer (50mM Tris pH8, lmM EDTA, 0.5% TritonXlO0, IM NaCl, 0.8M guanidine HCl)” (0042)
Chen does not specifically teach the use of proteinase K and SDS.
However, Goldenberger teaches the use of SDS and proteinase K to digest proteins in a sample.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to substitute SDS and proteinase K for SDS and Triton X100.  The artisan would be motivated to use SDS with proteinanse K as it is known to be an activator of proteinase K and disrupts membranes.  The artisan would have a reasonable expectation of success as the artisan is merely substituting one detergent for another.
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.
Claims 170-171, 173, 175-180, 182-185, and 189 rejected on the ground of nonstatutory double patenting as being unpatentable over claim1—21  of U.S. Patent No. 10,526,649. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims 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; anddetermining 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.
The claims of 649 are drawn to  A method for in-situ sequencing of target nucleic acids present in a biological sample comprising the steps of: (a) permeating the sample with a composition comprising precursors of a swellable material; (b) initiating polymerization to form a swellable material, wherein the swellable material is bound to the small molecule linker or a nucleic acid adaptor to form a sample-swellable material complex; (c) adding an aqueous solvent or liquid to cause the sample-swellable material complex to swell, thereby physically expanding the complex to form an enlarged sample; (d) modifying the target nucleic acids or the nucleic acid adaptor to form a nucleic acid adaptor useful for sequencing; (e) in situ sequencing of the nucleic acids in the enlarged sample; (f) digesting the sample: (g) isolating the nucleic acids from the digested sample; and (h) in vitro sequencing of the nucleic acids.  Dependent claim 2 draws the invention to wherein prior to or after step (a) the sample is contacted with a small molecule linker or a nucleic acid adaptor comprising a binding moiety and an anchor, wherein the binding moiety binds to target nucleic acids in the sample; and wherein the anchor comprises a polymerizable moiety. Claim 11 draws the invention to wherein prior to step (c) the sample is subjected to a disruption of the endogenous physical structure of the sample.
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 649 are a genus that encompass the instant claims and thus are obvious variants.
Dependent claims are coextensive in scope and/or obvious variants of 649, in view of the record.
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