Detailed Action
► The applicant's Preliminary Amendment filed 17 MAR 2025 has been entered. Following the entry of the Preliminary Amendment, Claim(s) 31-51 is/are pending.
► The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.
35 U.S.C. 103
► 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 Rejection(s) under 35 U.S.C. 103
► Instant Claim(s) 31, 33-34 and 41-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Church et al.[US 2018/0051322 – hereinafter “Church”] in view of . Collins et al. [ US 2001/0026918 – hereinafter “Collins”]
Instant Claim 31 is drawn to a method of processing a biological sample which comprises :
(a) providing said biological sample comprising a ribonucleic acid (RNA) molecule; (b) hybridizing a nucleic acid molecule to said RNA molecule, wherein said nucleic acid molecule comprises a first sequence complementary to said RNA molecule and a second sequence that is not complementary to said RNA molecule; (c) hybridizing a tethering oligonucleotide to said nucleic acid molecule, wherein said tethering oligonucleotide comprises a sequence complementary to said second sequence, and wherein said tethering oligonucleotide comprises a functional moiety; and (d) coupling said functional moiety of said tethering oligonucleotide to a three- dimensional (3D) matrix, thereby coupling said RNA molecule to said 3D matrix.
Church teach, see the entire document noting especially paras 6, 17,36-41 and 68-70, a method of to a method of processing a biological sample in order to detect target nucleic acid(s) (e.g. mRNA) which comprises most of the limitations of Claim 31 Church teach attaching probes/primers/ oligonucleotides (hereinafter oligos) to a Expansion microscopy- type 3D matrix via a functional moiety and then using said oligos in a method to detect a target nucleic acid, That said Church does not expressly teach the use of a nucleic acid molecule which comprises two parts: a first part which is complementary to a portion of the target mRNA molecule and a second portion, non-complementary to said target mRNA but rather complementary to a tethering oligonucleotides (i.e. intermediate oligonucleotide/probe). However the use of tethering /intermediate /bridging oligonucleotide probes of the type recited were known, consider at least Fig. 1 in Collins. There, Collins teach the use of a intermediate probe, ie. the CE=capture extender) which comprises a portion complementary to target and a second portion complementary to a tethering oligo (CP =capture probe of Collins which tethering oligo is immobilized to a solid support. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to modify the method of Church wherein an indirect means (i.e. via an intermediate/bridging-type oligonucleotide) is used to couple the target to the solid support (i.e. the 3D matrix) as taught by Collins rather than the direct means of Church. Please note that substitution of one known second method/reagent with known properties for a first known method/reagent with known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. As regards the motivation to make the substitution recited above, the motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making this obviousness rejection comes from the M.P.E.P. at 2144.07 and 2144.09, as well as, the SCOTUS decision in KSR International. Co. v. Teleflex, Inc., et al., 550 U.S.398 (2007).
As regards Instant Claim(s) 33-34 and 42 note that absent a showing, the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)).
As regards Instant Claim 41, see at least paras 6, 17 and 38-41 in Church wherein these inventors teach formation of an Expansion Microscopy- type 3D matrix..
As regards Instant Claim 43-49, see at least the rejection under 103 of Claim(s) 31 outlined above and/or the rejection under 103 of Claim(s) 35-38 outlined below..
As regards Instant Claim (s) 50-51, see at least paras 36 and Claim(s) 19-24 in Church.
► Instant Claim(s) 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Church et al.[US 2018/0051322 – hereinafter “Church”] in view of . Collins et al. [ US 2001/0026918 – hereinafter “Collins”] as applied above against Claim 31 and further in view of Shirai et al. [US 2011/0053150 – hereinafter “Shirai“].
As regards Instant Claim 32 note that Church teach reverse transcription from a primer thereby generating a cDNA which cDNA comprises a reverse complement of a sequence of an RNA, see at least paras 68-89. Furthermore note that Shirai, teach , see at least Fig.6 the solid phase extension of immobilized RT primer by reverse transcription on an RNA template which generates a reverse complement of a sequence of said RNA.
► Instant Claim(s) 35-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Church in view of . Collins as applied above against Claim 31 and further in view of Mignardi et al [Nucleic Acids Research 43(22) :e151 (2015 – hereinafter Mignardi”].
As regards Instant Claim(s) 35-38, note that Church teach hybridizing padlock probes, ligating the ends of said padlock probes and RCA followed by detection of said RCA product via probe hybridization and/or in situ sequencing , see especially paras 58-78. Church does not teach a gap filling embodiment of their method as it relates to the use of padlock probes However, gap filling embodiment of the padlock probe procedure were known, consider at least Fig. 1 of Mignardi.
As regards Instant Claim 39-40, see at least paras 36 and Claim(s) 19-24 of Church.
Non-Statutory Obviousness-type 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. See 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);and, 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) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b). It is noted that the doctrine of double patenting is also designed to protect third parties from harassment by multiple patent owners in connection with the same invention.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b). 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
NSODP Rejection(s)
► Instant Claim 31-51 is/are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over Claims 1-29 of U.S. Patent No. 11,193,163 – hereinafter “US-163’” in view of Church.
Although the conflicting claims are not identical, they are not
patentably distinct from each other. The scope encompassed by the invention recited in Claims 31-51 falls with the scope encompassed by the invention recited in Claims 1-29 of U.S. Patent No. 6,730,478.
Instant Claim 31 is drawn to a method of processing a biological sample which comprises :
(a) providing said biological sample comprising a ribonucleic acid (RNA) molecule; (b) hybridizing a nucleic acid molecule to said RNA molecule, wherein said nucleic acid molecule comprises a first sequence complementary to said RNA molecule and a second sequence that is not complementary to said RNA molecule; (c) hybridizing a tethering oligonucleotide to said nucleic acid molecule, wherein said tethering oligonucleotide comprises a sequence complementary to said second sequence, and wherein said tethering oligonucleotide comprises a functional moiety; and (d) coupling said functional moiety of said tethering oligonucleotide to a three- dimensional (3D) matrix, thereby coupling said RNA molecule to said 3D matrix.
The Claims of US-163’ teach/reasonably suggest a method for processing a biological sample which comprises all of the limitations of Instant Claim 31. As regards the limitation which requires the use of a tethering oligo comprising a functional moiety , consider especially Claim(s) 6-7 and 29 in US-163’.
As regards Instant Claim 32, see especially Claim 18 wherein US-163’ teach/ suggests reverse transcribing the target mRNA molecule.
As regards Instant Claim 33-34 and 42, absent a showing, the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)).
As regards Instant Claim 35, see especially Claim 26 wherein US-163’ teach/suggests
hybridizing a probe to a cDNA.
As regards Instant Claim(s) 36-39, see at least Claim(s) 8-15 in US-163’ wherein US-163’ teach/suggests the use of padlock probes and RCA..
Instant Claim(s) 40 is drawn to an embodiment of the method of Claim 31 wherein the functional moiety used is selected from a defined group of functional moiety comprises an amine, an acrydite, an alkyne, a biotin, an azide, a thiol, or an acryloyl group.
The Claims of US-163’ teach the use of functional moieties to couple their biomolecules to said 3D matrix but fail to teach the exact functional moieties recited. However, the use of the functional moieties recited to couple biomolecules to a 3-D matrix were known consider at least para 36 in Church..
Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to substitute the means of coupling of Church for that of US-163’. Please note that substitution of one known second method/reagent with known properties for a first known method/reagent with known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. As regards the motivation to make the substitution recited above, the motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making this obviousness rejection comes from the M.P.E.P. at 2144.07 and 2144.09, as well as, the SCOTUS decision in KSR International. Co. v. Teleflex, Inc., et al., 550 U.S.398 (2007).
Church teach the limitation(s) of Instant Claim 41, see especially paras 6, 17 and 38-41
Conclusion
C. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ethan Whisenant whose telephone number is (571) 272-0754. The examiner can normally be reached Monday-Friday from 8:30 am -5:30 pm EST or any time via voice mail. If repeated attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Anne Gussow, can be reached at (571) 272-6047.
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/ETHAN C WHISENANT/Primary Examiner, Art Unit 1683 ethan.whisenant@uspto.gov
EXAMINER SEARCH NOTES
25 NOV 2025 - ECW
Databases searched: All available via PE2E SEARCH
CAplus, Medline and BIOSIS via STNext; and Google Scholar (note the search terms used below)
Reviewed the parent(s), if any, and any search(es) performed therein : see the BIB data sheet
Reviewed, the search(es), if any, performed by prior examiners including any international examiners.
Planned Search
Search terms:
All Inventor(s) e.g. Daugharthy E?/au
ReadCoor
Expansion microscopy
3D matrix
Polymer$
mRNA OR DNA OR cDNA
probe$
(tether$ or bridg$ or intermediate) probe$
Solid (support or surface)
padlock probes
gap fill$
liga$
RCA
Hybridization
In situ sequencing
Functional moiety
Click chemistry
Amine
Alkene$
Biotin streptavidin or avidin
► See the Examiner’s PE2E SEARCH notes/strategy in IFW