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
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are still pending and herein discussed on their merits.
Priority/Benefit
Claim to the benefit of provisional application 63/412,375 is acknowledged, and the effective filing date of the instant application is considered to be 10/01/2022.
Information Disclosure Statement
Information disclosure statements from 3/18/24 and 12/12/23 have been received. The IDS entries from 12/12/23 have been crossed out and not considered, as they are duplicates of the entries from 3/18/24.
Claim Rejections - 35 USC § 112
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 36 and 37 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.
Regarding claims 36 and 37, it is unclear whether the language of claims 36 and 37 requires “the RCA product” to be inclusive of both the product from extending a primer and the primer itself. The instant application’s specification states that product or complex of the exogenous primer comprises a primer extension product (paragraph 010). As this definition is circular, the meaning of extension product and therefore RCA product remain unclear.
Additionally, the specification allows that the primer can comprise natural or synthetic nucleotides (paragraph 0083), examples of which include crosslink-able modified nucleotides like aminoallyl-dUTP (paragraph 0087). However, there is no discussion of modifications such as locked nucleic acids, which affect target binding properties. Therefore, one of skill in the art cannot determine the metes and bounds of the claimed subject matter in order to avoid infringement, and the claims are considered indefinite.
Claim Rejections - 35 USC § 102
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 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.
Claims 1, 3, 6, 7, 10, 20, 27, 41, 49, 50, 53, 56, 71-74, and 75 are rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Church et al. 2018 (U.S. Patent No. 10,138,509, issued 11/27/2018). The rejection of claim 6 is further evidenced by Thermo Fisher Scientific 2015 (accessed through: https://web.archive.org/web/20151024160411/https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/amine-reactive-crosslinker-chemistry.html).
Church et al. teaches methods of making a three-dimensional matrix of nucleic acids for the purposes of analysis (col 1, lines 24-26).
Regarding claim 1, Church teaches contacting a fixed biological sample with an agent to form a crosslinked matrix (col 5, lines 15-20), and then using a polymerase to generate a rolling circle amplification (RCA) product (col 8, lines 32-35). Although the reference does not explicitly teach that the RCA product is not covalently attached to the crosslinked matrix, the order of steps and neutralization of the crosslinker before RCA would be consistent with that limitation. In addition, the reference does teach that the RCA product may be immobilized within the matrix by steric factors or non-covalent bonds (col 6, lines 32-40).
Regarding claims 3, 6, and 7, Church teaches a crosslinking agent which comprises a plurality of functional groups A which are reactive with amines (“functional group B”) (col 4, lines 47-57). Although the reference does not explicitly teach that functional group A reacts with α- and ε-amino groups but not an aromatic amino group, it does teach suitable functional crosslinking groups (including amine-reactive groups generally and succinimide esters specifically) which are congruent with those limitations (col 4, lines 55-61; see excerpt from Thermo Fisher included below).
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Regarding claim 10, Church teaches a crosslinked matrix which has not been covalently bound to exogenous molecules (col 12, lines 28-50). In the cited embodiment, Church teaches circularizing endogenous cDNA generated in situ in a fixed sample and then using a crosslinking agent BS(PEG)9 to generate a crosslinked matrix. With this order of steps, the crosslinked matrix would be bound with endogenous and not exogenous molecules.
Regarding claims 26 and 27, Church teaches generating RCA product from circularized cDNA or a probe set hybridized to a nucleic acid in the sample (col 13, lines 14-21; col 12, lines 44-46). In this embodiment, the RCA primers serve as the set of probes which hybridize to nucleic acid (in the form of circularized cDNA) within the sample.
teaches generation of RCA product from circularizable probes hybridized to cDNA generated from mRNA (pg 395, col 2, 1st-2nd full paragraphs).
Regarding claims 36 and 37, Church teaches an embodiment where modified residues in the RCA product are not required (col 20, lines 27-35). Though the RCA products are not explicitly described as being either free of modified nucleic acid residues or composed only of naturally occurring residues, the specification states that nucleic acids within the invention’s three-dimensional matrix may be “naturally occurring” (col 4, lines 38-39). As the RCA products are nucleic acid molecules which reside in the three-dimensional matrix, it follows that they may also be composed of no modified or only naturally occurring nucleic acids.
Regarding claim 41, Church teaches an RCA product with a smaller diameter than a reference RCA product generated in a reference biological sample which was not subject to crosslinking prior to RCA (col 16, lines 4-7). Church does not explicitly teach the smaller RCA product in the same embodiment as a fixed and crosslinked biological sample. However, the principle underlying the smaller diameter (crosslinking of RCA products containing aminoallyl dUTP to one another) is present in several embodiments which are consistent with that embodiment, including Example 1: col 12, lines 46-51.
Regarding claims 49-50, Church teaches hybridizing a detectable probe to RCA product in a matrix using an identifier sequence in the RCA product and then detecting the signal from the detectable probe (col 12, lines 28-57).
Regarding claims 53 and 56, Church teaches detectable probes comprising a fluorescent label (col 10, lines 49-54) and fluorescence imaging (col 6, lines 8-31).
Regarding claims 71 and 72, Church teaches a crosslinking agent comprising a bis(sulfosuccinimidyl)suberate moiety with polyethylene glycol (PEG) spacers (col 12, lines 28-40).
Regarding claims 73-74, Church teaches a specific order of steps for sample analysis comprising: 1) contacting the fixed biological sample with circularizable probes and circularizing them, 2) crosslinking the sample, wherein the crosslinker does not react with the circularizable probe, 3) generating and RCA product, 4) adding a detectable probe and detecting its signal (col 12, lines 28-60). In this embodiment, crosslinking occurs before and after circularization instead of only after circularization. However, since claim 73 describes the method using the term ‘comprises,’ the orders of steps in Church’s embodiment are consistent with the limitations of the claim. Additionally, although crosslinking occurs before circularization, the crosslinking agent is neutralized before the probe set (‘RCA primer’ in the reference) is added to the sample (col 12, lines 37-46), meaning that the probe set does not react with the crosslinking agent.
Claims 1, 49, and 54 are rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Lee et al. (Lee et al. 2015. Nat Protoc 10, 442–458).
Lee et al. teaches methods for sample analysis which include contacting a fixed biological sample (pg 450, Procedure: 1(A) or 1(B)) with a crosslinking agent (pg 451, Procedure: 4), and then generating a rolling circle amplification product wherein the RCA product is not covalently linked to the crosslinked matrix (pg 451, Procedure: 14).
Lee also teaches contacting the sample with a detectable probe that hybridizes to an RCA product, wherein the probe comprises a region for binding to a fluorescently labeled probe, and then detecting the signal associated with that probe at a location in the sample (pg 442, col 2, 1st full paragraph). In this case, the detectable probe is a sequencing primer which hybridizes to an identifier sequence called an adapter in the RCA product and the fluorescently labeled probe binds to the detectable probe via ligation reaction (Figure 1b).
Claims 1 and 75 are rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Weibrecht et al. (Weibrecht et al. 2013. Nat Protoc 8, 355–372).
Weibrecht et al. teaches methods of analyzing biological samples comprising steps in the following order: 1) providing a fixed biological sample (pg 357: Preparation of starting material), 2) contacting sample with a crosslinking agent (pg 358: Postfixation), 3) contacting sample with circularizable probe set that binds the analyte and circularizing it (pg 358: RNaseH Digestion, hybridization, and ligation with Ampligase), 4) performing rolling circle amplification in which the product is not crosslinked to the matrix (pg 359: RCA), and 5) contacting the sample with a detectable probe that hybridizes to the RCA product then detecting a signal associated with the probe (pg 359: Detection probe hybridization).
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 5 is rejected under 35 U.S.C. 103 as being unpatentable over Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018) as applied to claims 1 and 3 above, in view of Thermo Fisher Scientific Inc. (DSS and BS3 Crosslinkers, published 2018, found at https://documents.thermofisher.com/TFS-Assets/LSG/manuals/MAN0011240_DSS_BS3_CrsLnk_UG.pdf) and Huang et al. (Huang et al. 2020. Genome Biol: 21, 225).
The teachings of Church (as evidenced by Thermo Fisher) are presented above. Church also teaches that in situ assays are important because spatial information provides clues to the function of RNA (col 1, lines 31-33).
Regarding claim 5, Church does not teach RCA in a sample where the crosslinking agent reacts with sample endogenous molecules comprising extracellular matrix components.
However, Thermo Fisher teaches crosslinking agents which are consistent with the instant application’s claims and known to be useful for cell-surface protein crosslinking (Thermo Fisher 2018: Introduction, 2nd paragraph).
Additionally, Huang et al. teaches that the function of RNAs on the cell surface are largely unknown but implicated in important cellular functions (Huang: Introduction, 1st paragraph).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention to modify Church in view of the teachings of Thermo Fisher and Huang in order to crosslink cell surface extracellular matrix components before performing in situ RCA, based on the teachings in Huang that investigating RNAs on the cell surface would be desired in order to understand important biological mechanisms like cell signaling and extracellular matrix anchoring involving RNAs (Huang: Introduction, 1st paragraph).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018) as applied to claim 1 above, in view of Gradinaru et al. (Patent Publication No. 2017/0199104, published 7/13/2017).
The teachings of Church (as evidenced by Thermo Fisher) are presented above.
Church does not teach the biological sample not being subject to clearing, lipid digestion/extraction, or protein digestion/extraction.
Gradinaru et al. teaches methods of rendering tissues transparent for analysis and stabilizing tissue architecture which do not degrade/extract proteins, so they can be later interrogated with microscopy (paragraphs 0046, 0053).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention to modify Church in view of the teachings of Gradinaru in order to conduct in situ microscopic analysis of proteins and nucleic acids while preserving tissue architecture (paragraph 0046).
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 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Hauling et al. (U.S. Patent No. 11,352,667), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (claim 1). Both sets of claims require:
forming a crosslinked matrix in a biological sample (ref claim 15), then
generating a rolling circle amplification product (ref claim 18)
Although the reference does not explicitly require that the crosslinked matrix not be covalently bound to residues in the RCA product, other elements are described as being crosslinked (ref claim 15), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, it does direct its claims to cell or tissue samples (ref claim 18), and fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20).
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of Neuta et al. (U.S. Patent No. 12,139,751) in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
forming a crosslinked matrix in a biological sample (ref claim 1, 13), then
generating a rolling circle amplification product (ref claim 13)
Although the reference does not explicitly describe that the crosslinked matrix is not covalently bound to residues in the RCA product, other elements of the assay are described as being immobilized in the matrix, immobilization occurs prior to amplification (ref claim 13), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20).
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Stahl et al. U.S. Patent No. 12,215,379), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
forming a crosslinked matrix in a biological sample (ref claim 5), then
generating a rolling circle amplification product (ref claim 1)
Although the reference does not explicitly describe that the crosslinked matrix is not covalently bound to residues in the RCA product, other elements of the assay are described as being immobilized in the matrix, immobilization occurs prior to amplification (ref claim 5), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the sample is fixed prior to crosslinking, fixing of biological samples such as those containing chromatin (claims 1 and 5) prior to crosslinking is conventional (Church: col 5, lines 15-20).
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of Delaney et al. (U.S. Patent No. 12,258,624), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
generating a rolling circle amplification product (ref claim 1)
in a crosslinked matrix in a fixed biological sample (ref claim 1, 2, 3, 14)
Although the reference does not explicitly describe that the crosslinked matrix is not covalently bound to residues in the RCA product, other elements of the assay which are described as being immobilized in the matrix, immobilization occurs prior to amplification (ref claim 1), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the sample is fixed prior to crosslinking, it does direct its claims toward biological samples such as tissue (claims 13, 14), and fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20).
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Daugharthy et al. (U.S. Patent No. 12,297,499), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1).
Both sets of claims require:
forming a crosslinked matrix in a biological sample (ref claim 2), then
generating a rolling circle amplification product (ref claim 16)
Although the reference does not explicitly describe that the crosslinked matrix is not covalently bound to residues in the RCA product, other elements of the assay are described as being immobilized in the matrix, immobilization occurs prior to amplification (ref claim 2), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the sample is fixed prior to crosslinking, fixation of biological samples, such as those containing nucleic acids (claim 1), is conventional (Church: col 5, lines 15-20).
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-, 39, 48-49, 52, 55, 58, 61, 68, 76, 79, 82, 87, 90, 92-94, 111, 116-117, 139, and 141 of Bava 2021 (Patent Application 17/346,079), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
generating a rolling circle amplification product (ref claim 76) in a crosslinked matrix in a biological sample (ref claim 82, 87)
Although the reference does not explicitly describe that the matrix is crosslinked, the matrices in which biological samples are embedded are often crosslinked (Church: col 5, lines 6-13). Although the reference does not specify that the matrix is not covalently bound to residues in the RCA product, embedding of the sample in the matrix occurs before RCA (ref claim 87), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8, 9, 11, 15, 20, 22, 25, 27, 30, 36, 42, 47, 49, 52, 54, and 67 (Patent Application 17/853,256), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1, 22). Both sets of claims require:
forming a crosslinked matrix in a biological sample (ref claim 42) and
generating a rolling circle amplification product (ref claim 22, 30)
Although the reference application does not explicitly require that the RCA product be non-covalently attached to the matrix, the requirement that the matrix-forming happens concurrently with or prior to producing the RCA product (ref claim 42) is consistent with that limitation of the instant application, and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40).
Although the reference application does not explicitly require that the biological sample be fixed prior to crosslinking, it does direct the claims to samples such as tissue samples (ref claim 54) and fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 150-169 of Daugharthy et al. (Patent Application 17/875,211), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 177). Both sets of claims require:
contacting a biological sample with a crosslinking agent (ref claim 150), then
generating a rolling circle amplification product (ref claims 165)
Although the reference application does not explicitly require that the RCA product be non-covalently attached to the matrix, the requirement that the matrix-forming attaches to the analyte (ref claim 150) is consistent with that limitation of the instant application, and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 12, 14, 18-19, 21-25, 27-29, and 31 of Costa et al. (Application No. 18/088,330), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1, 21, 27). Both sets of claims require:
generating a rolling circle amplification product (ref claim 1, 21, 27)
in a matrix in a biological sample (ref claim 1, 21, 22)
wherein the RCA product is not covalently attached to the matrix (1, 21, 22)
Although the reference does not explicitly specify that the matrix is crosslinked, methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 6, 9, 11-12, 15-17, 21-23, 25, 28-29, 38, 44, 66, 106 of Jakobsen et al. (Patent Application 18/313,251), in view of Lee et al. (Lee et al. 2015. Nat Protoc 10, 442–458).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1).
Both sets of claims require:
contacting a fixed biological sample with a crosslinking agent (ref claim 38)
Although the reference claims do not require that there be rolling circle amplification product in the crosslinked matrix, the claims are directed to detection of analytes using methods including sequencing by ligation (ref claim 66), which can require generating a rolling circle amplification product (Lee: pg 442, col 2, 1st paragraph). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 18, 20, 24, 26-27, 30, 45-48, 56 of Kuhnemund (Patent Application 18/313,256), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
generating a rolling circle amplification product (ref claim 1)
in a matrix in a biological sample (ref claim 46, 47)
wherein the RCA product is not covalently attached to the matrix (ref claim 9)
Although the reference does not explicitly specify that the matrix is crosslinked, the matrices in which biological samples are embedded are often crosslinked (Church: col 5, lines 6-13). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 8, 10-11, 17, 24-28, 31-34, 45-46, 68 of Costa et al. (Patent Application 18/391,284), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 68). Both sets of claims require:
contacting a biological sample with a crosslinking agent (ref claim 1, 33, 68),
generating a rolling circle amplification product (ref claims 46, 68)
Although the reference application does not explicitly require that the RCA product be non-covalently attached to the matrix , other elements of the assay are described as being immobilized in the matrix, immobilization occurs prior to amplification (ref claim 1, 46, 68), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 11, 15, 22, 28-29, 32-33, 45, 52-53, 79-80, 85, 94-95, 109-110 of Feng et al. (Patent Application 18/478,248), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1, 29). Both sets of claims require:
contacting a biological sample with a crosslinking agent (ref claim 1),
generating a rolling circle amplification product in the crosslinked matrix (ref claims 85)
Although the reference does not explicitly specify that the matrix is not covalently bound to residues in the RCA product, crosslinking can happen to the probe instead (ref claim 1), which is consistent with the instant claim’s limitations, and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 56-75 of Mignardi (Patent Application 18/653,257), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 56).
Both sets of claims require:
contacting a fixed biological sample (ref claim 56, 73) with a crosslinking agent (ref claim 56, 69, 71, 74), and
generating a rolling circle amplification (RCA) product in the crosslinked matrix (ref claims 59, 60)
Although the reference application does not explicitly state that the RCA product not be covalently bound to the crosslinked matrix, the process of crosslinking is directed toward a probe and not the RCA product (ref claim 56), which is consistent with the limitations of the instant application, and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21, 23-24, 26, 28, 31, 36-37, 40, 43-44, 50-51, 55, 57, 58-60, 124 of Costa et al. (Patent Application 18/661,391), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claims 1, 38). Both sets of claims require:
contacting a biological sample with a crosslinking agent (ref claim 21),
generating a rolling circle amplification (RCA) product in the crosslinked matrix (ref claims 37)
Although the reference application does not explicitly state that the RCA product not be covalently bound to the crosslinked matrix, the process of crosslinking is directed toward a probe and not the RCA product (ref claim 56), which is consistent with the limitations of the instant application, and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 13-14, 16, 21, 35-37, 44-45, 51, 57, 69, 72 of Bent et al. (Application No. 18/818,462), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
generating a rolling circle amplification product (ref claim 13, 69)
in a crosslinked matrix in a biological sample (ref claim 1, 69)
Although the reference does not explicitly specify that the sample is fixed, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). Although the reference does not explicitly specify that the matrix is not covalently bound to residues in the RCA product, covalent attachment to the matrix is not required by the claims in the reference, embedding in the crosslinked matrix can occur before RCA (ref claim 69), and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 146-165 of Costa et al. (Patent Application 18/955,449), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 146). Both sets of claims require:
contacting a biological sample with a crosslinking agent (ref claim 146), and then
generating a rolling circle amplification (RCA) product in the crosslinked matrix (ref claims 157, 158)
Although the reference application does not explicitly state that the RCA product not be covalently bound to the crosslinked matrix, the process of crosslinking is not directed toward the RCA product (ref claim 146, 157, 158), which is consistent with the limitations of the instant application, and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7, 11, 14, 19-20, 25, 29, 31-32, 42, 46, 53, 58, 60, 65, 71 of Mignardi (Patent Application 19/053,140), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are directed to methods of sample analysis (ref claim 46). Both sets of claims require:
generating a rolling circle amplification product (ref claim 1) in a crosslinked matrix in a biological sample (ref claim 1, 29, 31, 46)
Although the reference application does not explicitly state that the RCA product not be covalently bound to the crosslinked matrix, the process of crosslinking is not directed toward the RCA product (ref claim 1, 29, 31), occurs prior to RCA, and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference does not explicitly require that the biological sample is fixed prior to crosslinking, fixing samples prior to crosslinking is conventional (Church: col 5, lines 15-20).This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 120-149 of Delaney et al. (Patent Application 19/059102), in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. . Both sets of claims are directed to methods of sample analysis (ref claim 146-147). Both sets of claims require:
using a polymerase to generate a rolling circle amplification product (ref claim 120) in a crosslinked matrix (ref claim 124, 125) in a fixed biological sample (124-125, 148)
Although the reference does not explicitly specify that the matrix is not covalently bound to residues in the RCA product, covalent attachment to the matrix is not required by the claims in the reference and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). Although the reference claims are directed to an RCA-based detection system (ref claim 120) and not to a method, it would be obvious to employ the instant application’s method through the use of the reference’s system. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-87 of Patent Application 19/327,701, in view of Church et al. (U.S. Patent No. 10,138,509, issued 11/27/2018).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
generating a rolling circle amplification product (ref claim 44)
in a crosslinked matrix (ref claim 56, 77) in a fixed biological sample (73)
Although the reference does not explicitly specify that the matrix is not covalently bound to residues in the RCA product, covalent attachment to the matrix is not required by the claims in the reference and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5, 6-7, 10, 20, 26-27, 36-37, 41, 49-50, 53-54, 56, 71-75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-86 of Patent Application 19/382,920, in view of [reference].
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of sample analysis (ref claim 1). Both sets of claims require:
generating a rolling circle amplification product (ref claim 1)
in a crosslinked matrix (ref claim 78, 80) in a fixed biological sample (ref claim 74, 75)
Although the reference does not explicitly specify that the matrix is not covalently bound to residues in the RCA product, covalent attachment to the matrix is not required by the claims in the reference and methods of immobilizing RCA products by steric factors or non-covalent bonds are conventional (Church: col 6, lines 32-40). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/C.M.J./ Examiner, Art Unit 1682
/AMANDA HANEY/ Primary Examiner, Art Unit 1682