DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. 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 (modified)
2. Applicant's election with traverse of Group I, claims 1-2, 4, 6, 8, and 12 in the reply filed on 08/28/2025 is acknowledged. Applicant’s arguments/remarks to examine inventions of Group II claims 13, 16-18, 21-22, and 27 are considered and found persuasive. The restriction requirement for the inventions of Group II (claims 13, 16-18, 21-22, and 27) is withdrawn in this office action.
Applicant added new claims 71-79 (claim listing 05/27/2026).
Applicant cancelled claims 2, 6, 16, 22, 27, 30, 32-33, and 37 (claim listing 05/27/2026).
The modified Group I encompass claims 1, 4, 8, 12-13, 17-18, 21 and 71-77.
The inventions of previous Group III are now identified as modified Group II claims 28-30, 32-22, 37, and 39 are restricted.
The modified restriction requirement in view of applicant’s arguments/remarks as recited above is made FINAL.
Priority
3. This application is a national stage application, filed under 35 U.S.C. § 371, of International Patent Application No. PCT/US2020/055904 filed on October 16, 2020, which claims benefit of and priority to U.S. Provisional Patent Application No. 62/915,913 filed on October 16, 2019, and U.S. Provisional Patent Application No. 63/057,980 filed on July 29, 2020.
Status of Claims (modified)
4. Claims 1, 4, 8, 12-13, 17-18, 21, 28-29, 39, and 71-79 as filed on 05/27/2026 are pending.
5. Applicant cancelled claims 2, 6, 16, 22, 27, 30, 32-33, and 37 (claim listing 05/27/2026).
6. Modified Group II claims 28-30, 32-33,37 and 39 are withdrawn from consideration due to restriction/election.
7. Modified Group I claims 1, 4, 8, 12-13, 17-18, 21, and 71-77 (claim listing 05/27/2026) are under examination in this office action.
Information Disclosure Statement
8. The information disclosure statement (IDS) submitted on 01/30/2026 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
Claim Objections
9. Claims 78-79 are objected to because of the following informalities:
The new claims 78-79 are dependent on withdrawn claim 28. Applicant is required to indicate the status of the new claims that are dependent on a withdrawn claim 28.
Appropriate correction is required.
Claim Interpretation
10. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1: The invention of claim 1 is interpreted to be directed to a composition for detecting a biological target, the composition comprising: a nucleic acid barcode conjugated to a binding moiety; a CRISPR-Cas protein comprising a CRISPR RNA (crRNA) that can recognize and bind at least a portion of the nucleic acid barcode; and a reporter construct comprising a nucleic acid conjugated to a detectable signal molecule; wherein the binding moiety is an antibody or antigen binding fragment thereof, a fusion protein, an aptamer, a peptide-MHC, a lectin, a saccharide, or a multimeric construct; and wherein the binding moiety binds to the biological target, and wherein the biological target is a cell, protein, or small molecule; and wherein, when the crRNA is bound to at least a portion of the nucleic acid barcode, the CRISPR-Cas protein cleaves the nucleic acid of the reporter construct, thereby releasing the detectable signal molecule.
Claim 13: A method of detecting a biological target in a sample, the method comprising:
contacting the sample with the composition of claim 1, and
detecting presence or absence of the detectable signal molecule in the sample, thereby detecting presence or absence of the biological target.
Withdrawn Rejections
11. Withdrawn rejection of claims 35 U.S.C. 112(b) in view of applicant’s amendment of claims 1, 12, and 18 as per claim listing 05/27/2026.
Claim Rejections - 35 USC § 112 (a) Enablement Requirement
(rejection modified and maintained in view of amended claims)
12. The claims 1, 4, 8, 12-13, 17-18, 21, and 71-77 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for antibody, a barcoded probe binding to antibody and biological target recognized by antibody, CRISPR-Cas does not reasonably provide enablement for full scope of the biological target (any biological target). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C.1988). Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including the nature of the invention, the state of the prior art, the breadth of the claims, the amount of guidance in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, and the quantity of experimentation necessary. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention. The invention of claims 1, 4, 8, 12-13, 17-18, 21, and 71-77 are directed to detection of a biological target by using a bar-coded nucleic acid probe that is conjugated to a binding moiety (e.g. antibody, fusion protein, aptamer) through a first end and detectable signal molecule through second end. The probe is linked to the binding moiety by a poly A spacer sequence, and at least a portion of the nucleic acid barcode is recognized and bound by a CRISPR-Cas protein. The inventions, inter alia, comprises the nucleic acid barcode is RNA and is recognized and bound by type VI CRISPR-Cas proteins or the barcode is DNA is recognized and bound by type V CRISPR-Cas proteins.
Claim 13: The invention of claims 13 A method of detecting a biological target in a sample, the method comprising: a) contacting the sample with the composition of claim 1, and
detecting presence or absence of the detectable signal molecule in the sample, thereby detecting presence or absence of the biological target.
One of the ordinary skills is unable to envision all species and structure of a species of a genus “biological target” that encompass any species of a biological target, and all species and structure of a species of a genus “binding moiety” (e.g. antibody) that are recited in the inventions of the elected claims without reciting a specific structure in the claim limitation or even in the specification. The enablement for antibody or fragment thereof, a barcoded probe linked to antibody and biological target recognized by antibody as recited in the specification, however, does not reasonably provide enablement for full scope of the probe, full scope of binding moiety (e.g. antibody) and biological target (any biological target).
Working examples. The specification does not provide a working example a range of species that would be expected to encompass in a genus “biological target” and in a genus “binding moiety” that are recited in the inventions of the elected claims without reciting a specific structure in the claim limitation or in the specification. The applicant fails to provide evidence of embodiments encompassed by the claims e.g. claims directed to any CRISPR-Cas based detection of a biological target for the claimed genus or genera of “biological target” and in a genus or genera of “binding moiety” at the time of effective filing date of the invention. In the absence of applicant providing examples to satisfy the claim limitations directed to genus or genera of “biological target” and in a genus or genera of “binding moiety” (e.g. antibody) it is an extraordinarily high burden on one the ordinary skills to arrive at the claimed and enabled inventions based on the instant application specification. For the reasons discussed above, it would have required undue experimentation for one skilled in the art before the effective filing date of the claimed invention to practice over the full scope of the claimed invention.
The breadth of the claims: The claims 1, 4, 8, 12 and 71-77 are drawn to a product and the claims 13, 17-18, and 21 are drawn to the methods of use of the product. The claims are very broad due to the claim limitations reciting a genus “binding moiety” (e.g. antibody) and a genus “biological target” without specifying a structure”, however, defines the “binding moiety” and “biological target” by a function of binding. One of the ordinary skills in the art cannot envision “a species” or the structure of broad genus “binding moiety” and a genus “biological target”. There is unpredictability in the art the required function of “binding” of a “binding moiety to a biological target is broad because the binding of a binding moiety requires a specific structure to bind specifically a biological target for the diagnostics specificity and the claimed ultra sensitivity of the CRISPR-Cas based assay. The specification does not provide specific examples for the range of species and the structure of species that would encompass the genera “binding moiety” and “biological target”. It is unpredictable in the art and not possible to envision by one of the ordinary skills in the art as to how the function of “binding” by a generic “binding moiety could be achieved to bind to a generic “biological target” and yet the assay would be specific and ultra-sensitive for different numerous possible species of the biological targets encompassed in the claimed genus “biological target”.
Guidance in the specification: As indicated in the written description rejection above, the specification does not describe a specific structure of a species of a genus “binding moiety” (e.g. antibody) and a genus “biological target”. The claim limitations recite a genus “binding moiety” and a genus “biological target”. And not a species of antibody with a defined structure or CDR sequences, and without specifying a structure”, however, defines the “binding moiety” and “biological target” by a function of binding. One of the ordinary skills in the art cannot envision “a species” or the structure of broad genus “binding moiety” and a genus “biological target”. There is unpredictability in the art the required function of “binding” of a “binding moiety to a biological target is broad because the binding of a binding moiety requires a specific structure to bind specifically a biological target for the diagnostics specificity and the claimed ultra sensitivity of the CRISPR-Cas based assay. The specification does not provide specific examples for the range of species and the structure of species that would encompass the genera “binding moiety” and “biological target”. It is unpredictable in the art and not possible to envision by one of the ordinary skills in the art as to how the function of “binding” by a generic “binding moiety could be achieved to bind to a generic “biological target” and yet the assay would be specific and ultra-sensitive for different numerous possible species of the biological targets encompassed in the claimed genus “biological target”.
The level of one of ordinary skill. The level of skill required for PHOSITA is high that require a researcher with a PhD degree and several years of research experience or PHOSITA with a fresh PhD degree and guidance from highly experienced mentor, Professor who is leader in the field of research or Principal Scientist that has research experience in molecular biology, biochemistry, cell biology, cancer biology, virology, and genetic engineering.
Unpredictability of the art. The claims 1, 4, 8, 12 and 71-74 are drawn to a product (CRISPR-Cas based specific binding moiety conjugated barcoded nucleic acid detection probe) and the claims 13, 17-18, 21, and 75-77 are drawn to the methods of use of the product. The claims are very broad due to the claim limitations reciting a genus “binding moiety” and a genus “biological target” without specifying a structure”, however, defines the “binding moiety” and “biological target” by a function of binding. One of the ordinary skills in the art cannot envision “a species” or the structure of broad genus “binding moiety” and a genus “biological target”. There is unpredictability in the art the required function of “binding” of a “binding moiety to a biological target is broad because the binding of a binding moiety requires a specific structure to bind specifically a biological target for the diagnostics specificity and the claimed ultra sensitivity of the CRISPR-Cas based assay. The specification does not provide specific examples for the range of species and the structure of species that would encompass the genera “binding moiety” and “biological target”. It is unpredictable in the art and not possible to envision by one of the ordinary skills in the art as to how the function of “binding” by a generic “binding moiety could be achieved to bind to a generic “biological target” and yet the assay would be specific and ultra-sensitive for different numerous possible species of the biological targets encompassed in the claimed genus “biological target”. Both the genus “binding moiety” and a genus “biological target” would encompass the species in the specification as well as other species known in the art which go beyond the preferred constructs of the specification and prior art.
Zhou et al 2024 in an article reviewed “Tumor biomarkers for diagnosis, prognosis and targeted therapy” and provide evidence for early screening of tumors to date, thousands of these biomarkers including proteins, cytokines, metabolites, hormones, microRNA, and circulating DNA have been explored, and several of them have been successfully developed and used in the early screening of cancers (See, abstract, entire article).
Yang et al 2021 reviewed CRISPR-Cas diagnostic systems show high sensitivity and specificity in detecting cancer markers, but their unpredictability arises from technical challenges, including potential off-target effects. Despite significant improvements in this field, several technical challenges need to be addressed, such as off-target activity. The targeting specificity depends upon the gRNA of Cas9 and PAM sequences, and off-target cleavage in the genome (See, abstract, entire article).
Additionally, in the recently decided Amgen v. Sanofi (590 U.S. 594; 143 S.Ct. 1243 May 18, 2023) Supreme Court decision addressing enablement, the Court held that enablement of an unpredictably broad functional claim (e.g. functionally specific analogous antibodies) requires sufficient disclosure in light of the state of the prior art as to how to enable the making (e.g. protocols) and use for the full range of the claimed invention without unreasonable or undue experimentation.
For the reasons discussed above, it would have required an undue experimentation for one skilled in the art before the effective filing date of the claimed invention to practice over the full scope of the invention claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art. The enablement inquiry for claims that include functional requirements and there is unpredictability of the art and guidance in specification fall short is addressed in “Amgen v. Sanofi, Aventisub LLC, 987 F.3d 1080, 1086 (Fed. Cir. 2021)”.
Claim Rejections - 35 USC § 112, Written description
(rejection modified and maintained in view of amended claims)
13. 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.
The claims 1, 4, 8, 12-13, 17-18, 21, and 71-77 are 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 claims 1, 4, 8, 12-13, 17-18, 21, and 71-77 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.
The claims 1, 4, 8, 12 and 71-74 are drawn to a product and the claims 13, 17-18, 21 and 75-77 are drawn to the methods of use of the product. The product is directed to CRISPR-Cas system-based diagnostics comprising a binding moiety to which a barcoded nucleic acid fluorescent probe (DNA or RNA) is linked. The binding moiety specifically binds to a biological target and the CRISPR-Cas guide RNA recognizes and bind to a portion of a sequence in a barcoded nucleic acid probe. The binding moiety (that binds specifically to the biological target) is recited as an antibody or antigen binding fragment thereof, a fusion protein, an aptamer, a peptide-MHC, a lectin, a saccharide, or a multimeric construct. The claim limitation recites biological targets as cell-surface protein, an intracellular component, a cell surface receptor, a small molecule, a soluble protein, a cell, or a cancer-specific cell surface marker, an immune cell, a tumor cell, an antigen-specific cell, or a cancer stem cell. The biological target has different structures and biological function and are associated with different disease conditions. The methods claim limitations are directed to make use of the product to detect biological targets.
The breadth of the claims: The claims 1, 4, 8, 12 and 71-74 are drawn to a product and the claims 13, 17-18, 21 and 75-77 are drawn to the methods of use of the product. The claims are very broad due to the claim limitations reciting a genus “binding moiety” and a genus “biological target” without specifying a structure”, however, defines the “binding moiety” and “biological target” by a function of binding. One of the ordinary skills in the art cannot envision “a species” or the structure of broad genus “binding moiety” and a genus “biological target”. There is unpredictability in the art the required function of “binding” of a “binding moiety to a biological target is broad because the binding of a binding moiety requires a specific structure to bind specifically a biological target for the diagnostics specificity and the claimed ultra sensitivity of the CRISPR-Cas based assay. The specification does not provide specific examples for the range of species and the structure of species that would encompass the genera “binding moiety” and “biological target”. It is unpredictable in the art and not possible to envision by one of the ordinary skills in the art as to how the function of “binding” by a generic “binding moiety could be achieved to bind to a generic “biological target” and yet the assay would be specific and ultra-sensitive for different numerous possible species of the biological targets encompassed in the claimed genus “biological target”.
Guidance in the specification: As indicated in the written description rejection above, the specification does not describe a specific structure of a species of a genus “binding moiety” and a genus “biological target”. The claim limitations recite a genus “binding moiety” and a genus “biological target”. And not a species. without specifying a structure”, however, defines the “binding moiety” and “biological target” by a function of binding. One of the ordinary skills in the art cannot envision “a species” or the structure of broad genus “binding moiety” and a genus “biological target”. There is unpredictability in the art the required function of “binding” of a “binding moiety to a biological target is broad because the binding of a binding moiety requires a specific structure to bind specifically a biological target for the diagnostics specificity and the claimed ultra sensitivity of the CRISPR-Cas based assay. The specification does not provide specific examples for the range of species and the structure of species that would encompass the genera “binding moiety” and “biological target”. It is unpredictable in the art and not possible to envision by one of the ordinary skills in the art as to how the function of “binding” by a generic “binding moiety could be achieved to bind to a generic “biological target” and yet the assay would be specific and ultra-sensitive for different numerous possible species of the biological targets encompassed in the claimed genus “biological target”.
The specification does not provide a working example for a species within the claimed broad genus of “binding moiety” and a genus of “biological target” for the inventions of the elected claims. The invention of the elected claims 1, 4, 8, 12 and 71-74 are drawn to a product and the claims 13, 17-18, 21 and 75-77 are drawn to the methods of use of the product are drawn to different genera of the “binding moiety” and a “biological target. The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004).
To provide adequate written description and evidence of possession of a claimed genus, especially where the genus, especially where the genus requires a difficult to achieve and thus unpredictable function (e.g. function of binding of a “binding moiety” to a “generic or specific “biological target”) the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of using the claimed product, or any combination thereof. In this case, the only factor present in the claims is a genus “binding moiety” to a “generic “biological target” and a function binding.
There is no disclosure of any complete or partial structure of the said generic “binding moiety” and a “generic “biological target” component, physical and/or chemical properties of the component, structure/function correlation of the component, methods of using the component, or any combination thereof.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics for a generic “binding moiety” and a generic “biological target” the specification does not provide adequate written description of the claimed genus.
A definition by function alone does not suffice to sufficiently describe a coding sequence because it is only an indication of what the gene does, rather than what it is. EliLily, 119 F.3 at 1568, 43 USPQ2d at 1406. The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the detailed chemical structure encompassed by a genus “binding moiety” and a genus “biological target” capable of carrying out the claimed function”. Given that the specification has only described the function of a component, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph.
The applicant/inventor needs to show that they have truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, the applicant/inventor has only a research plan, leaving it to others to explore and figure out the unknown contours of the claimed genus." AbbVie Deutsch/and GmbH & Co. v. Janssen Biotech, 759 F.3d 1285, 1300 (Fed. Cir. 2014). "In other words, the test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad, 598 F.3d at 1351.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated: “A written description of an invention involving a chemical genus, like a description of a chemical species requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or sub-combinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representatives, the Courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618.
Claim Rejections - 35 USC § 102 (New)
14. 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 8, 12-13, 17-18, 21 and 72-77 are rejected under 35 U.S.C. 102(a)(1)/ (a)(2) as being anticipated by Abudayyeh et al 2018 (WO2018170340A1, 09/20/2018).
Claims 1, 72-73: Abudayyeh et al 2018 (WO2018170340A1) is in the art and directed to a polypeptide detection system comprising: a CRISPR system comprising an effector protein and one or more guide RNAs designed to bind a trigger RNA, an RNA-based masking construct; and one or more detection aptamers comprising a masked RNA polymerase promoter binding site or a masked primer binding site. Detection of proteins (para [0258]) aptamer may further incorporate a barcode or other identifying sequence that identifies a given aptamer and its target. Detecting nucleic acid tagged items, the nucleic acid identifiers may also be a nucleic acid barcode (para [0443]). In other example embodiments, the dead CRISPR effector protein may bound to a solid substrate e.g. polysaccharides (para [0251]). In some embodiments, the system may be used to detect viruses (see, para [0347], claims 32-33) in samples (See, abstract, claims 31-32). The immobilized reagent may be a protein, and the labeled minding partner may be a labeled antibody (para [0219], [0226]). In other embodiments, the CRISPR effector protein is bound by an antibody specific for the effector protein (para [0276], [0289]). One or more nucleic acid barcodes can be attached, or "tagged," to a target molecule and/or target nucleic acid. This attachment can be direct (for example, covalent or non-covalent binding of the barcode to the target molecule) or indirect (for example, via an additional molecule, for example, a specific binding agent, such as an antibody (or other protein) or a barcode receiving adaptor (or other nucleic acid molecule). Target molecules and/or target nucleic acids can be labeled with multiple nucleic acid barcodes in combinatorial fashion, such as a nucleic acid barcode concatemer (para [0443]). In contrast, antigen- and antibody-based tests are faster and require minimal equipment but have reduced sensitivity and specificity and can take months to develop. An ideal diagnostic would combine the sensitivity, specificity, and flexibility of nucleic acid diagnostics with the low cost and speed of antigen-based tests. Such a diagnostic could be rapidly developed and deployed in the face of emerging viral outbreaks and would be suitable for disease surveillance in the field (para [0536]). In certain example embodiments, the CRISPR effector protein is a CRISPR Type VI RNA-targeting effector protein (see, para [0028]). In certain embodiments, the CRISPR system as provided herein can make use of a crRNA or analogous polynucleotide comprising a guide sequence, wherein the polynucleotide is an RNA, a DNA or a mixture of RNA and DNA, and/or wherein the polynucleotide comprises one or more nucleotide analogs (see, para [0198], [0199], [0204]-[0205]). crRNA, and an RNA reporter that fluoresces when cleaved (see, para [0110], [0127], [0268], [0270]), Biomarker sample types (see para, [0394]- [0397]). The CRISPR effector system-based diagnostic or quantification of a cell via receptor 9e.g. T cell, CAR T cell) for therapeutic applications (see para, [0438]-[0441]). A method of detecting viruses, comprising: exposing a CRISPR system of any one of claims 1 or 2 to a sample; activating the RNA effector protein via binding of the one or more guide RNAs to the one or more microbe-specific target RNAs or one or more trigger RNAs such that a detectable positive signal is produced; and detecting the detectable positive signal, wherein detection of the detectable positive signal indicates a presence of one or more viruses in the sample (See, claims 21-23).
Claim 4: The added limitation of claim 4 is anticipated, wherein the detectable signal molecule is a fluorescent reporter (see, para [0270], [0588], [0610]). A positive detectable signal may be any signal that can be detected using optical, fluorescent, chemiluminescent, electrochemical or other detection methods known in the art (see, para [0218]).
Claim 8: The added limitation of claim 8 is anticipated, In one embodiment, the RNA targeting effector protein is a CRISPR Type VI RNA- targeting effector (see, para [0022]).
Claim 12: The added limitation of claim 12 is anticipated, wherein the biological target is an immune cell marker, a tumor-specific cell marker, an antigen-specific cell marker, or a cancer-specific stem cell marker (See, para [para [0434], [0435], [0439]).
Claims 17-18: The added limitation of claim 17 are anticipated flow cytometry (see para [0270]), mass spectrometry (see para [0593]), a fluorescence plate reader (para [0466]), ELISA (para [0567]), hand-held spectrophotometers that enable detection of signals outside the visible range (para [0258]).
Claims 18: The added limitation of claim 18 is anticipated, wherein the biological target is an immune cell marker, a tumor-specific cell marker, an antigen-specific cell marker, or a cancer-specific stem cell marker (See, para [para [0434], [0435], [0439]).
Claim 21: The added limitation of claim 21 is anticipated, wherein the sample comprises a biopsy, tissue, urine, blood, serum, plasma, lymphatic fluid, saliva, mucus, nasal swab with or without viral transport medium, sputum, bronchoalveolar lavage fluid, or biological fluid (See, para [0265] – [0266], [0332], [0336]).
Claim 74. The added limitation of claim 74 is anticipated, wherein the second nucleic acid molecule further comprises a quencher (see, para [0360]).
Claim 75. The added limitation of claim 75 is anticipated, wherein step a) further comprises: i) contacting the sample with the nucleic acid barcode conjugated to the binding moiety; ii) amplifying the nucleic acid barcode; and iii) contacting the sample with the CRISPR-Cas protein and the reporter construct (See, claims 8-11, para [0015], [0017], [0028], [0110], [0114], [0116], [0118], [0119]).
Claim 76. The added limitation of claim 75 is anticipated wherein amplification of the nucleic acid barcode comprises loop-mediated isothermal amplification (LAMP), recombinase polymerase amplification (RPA) (see para [0017]), nucleic acid sequence-based amplification (NASBA) (see para [0017]), strand displacement amplification (SDA) (see para [0239]), rolling circle amplification (RCA) (see para [0239]),, or helicase dependent amplification (HDA) (see para [0239]).
Claim 77. The added limitation of claim 77 is anticipated, wherein, if the detectable signal molecule is present, step b) further comprises: i) measuring an amount of the detectable signal molecule; and ii) quantifying the amount of the biological target in the sample based on the amount of the detectable signal molecule; wherein the limit of detection is 1 fM of nucleic acid barcode (See, above disclosures, aM and fM detection limit Fig 19, Figs 13- 14, and elsewhere in the prior art).
Claim Rejections - 35 USC § 103
(rejection modified and maintained in view of amended claims)
15. 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
16. Claims 1, 4, 8, 12-13, 17-18, 21, and 71-77 are rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh et al 2018 (WO2018170340A1, 09/20/2018), and further in view of Abate et al 2018 (US20180216160A published 08/02/2018), Gootenberg et al 2018 (Science, 2018, 360, 6387, p. 439-444), Zhou et al 2018, (Nature Communications, vol 9,5012), Lane et al 2008 (Langmuir 2008, 24, 7394-7399), and Kazane et al 2012 (PNAS, vol. 109, no. 10, p. 3731–3736, published 03/06/2012), Konry et al 2011 (Small. 2011 February 7; 7(3), East-Seletsky et al 2016 (Nature, 2016, vol 538, p. 276-286), Hille et al 2018 (Cell. 2018 Mar 8;172(6):1239-1259), Guo et al 2020 (Cell discovery, 6(1), 34, published online 19 May 2020, cited on IDS filed on 01/30/2026) and Yuan et al 2019 (bioRxiv preprint doi.org/10.1101/615724; this version posted May 7, 2019).
Claims 1, 4, 8, 12-13, 17-18, 21, and 71-77: The prior arts applied to the claims teaches both the product and claimed method for the use of the product for detecting a biological target in a biological sample, as recited below.
Claims 1, 72-73: Abudayyeh et al 2018 (WO2018170340A1) is in the art and directed to a polypeptide detection system comprising: a CRISPR system comprising an effector protein and one or more guide RNAs designed to bind a trigger RNA, an RNA-based masking construct; and one or more detection aptamers comprising a masked RNA polymerase promoter binding site or a masked primer binding site. Detection of proteins (para [0258]) aptamer may further incorporate a barcode or other identifying sequence that identifies a given aptamer and its target. Detecting nucleic acid tagged items, the nucleic acid identifiers may also be a nucleic acid barcode (para [0443]). In other example embodiments, the dead CRISPR effector protein may bound to a solid substrate e.g. polysaccharides (para [0251]). In some embodiments, the system may be used to detect viruses (see, para [0347], claims 32-33) in samples (See, abstract, claims 31-32). The immobilized reagent may be a protein, and the labeled minding partner may be a labeled antibody (para [0219], [0226]). In other embodiments, the CRISPR effector protein is bound by an antibody specific for the effector protein (para [0276], [0289]). One or more nucleic acid barcodes can be attached, or "tagged," to a target molecule and/or target nucleic acid. This attachment can be direct (for example, covalent or non-covalent binding of the barcode to the target molecule) or indirect (for example, via an additional molecule, for example, a specific binding agent, such as an antibody (or other protein) or a barcode receiving adaptor (or other nucleic acid molecule). Target molecules and/or target nucleic acids can be labeled with multiple nucleic acid barcodes in combinatorial fashion, such as a nucleic acid barcode concatemer (para [0443]). In contrast, antigen- and antibody-based tests are faster and require minimal equipment but have reduced sensitivity and specificity and can take months to develop. An ideal diagnostic would combine the sensitivity, specificity, and flexibility of nucleic acid diagnostics with the low cost and speed of antigen-based tests. Such a diagnostic could be rapidly developed and deployed in the face of emerging viral outbreaks and would be suitable for disease surveillance in the field (para [0536]). In certain example embodiments, the CRISPR effector protein is a CRISPR Type VI RNA-targeting effector protein (see, para [0028]). In certain embodiments, the CRISPR system as provided herein can make use of a crRNA or analogous polynucleotide comprising a guide sequence, wherein the polynucleotide is an RNA, a DNA or a mixture of RNA and DNA, and/or wherein the polynucleotide comprises one or more nucleotide analogs (see, para [0198], [0199], [0204]-[0205]). crRNA, and an RNA reporter that fluoresces when cleaved (see, para [0110], [0127], [0268], [0270]), Biomarker sample types (see para, [0394]- [0397]). The CRISPR effector system-based diagnostic or quantification of a cell via receptor 9e.g. T cell, CAR T cell) for therapeutic applications (see para, [0438]-[0441]). A method of detecting viruses, comprising: exposing a CRISPR system of any one of claims 1 or 2 to a sample; activating the RNA effector protein via binding of the one or more guide RNAs to the one or more microbe-specific target RNAs or one or more trigger RNAs such that a detectable positive signal is produced; and detecting the detectable positive signal, wherein detection of the detectable positive signal indicates a presence of one or more viruses in the sample (See, claims 21-23).
Claim 4: The added limitation of claim 4 is rendered obvious, wherein the detectable signal molecule is a fluorescent reporter (see, para [0270], [0588], [0610]). A positive detectable signal may be any signal that can be detected using optical, fluorescent, chemiluminescent, electrochemical or other detection methods known in the art (see, para [0218]).
Claim 8: The added limitation of claim 8 is rendered obvious, In one embodiment, the RNA targeting effector protein is a CRISPR Type VI RNA- targeting effector (see, para [0022]).
Claim 12: The added limitation of claim 12 is rendered obvious, wherein the biological target is an immune cell marker, a tumor-specific cell marker, an antigen-specific cell marker, or a cancer-specific stem cell marker (See, para [para [0434], [0435], [0439]).
Claim 17: The added limitation of claim 17 are rendered obvious flow cytometry (see para [0270]), mass spectrometry (see para [0593]), a fluorescence plate reader (para [0466]), ELISA (para [0567]), hand-held spectrophotometers that enable detection of signals outside the visible range (para [0258]).
Claims 18: The added limitation of claim 18 is rendered obvious, wherein the biological target is an immune cell marker, a tumor-specific cell marker, an antigen-specific cell marker, or a cancer-specific stem cell marker (See, para [para [0434], [0435], [0439]).
Claim 21: The added limitation of claim 21 is rendered obvious, wherein the sample comprises a biopsy, tissue, urine, blood, serum, plasma, lymphatic fluid, saliva, mucus, nasal swab with or without viral transport medium, sputum, bronchoalveolar lavage fluid, or biological fluid (See, para [0265] – [0266], [0332], [0336]).
Claim 74. The added limitation of claim 74 is rendered obvious, wherein the second nucleic acid molecule further comprises a quencher (see, para [0360]).
Claim 75. The added limitation of claim 75 is rendered obvious, wherein step a) further comprises: i) contacting the sample with the nucleic acid barcode conjugated to the binding moiety; ii) amplifying the nucleic acid barcode; and iii) contacting the sample with the CRISPR-Cas protein and the reporter construct (See, claims 8-11, para [0015], [0017], [0028], [0110], [0114], [0116], [0118], [0119]).
Claim 76. The added limitation of claim 75 is rendered obvious wherein amplification of the nucleic acid barcode comprises loop-mediated isothermal amplification (LAMP), recombinase polymerase amplification (RPA) (see para [0017]), nucleic acid sequence-based amplification (NASBA) (see para [0017]), strand displacement amplification (SDA) (see para [0239]), rolling circle amplification (RCA) (see para [0239]),, or helicase dependent amplification (HDA) (see para [0239]).
Claim 77. The added limitation of claim 77 is anticipated, wherein, if the detectable signal molecule is present, step b) further comprises: i) measuring an amount of the detectable signal molecule; and ii) quantifying the amount of the biological target in the sample based on the amount of the detectable signal molecule; wherein the limit of detection is 1 fM of nucleic acid barcode (See, above disclosures, aM and fM detection limit Fig 19, Figs 13- 14, and elsewhere in the prior art).
Abudayyeh et al 2018 (WO2018170340A1) teaches a spacer, however, do not teach poly A spacer (instant claim 71).
Abate et al 2018 (US20180216160A) is in the art and teaches a nucleic acid barcode probe conjugated to an affinity reagent (a binding moiety) for detecting a target molecule, a molecular target, the molecular target is a component of a cell (biological target) in biological sample, in tissue (See, para [0050]), proteomic analysis/profiling. The affinity reagent comprises an antibody or an antigen binding antibody fragment, a peptide, affinity reagents such as antibodies can be conjugated with nucleic acid labels, e.g., oligonucleotides including barcodes, the antibody bind to the proteins within or on cells, thereby associating the nucleic acids carried by the affinity reagents to the cells to which they are bound, probes with fluorescent dyes (See, para [0359]) for exemplary fluorophores include indocarbocyanine (C3), indodicarbocyanine (C5), Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Alexa Fluor 546, Alexa Fluor-555, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680), thus, the nucleic acid barcode probe can be conjugated to a binding moiety through one end and a detectable signal molecule through another end, wherein the binding moiety binds a biological target (See, claims 1-3, abstract, para [0003], [0231], [0296], [0353]-[0354], [0359]), preparing ssDNA barcodes by exemplary nucleic acid amplification methods that can be used to amplify the single barcodes include: PCR, strand displacement amplification, rolling circle amplification, helicase dependent isothermal amplification, recombinase based PCR (twistamp), and loop mediated amplification (LAMP) (See, para [0117], discloses the use of the mass spectrometry or the flow cytometry, and fluorescence methods for single cell proteomics detection ([0239]).
Abate et al 2018 teaches a CRISPR-Cas system and its uses, poly A tail spacer (See, [0266], (para [0102], [1174]).
Abate et al 2018 (US20180216160A) does not teach that at least a portion of the nucleic acid barcode can be recognized and bound by a CRISPR-Cas protein; does not teach poly A spacer to one end of the barcoded nucleic acid probe.
Gootenberg et al 2018 discloses a technology of nucleic acid fluorescence detection probing using CRISPR-Cas proteins, multiplexed and portable nucleic acid detection platform with Cas13, Cas12a, and Csm6 (type VI and type V CRISPR-Cas) for rapid detection of nucleic acids that combines isothermal preamplification with Cas13 to detect single molecules of RNA or DNA with an example of detection of Dengue or Zika virus single-stranded RNA with a quantitative measurement of input as low as 2 attomolar (aM) (0.002 femtomolar (fM) by recognizing nucleic acid barcode by CRISPR-Cas protein. The CRISPR-Cas endonuclease causes collateral cleavage of reporter, which implies that the use of the endonuclease causes the release of the detectable fluorescent molecule (See, abstract, p. 2, Fig 1-3, entire article), discloses the fact that the sample may imply a biopsy sample (p.2, fig. 3).
Gootenberg et al 2018 discloses the use of a type V or type VI Cas proteins (Cas 12, Cas 13) for method of ultrasensitive detection rendering obvious the claims 13, 22, and 27 limitations obvious (See, abstract, Fig 1-3, entire article).
Zhou et al 2018 teaches a CRISPR–Cas9-triggered strand displacement amplification method for ultrasensitive DNA detection (See, abstract, Fig 1-3, entire article).
Lane et al 2008 teaches poly A spacer (instant claim 77 limitation) in DNA or nucleic acid probe (See, abstract).
Kazane et al 2012 is in the art teaches detection of biological target Her2 receptor on Her2+ cancer cells (cancer specific cell surface marker) with a specific antibody against Her2 receptor bound to a fluorescent nucleic acid probe in a blood sample (See, abstract, Fig 1, entire article, p.5 col 2 para 2) (instant claims 2 and 12 limitations).
Konry et al 2011 teaches ultrasensitive detection of low-abundance surface-marker protein, an epithelial cell adhesion molecule (EpCAM) is frequently expressed on Circulating tumor cells carcinomas using isothermal rolling circle amplification in microfluidic platform (See, abstract, Fig 1-2, p. 3 para 2.2).
East-Seletsky et al 2016 is in the CRISPR-Cas art and teaches CRISPR- Cas type specificity, nucleic acid barcode is RNA bound and recognized by type VI CRISPR-Cas protein and teaches nucleic acid barcode is DNA bound and recognized by type V CRISPR-Cas protein (See, abstract, entire article).
Hille et al 2018 is in the art and provides a review on different types of CRISPR-Cas systems type I-III and type V-VI with nucleic acid (RNA or DNA target) target properties and specificities (See, entire article, Fig 2-6).
Guo et al 2020 teaches detection of SARS-CoV-2 detection with CRISPR diagnostics (See, abstract, entire article).
Yuan et al 2019 teaches universal and naked-eye gene detection platform 2 based on CRISPR/Cas12a/13a system, inter alia, for ASFV virus with detection limit of target in fM (See, abstract, entire article).
Optimization of detection sensitivity of target lower concentration (e.g. 1 fM detection limit in instant claim 77) within prior art conditions fall under routine experimentation. See, MPEP 2144.05.
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the teachings of Abudayyeh et al 2018 with additional teachings of Abate et al 2018, Gootenberg et al 2018, Zhou et al 2018, Lane et al 2008, Kazane et al 2012, Konry et al 2011, East-Seletsky et al 2016, Hille et al 2018 and Guo et al 2020 to arrive at the inventions of the claims 1, 4, 8, 12-13, 17-18, 21, and 71-77. One of the ordinary skills would have been motivated to develop a barcoded nucleic acid fluorescent probe conjugated to a binding moiety recognizing and binding to a biological target specifically and CRISPR-Cas based cleavage of the isothermal amplified probe comprising a fluorescent molecule to amplify the signal to detect the biological target at ultrasensitive quantity level in fM and method of use or application for detection of the biological target at ultrasensitive quantity level in fM in a biological sample. The motivation would be to develop a barcoded nucleic acid probe product and a method for ultrasensitive detection of a biological target to increase sensitivity and specificity of the assay for commercial success. There would be a reasonable expectation of success given the applied prior art teachings as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1, 4, 8, 12-13, 17-18, 21, and 71-77. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-G).
17. Relevant Prior Arts
Stoeckius et al 2018. Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics. Genome Biol 19, 224.
Giedt et al 2018. Single-cell barcode analysis provides a rapid readout of cellular signaling pathways in clinical specimens. Nat Commun 9, 4550 (2018). Developed an antibody-DNA barcoding approach where harvested cells can be rapidly re-stained through the use of custom designed oligonucleotide-fluorophore conjugates. We show that this approach can be used to interrogate drug-relevant pathways in scant clinical samples. Using the PI3K/PTEN/CDK4/6 pathways in breast cancer as an example.
Bentzen et al 2016. Large-scale detection of antigen-specific T cells using peptide-MHC-I multimers labeled with DNA barcodes. Nat Biotechnol 34, 1037–1045 (2016).
Niemeyer et al 2005. Immuno-PCR: high sensitivity detection of proteins by nucleic acid amplification. Trends Biotechnol. 2005 Apr;23(4):208-16.
Pardeeet al 2016. Rapid, Low-Cost Detection of Zika Virus Using Programmable Biomolecular Components CRISPR-Cas9. Cell. 2016 May 19;165(5):1255-1266. Pardeet al 2016 reported a pipeline for the rapid design, assembly, and validation of cell-free, paper-based sensors for the detection of the Zika virus RNA genome. By linking isothermal RNA amplification to toehold switch RNA sensors, we detect clinically relevant concentrations of Zika virus sequences and demonstrate specificity against closely related Dengue virus sequences. When coupled with a novel CRISPR/Cas9-based module, our sensors can discriminate between viral strains with single-base resolution. Successfully demonstrated a simple, field-ready sample-processing workflow and detect Zika virus from the plasma of a viremic macaque.
Guo, L., Sun, X., Wang, X., Liang, C., Jiang, H., Gao, Q., ... & Li, W. (2020). SARS-CoV-2 detection with CRISPR diagnostics. Cell discovery, 6(1), 34. (Year: 2020).
Broughton, J.P., Deng, X., Yu, G. et al. CRISPR–Cas12-based detection of SARS-CoV-2. Nat Biotechnol 38, 870–874 (2020). (Year: 2020).
Pickar-Oliver, A., & Gersbach, C. A. (2019). The next generation of CRISPR–Cas technologies and applications. Nature reviews Molecular cell biology, 20(8), 490-507. (Year: 2019).
Response to Arguments
18. Applicant’s arguments filed in response to Non-Final Rejection office action of 10/01/2025 with respect to claims 1-2, 4, 6, 8, 12-13, 16-18, 21-22, and 27 have been considered but are moot because the new ground of rejection for instant amended claims 1, 4, 8, 12-13, 17-18, 21, and 71-77 under examination does not rely only on reference applied in the prior rejection of record for all the teaching or matter specifically challenged in the argument. Additional references and teachings are applied for new 35 USC 102 rejection, and prior 35 USC 103 rejection that is modified in this action.
Conclusion
19. No claim is allowed.
20. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
21. A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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