DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I+, drawn to a composition comprising a truncated Cas protein of Cas Type VI, Cas13, or SEQ ID NOs:4102-5203, or full-length Cas13 protein of SEQ ID NOs:1-4902, in the reply filed on 10/16/2025 is acknowledged.
Claim 42 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/16/2025.
Applicant’s election without traverse of the Cas protein sequence species of SEQ ID NO:5260 (claim 2) and SEQ ID NO:2771 (claim 5) in the reply filed on 10/16/2025 is acknowledged. As claim 5 does not recite SEQ ID NO:2771, SEQ ID NOs:76, 2770, 2773 were searched for claim 5. The species election requirement for claim 5 has been withdrawn.
Claims Status
Claims 3-4, 6, 9-12, 14-18, 20, 25-26, 28-30, 32-33, 36, 38-39, 41, 43, 46, 49-50, 54, 56-57, 61-64, 66-67, 70, 72-73, 75, 78-79, 81, 83-84, 86 is/are cancelled. Claims 1-2, 5, 7-8, 13, 19, 21-24, 27, 31, 34-35, 37, 40, 42, 44-45, 47-48, 51-53, 55, 58-60, 65, 68-69, 71, 74, 76-77, 80, 82, 85, 87 is/are currently pending with claims 42 withdrawn. Claims 1-2, 5, 7-8, 13, 19, 21-24, 27, 31, 34-35, 37, 40, 44-45, 47-48, 51-53, 55, 58-60, 65, 68-69, 71, 74, 76-77, 80, 82, 85, 87 is/are under examination.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Hyperlinks were found in paragraphs [0491], [1187], and [1288]. Applicant is advised to review the specification in order to ensure that all hyperlinks are identified and appropriately removed.
Claim Objections
Claims 1, 80 are objected to because of the following informalities:
Claim 1 recites “a guide sequence capable of forming of complex” in line 4. This is not grammatically correct, and should be amended to read “a guide sequence capable of forming a complex”.
Claim 80 recites “the target nucleic acid is DNA molecule” in line 1. This is not grammatically correct, and should be amended to read “the target nucleic acid is a DNA molecule”.
Appropriate correction is required.
Claim Interpretation
Claim 2 recites multiple limitations in lines 10-18 which are preceded by the term “optionally”, including the following: “optionally, wherein the Cas protein exhibits collateral nuclease activity and cleaves a non-target sequence, or is catalytically inactive; or wherein the Cas protein comprises one or more nuclear localization signals, or one or more nuclear export signals” (lines 10-13). As the Cas protein comprising one or more NLS or NES is presented in the alternative to the Cas protein exhibiting collateral nuclease activity or catalytic inactivity, the broadest reasonable interpretation is that the Cas protein comprising an NLS or NES is also optional.
Claim 5 recites multiple limitations in lines 9-17 which are preceded by the term “optionally”, including the following: “optionally, wherein the Cas protein exhibits collateral nuclease activity and cleaves a non-target sequence, or is catalytically inactive; or wherein the Cas protein comprises one or more nuclear localization signals, or one or more nuclear export signals” (lines 9-12). As the Cas protein comprising one or more NLS or NES is presented in the alternative to the Cas protein exhibiting collateral nuclease activity or catalytic inactivity, the broadest reasonable interpretation is that the Cas protein comprising an NLS or NES is also optional.
Claims 31 and 34 only recite further limitations regarding the adenosine deaminase domain recited as optional in claim 27. As claims 31 and 34 are only drawn to further limitations of an optional limitation of claim 27, all limitations of claims 31 and 34 are considered to be optional.
Claim 51 only recites further limitations regarding “the first Cas protein” and “the second Cas protein” of claim 48, which are limitations only recited in an optional limitation in lines 6-7 of claim 48. As claim 51 is only drawn to further limitations of optional limitations of claim 48, all limitations of claim 51 are considered to be optional.
Claim 44 recites an intended use of the claimed product “A system…comprising…a Cas protein of claim 1; one or more detection aptamers…and an oligonucleotide-based masking construct comprising a non-target sequence”. According to MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. The intended use recited in claim 44 does not appear to impart any structure to the claimed product. Therefore for the purpose of examination, claim 44 is directed to “A system…comprising…a Cas protein of claim 1; one or more detection aptamers…and an oligonucleotide-based masking construct comprising a non-target sequence”.
Claim 47 recites an intended use of the claimed product “A system…comprising: a Cas protein of claim 1; at least one guide polynucleotide…and an oligonucleotide-based masking construct comprising a non-target sequence” (lines 1-7). According to MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. The intended use recited in claim 47 does not appear to impart any structure to the claimed product. Therefore for the purpose of examination, claim 47 is directed to “A system…comprising: a Cas protein of claim 1; at least one guide polynucleotide…and an oligonucleotide-based masking construct comprising a non-target sequence” (lines 1-7).
Claim 68 recites an intended use of the claimed product “The composition of claim 1”. According to MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. The intended use recited in claim 68 does not appear to impart any structure to the claimed product. Therefore for the purpose of examination, claim 68 is directed to the composition of claim 1.
Claim Rejections - 35 USC § 112
112(b):
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 21, 27, 31, 47, 53, 55 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a guide sequence capable of forming of complex with the Cas protein and directing the complex to bind to a target sequence” (lines 4-5). It is well-known in the art that a tracrRNA sequence is required to complex a guide sequence to a Cas protein, and that a crRNA sequence is required for a guide sequence to direct the guide sequence-Cas protein complex to bind to a target sequence. However, claim 21 recites that the composition further comprises a tracrRNA. It is not clear whether the tracrRNA of claim 21 is in addition to the tracrRNA implied by the required functional limitations of claim 1, and whether the additional tracrRNA is part of the guide sequence of claim 1. As a result, the metes and bounds of claim 21 are unclear, and claim 21 is thus rendered indefinite.
Claim 27 recites the limitation "The composition of claim 24" in 1. There is insufficient antecedent basis for this limitation in the claim. Claim 24 recites both “A non-naturally occurring or engineered composition for modifying nucleotides in a target nucleic acid” and “the composition of claim 1” (lines 1-3). It is unclear whether “the composition” of claim 27 refers to the composition of claim 1 or the composition comprising the composition of claim 1, recited in claim 24. Claim 31 depends on claim 27 and recites “The composition of claim 27” in line 1. As the antecedent basis of the composition recited in claim 27 is unclear, so, too, is the antecedent basis of the composition recited in claim 31 unclear, rendering claim 31 indefinite.
Claim 31 recites the limitations “optionally, wherein the one or more mutations comprise an E620G or Q696L substitution, optionally, (i) E488Q and E620G substitutions; (ii) E488Q and Q696L substitutions; or (iii) E488Q and V505I substitutions” (lines 3-7). As there is no modifier such as “and” or “or” between the first limitation “wherein the one or more mutations comprise an E620G or Q696L substitution” and the second limitation of (i)-(iii), it is unclear whether these limitations are all alternatives of each other, and therefore, the metes and bounds of the claim are unclear and claim 31 is rendered indefinite.
The term “a degree of complementarity” in claim 47 is a relative term which renders the claim indefinite. The term “degree of complementarity” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. A “degree of complementarity” does not indicate the threshold of complementarity required by the claim, and thus the metes and bounds of claim 47 are unclear, and claim 47 is rendered indefinite.
Claim 53 recites the limitation "the cell or progeny thereof" in line 9. There is insufficient antecedent basis for this limitation in the claim. Claim 53 recites in line 3-4 the limitation that “the nucleotide sequence encoding the Cas protein is codon optimized for expression in a eukaryotic cell”. However, this recitation of a cell is merely part of a functional descriptor, and not a recitation of a particular cell. Therefore, it is unclear to what cell the limitation “the cell or progeny thereof” in line 9 refers.
Claim 55 recites “The vector system of claim 53, which is comprised in a single vector.” The vector system of claim 53 comprises one or more vectors (line 1). It is unclear what structure claim 55 requires that comprises one or more vectors comprised within another, single vector.
112(d):
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2 depends on claim 1. While claim 1 requires that the Cas protein be less than 900 amino acids in size, not all of the Cas protein sequences recited in claim 2 are less than 900 amino acids in size. For example, SEQ ID NO:2771 is 905 amino acids long; SQ ID NO:2772 is 900 amino acids long. Thus, multiple limitations of claim 2 fail to include all the required limitations of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
112(a):
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.
Written Description:
Claims 13, 19, 24, 27, 34-35, 37, 44-45, 48, 51 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 claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claim 13 recites that the Cas protein of claim 1 is a nickase. The disclosure only discloses Cas13 proteins, but does not disclose the structure of a Cas13 nickase. Paragraph [0338] discloses that a dead Cas13 protein may have nickase activity, but does not disclose which dead Cas13 proteins have nickase activity, and what structural modifications of Cas13 provide nickase activity. A search of the art does not provide evidence of Cas13 nickase proteins. An artisan would not be able to determine that the applicants were in possession of Cas13 nickase proteins, or any Cas nickase comprising one or more HEPN domains and having fewer than 900 total amino acids.
Claim 19 recites that “the recombination template is inserted by homology-directed repair (HDR).” However, claim 19 does not describe what structure the recombination template is inserted into. The specification, paragraph [0827], teaches that in some embodiments, a recombination template is inserted into the cleaved target polynucleotide. The disclosure does not describe the insertion of a recombination template into any structure that is not the target polynucleotide. Thus, there is insufficient written description of recombination templates that can be inserted into any structure through HDR.
Claim 24 recites the limitation “a nucleotide deaminase associated with the Cas protein” (line 4). Claim 24 does not specify in what way or by what structure the deaminase and the Cas protein are “associated”. The specification, in paragraphs [0086] and [0347], links the phrase “associated with”, as it relates to the deaminase and Cas protein, to “fused to” (“associated with (e.g., fused to)”, paragraph [0086]). Paragraph [0347] further describes association between the deaminase and the Cas protein as “via fusion protein or suitable linker”. No other structure enabling association between two proteins is disclosed. As such, the disclosure only provides sufficient written description for a deaminase and a Cas protein associated by fusion or a linker.
Claim 27 recites that the deaminase and the Cas protein are “covalently or non-covalently linked” (line 2). However, the disclosure only discloses covalent linkages. It is not apparent, based on the disclosure, what structures are encompassed by non-covalent linkages between two protein sequences. As such, the disclosure only provides sufficient written description for covalent linkages.
Claim 34 recites an adenosine deaminase which “has cytidine deaminase activity” (lines 1-2). The specification discloses that “In certain examples, the engineered adenosine deaminase has both cytidine deaminase activity and adenosine deaminase” (paragraph [0476]). However, the specification does not provide any specific structures of variants of adenosine deaminases which can have both cytidine deaminase and adenosine deaminase activities. An artisan would therefore not be able to determine that the applicants were in possession of adenosine deaminase variants with both cytidine deaminase and adenosine deaminase activities.
Claim 35 recites nucleotide deaminases or catalytic domains of nucleotide deaminases which are “modified to increase activity against a DNA-RNA heteroduplex, or modified to reduce off-target effects” (lines 2-3). However, the specification does not disclose any specific structural modifications that result in “increased activity against a DNA-RNA heteroduplex” or “reduced off-target effects”. As such, an artisan would not be able to determine that the applicants were in possession of nucleotide deaminase variants comprising structural modifications resulting in “increased activity against a DNA-RNA heteroduplex” or “reduced off-target effects”.
Claim 37 recites that “modification of the nucleotides in the target nucleic acid remedies a disease caused by a G[Wingdings font/0xE0]A or C[Wingdings font/0xE0]T point mutation or a pathogenic SNP…or…caused by a T[Wingdings font/0xE0]C or A[Wingdings font/0xE0]G point mutation or a pathogenic SNP.” Claim 37 also recites that the disease optionally comprises “cancer, haemophilia, beta-thalassemia, Marfan syndrome, or Wiskott-Aldrich syndrome” (lines 3-4). The specification does not provide a description of methods by which the composition of claim 24 is administered to a patient in need or an animal model representative of any disease, wherein the composition is targeted to any therapeutically-relevant nucleotide sequence, and wherein administration of the composition and modification of the therapeutically-relevant nucleotide sequence results in remediation of a disease. While cancer, haemophilia, beta-thalassemia, Marfan syndrome, and Wiskott-Aldrich syndrome are listed as possible target disease, the disclosure does not teach any particular target sequence and modification of said target sequence which would remedy any of these disease, not does the disclosure provide evidence that the claimed composition is capable of treating any of these diseases. An artisan would not be able to determine, based on the present disclosure, that the applicants were in possession of a composition which could remedy any disease.
Claim 44 recites “detection aptamers, each designed to bind to one or more target polypeptides, each detection aptamer comprising a masked promoter binding site or masked primer binding site and a trigger sequence template” (lines 4-6). However, the disclosure has not provided a structure by which an aptamer can bind to a polypeptide. Paragraph [0027] teaches that the aptamer “comprises a polynucleotide-tethered inhibitor that sequesters an enzyme” in an embodiment. A search of the term “polynucleotide-tethered inhibitor” does not produce results, indicating that this is not a term commonly used in the art. It is unclear what structure is described by “a polynucleotide-tethered inhibitor”. An artisan would not be able to determine the structures required to fulfill the limitations of claim 44 regarding detection aptamers.
Claim 45 recites “nucleic acid amplification reagents” (lines 1-2). The specification only describes isothermal amplification reagents, wherein these reagents are used for “nucleic-acid sequence-based amplification, recombinase polymerase amplification, loop-mediated isothermal amplification, strand displacement amplification, helicase-dependent amplification, or nicking enzyme amplification” (paragraph [0024]). In paragraph [0463], foreign patent documents WO2020006036, WO2020006049, and WO2020006067 are incorporated by reference to teach specific isothermal amplification reagents for use in helicase isothermal amplification, transposase isothermal amplification, and nickase isothermal amplification. However, the structures of other nucleic acid amplification reagents, including recombinase polymerase amplification, loop-mediated isothermal amplification, and strand displacement amplification reagents are not disclosed. An artisan would not be able to determine that the applicants were in possession of a number of amplification reagents representative of the full genus of nucleic acid amplification reagents.
Claims 48 and 51 require a Cas protein “linked to an inactive first portion of an enzyme or reporter moiety, wherein the enzyme or reporter moiety is reconstituted when contacted with a complementary portion of the enzyme or reporter moiety” (claim 48). However, the specification and drawings do not provide any structures fulfilling these requirements. It would not be clear to an artisan what enzymes or reporter moieties would fulfill these requirements, nor would it be clear to an artisan that the applicants were in possession of such enzymes or reporter moieties. As such, claims 48 and 51 lack sufficient written description.
Enablement:
Claims 24, 37, 68, 74, 87 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 methods of modifying target nucleic acids in vitro, and compositions for use in these methods, does not reasonably provide enablement for methods of treating any disease, or for compositions having the function of treating any disease. 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 or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed methods of claims 74 and 87 is that they encompass methods of treating or preventing any disease in a subject of any species by administering the claimed composition. The broadest reasonable interpretation of the required function of the composition of claim 37, and of a function encompassed by the composition of claim 24, and of the intended use and only further limitation of the composition of claim 68, is that the composition be capable of “remedying” or treating any disease when administered. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
Claim 37 recites that the claimed composition can be used to remedy “a disease caused by a G[Wingdings font/0xE0]A or C[Wingdings font/0xE0]T point mutation or a pathogenic SNP…or…caused by a T[Wingdings font/0xE0]C or A[Wingdings font/0xE0]G point mutation or a pathogenic SNP”, wherein the disease can comprise “cancer, haemophilia, beta-thalassemia, Marfan syndrome, or Wiskott-Aldrich syndrome”. The specification does not provide a description of methods by which the composition of claim 1 is administered to a patient in need or an animal model representative of any disease, wherein the composition is targeted to any therapeutically-relevant nucleotide sequence, and wherein administration of the composition and modification of the therapeutically-relevant nucleotide sequence results in remediation of a disease. While cancer, haemophilia, beta-thalassemia, Marfan syndrome, and Wiskott-Aldrich syndrome are listed as possible target disease, the disclosure does not teach any particular target sequence and modification of said target sequence which would remedy any of these disease, not does the disclosure provide evidence that the claimed composition is capable of treating any of these diseases. The art at the time of filing taught that while Cas13 showed promise for therapeutic applications in vivo, delivery in vivo and side effects were unresolved challenges that must still be overcome in order to enable the use of CRISPR/Cas13 systems in therapeutic applications, and CRISPR/Cas13 knockdown of mRNA had not yet been shown (see Granados-Riveron, 2018, page 4109 and Table 1). The specification as filed does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses only in vitro administration of the composition of claim 1, in mammalian cells (HEK293FT) and bacterial cells (E. coli) (see Figs. 22, 23; paragraphs [1294]-[1307]); the specification does not disclose any working examples comprising in vivo administration of the claimed compositions.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is treatment or prevention of any disease in any subject, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials, or in animal models that are predictive of treatment in a representative number of diseases, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, Claims 24, 37, 68, and 87 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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.
(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.
Claim(s) 1-2, 7-8, 21-23, 44-45, 47, 52-53, 55, 58-60, 65, 68-69, 74, 76-77, 80, 82, 85 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Abudayyeh (WO2018107129A1, published 06/14/2018).
Regarding claim 1, Abudayyeh teaches an engineered composition comprising a Cas protein comprising at least one HEPN domain and being less than 900 amino acids in length, and a guide sequence capable of forming a complex with the Cas protein and directing the complex to bind to a target sequence (claims 1, 4-6; paragraph [0189]; Table 5, SEQ ID NO:568 is less than 900 amino acids long).
Regarding claim 2, Abudayyeh teaches that the Cas protein is a Cas13 (Table 5, paragraph [0189]; claims 10-11, 13-15).
Regarding claim 7, Abudayyeh teaches that the composition comprises two or more guide sequences capable of hybridizing two different target sequences (paragraph [0248]).
Regarding claim 8, Abudayyeh teaches that the guide sequence is capable of hybridizing to one or more target sequences in eukaryotes or prokaryotes (paragraph [0332], in order to use the composition to test for bacterial, or human, animal, or plant, materials, the guide sequences must be able to hybridize to prokaryotic or eukaryotic sequences).
Regarding claim 21, Abudayyeh teaches that the composition comprises a tracrRNA sequence (paragraph [0196]).
Regarding claim 22, Abudayyeh teaches that the Cas protein comprises two HEPN domains (paragraph [0159]).
Regarding claims 23, 52, Abudayyeh teaches nucleic acid sequences encoding a Cas protein, that are transcribed to mRNA (paragraph [0152]), and nucleic acids encoding guide sequences (claims 1, 4-6; paragraph [0189]).
Regarding claim 44, Abudayyeh teaches a polypeptide detection system comprising: a Cas protein (claims 2, 5-6, 10); one or more detection aptamers comprising a masked promoter binding site or a masked primer binding site (claim 2) and a trigger sequence template (paragraph [0144], the aptamer sequence serves as a trigger RNA template); and an oligonucleotide-based masking construct (claim 2) comprising a non-target sequence (paragraph [0013], [0014]: the RNA-based masking construct is not a target sequence, because the target sequences of claim 44 are polypeptide sequences, not polynucleotide sequences).
Regarding claim 45, Abudayyeh teaches that the system further comprises nucleic acid amplification reagents (claim 3).
Regarding claim 47, Abudayyeh teaches a nucleic acid detection system comprising: a Cas protein (claims 1, 5-6, 10); one or more guide RNAs designed to bind to target molecules; and an RNA-based masking construct comprising a non-target sequence (claim 1), wherein the Cas protein cleaves the RNA-based masking construct once activated by the one or more target sequences (paragraph [0146]).
Regarding claim 53, Abudayyeh teaches a vector comprising one or more vectors comprising: a first regulatory element operably linked to a nucleotide sequence encoding a Cas protein; and a second regulatory element operably linked to a nucleotide sequence encoding the guide sequence (paragraphs [0155], [0157]-[0158]).
Regarding claims 55 and 58, Abudayyeh teaches delivery vehicles comprising the CRISPR composition and a delivery vehicle or single vector (paragraph [0155]).
Regarding claim 59, Abudayyeh teaches that the delivery vehicle comprises one or more vectors encoding the Cas protein and the guide sequences (paragraphs [0155], [0157]-[0158]).
Regarding claim 60, Abudayyeh teaches that the delivery vehicle is an AAV viral vector (paragraphs [0155], [0157]-[0158]).
Regarding claim 65, Abudayyeh teaches that the CRISPR composition may be introduced into a cell, wherein the cell is a eukaryotic cell (paragraph [0153]).
Regarding claim 68, Abudayyeh teaches that the CRISPR systems can be used to detect therapeutically-relevant mutations in order to inform a therapeutic method of treatment (paragraphs [0365]-[0368], [0379]).
Regarding claims 69 and 74, Abudayyeh teaches that the CRISPR systems can be used in methods for modifying a target locus of interest, the method comprising contacting the target sequences with the CRISPR composition (paragraph [0441]).
Regarding claim 76, Abudayyeh teaches a method for detecting a target nucleic acid in a sample, comprising: contacting the sample with the nucleic acid detection CRISPR system, wherein activation of the CRISPR protein via binding of the guide RNAs to the target sequences results in modification of the RNA-based masking construct, producing a detectable positive signal; and detecting the detectable positive signal (claim 72).
Regarding claim 77, Abudayyeh teaches that the method further comprises contacting the sample with nucleic acid amplification reagents (claims 75-77).
Regarding claim 80, Abudayyeh teaches that the target nucleic acid is a DNA molecule, and the method further comprises contacting the target DNA with a primer comprising an RNA polymerase site (claim 74) and an RNA polymerase (paragraph [0240]).
Regarding claim 82, Abudayyeh teaches that the masking construct comprises:
a silencing RNA that suppresses generation of a gene product encoded by a reporting construct, wherein the gene product generates the detectable positive signal when expressed (claim 18);
a ribozyme that generates the negative detectable signal, and wherein the positive detectable signal is generated when the ribozyme is deactivated (claim 19);
a ribozyme that converts a substrate to a first color and wherein the substrate converts to a second color when the ribozyme is deactivated (claim 20);
an aptamer (claim 21);
an RNA oligonucleotide to which a detectable ligand and a masking component are attached (claim 27);
a nanoparticle held in aggregate by bridge molecules, wherein at least a portion of the bridge molecules comprises RNA, and wherein the solution undergoes a color shift when the nanoparticle is disbursed in solution (claim 28);
a quantum dot linked to one or more quencher molecules by a linking molecule, wherein at least a portion of the linking molecule comprises RNA (claim 31); or
RNA in complex with an intercalating agent, wherein the intercalating agent changes absorbance upon cleavage of the RNA (claim 32).
Regarding claim 85, Abudayyeh teaches that the one or more guide RNAs comprise a mismatch (claim 34).
Claim(s) 1, 7-8, 24, 27, 31, 35, 40, 52-53, 55, 58-60, 65, 74 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cheng (US 20190002889 A1).
Regarding claim 1, Cheng teaches an engineered composition comprising a Cas13 protein (which comprises at least on HEPN domain and is less than 900 amino acids in size) and a guide sequence capable of forming a complex with the Cas protein and directing the complex to bind to a target sequence (claims 1, 19-20, 24, 26-28).
Regarding claim 7, Cheng teaches that the composition may comprise two or more guide RNAs capable of hybridizing to two different target sequences (paragraph [0225]).
Regarding claim 8, Cheng teaches that the guide RNAs are capable of hybridizing to target sequences in prokaryotic or eukaryotic cells (paragraph [0266]).
Regarding claims 24 and 27, Cheng teaches that the Cas13 protein of the engineered composition is fused to a deaminase (claim 147), wherein the deaminase is ADAR2 or another adenosine deaminase (claim 147).
Regarding claims 31 and 35, Cheng teaches that the deaminase domain comprises two mutations (E488Q and T375G), which provide “hyperactivity and greater specificity” (paragraph [0399]).
Regarding claims 40 and 74, Cheng teaches that the Cas-deaminase fusion protein modifies nucleotides in a target nucleic acid, specifically a target RNA (claims 19, 162; paragraph [0268]).
Regarding claims 52-53, 55, 58-60, Cheng teaches that the system can be encoded in nucleic acids and comprised in one or more vectors for delivery, including viral vectors (paragraphs [0052]-[0055]).
Regarding claim 65, Cheng teaches a eukaryotic cell comprising the composition (claims 119-120).
Claim(s) 1-2, 19, 21-23, 71, 74 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kohn (WO 2017143071 A1).
Regarding claims 1, 21-23, Kohn teaches a composition comprising a C2C2 Cas protein or an mRNA encoding a C2C2 Cas protein (also known as Cas13a, see instant specification paragraph [0440], thus inherently having two HEPN domains) and at least one guide RNA (claims 1, 5, 6, 10; paragraphs [0003], [0011], a nucleic acid encoding the protein must either be a DNA molecule that is transcribed to mRNA, or must be an mRNA molecule, in order to produce the encoded protein). Kohn teaches that the C2C2 protein can be a modified or truncated version of any one of SEQ ID NOs:1124-1135 having 100-1300 amino acids in length (paragraph [0189]), thus encompassing proteins under 900 amino acids long.
Regarding claim 2, Kohn teaches that the Cas protein is C2C2 (otherwise known as Cas13a).
Regarding claims 19 and 71, Kohn teaches that the composition further comprises a recombination template (donor template ) (claim 11), which is inserted into a target sequence by homology-directed repair (paragraph [0246]).
Regarding claim 74, Kohn teaches a method of modifying one or more nucleotides in a target sequence, comprising contacting the one or more target sequences with the composition (claims 1, 5, 6, 10).
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.
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.
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.
Claim(s) 1-2, 5, 7-8, 21-23, 44-45, 47, 52-53, 55, 58-60, 65, 68-69, 74, 76-77, 80, 82, 85 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh (WO2018107129A1, published 06/14/2018), in view of NCBI Reference Sequence: WP_117998314.1 (2018).
Regarding claim 1, Abudayyeh teaches an engineered composition comprising a Cas protein comprising at least one HEPN domain and being less than 900 amino acids in length, and a guide sequence capable of forming a complex with the Cas protein and directing the complex to bind to a target sequence (claims 1, 4-6; paragraph [0189]; Table 5, SEQ ID NO:568 is less than 900 amino acids long).
Regarding claim 2, Abudayyeh teaches that the Cas protein is a Cas13 (Table 5, paragraph [0189]; claims 10-11, 13-15).
Regarding claim 5, Abudayyeh teaches that the Cas13 protein may be the Cas13a protein from Eubacterium rectale (claim 14; paragraphs [0178]; Table 1). However, the sequence provided by Abudayyeh for the C2C2 protein from E. rectale is not the same as the sequence of instant SEQ ID NO:76. However, instant SEQ ID NO:76 was known in the art at the time of filing to be a known sequence of Cas13a (also known as C2C2) from an E. rectale strain (see alignment below). It would have been obvious to an artisan at the time of filing to substitute the E. rectale Cas13a of Abudayyeh with any other known E. rectale Cas13a protein, including the known E. rectale Cas13a protein of instant SEQ ID NO:76, as these would reasonably be assumed to be functional equivalents, being orthologs derived from different strains of the same species.
PNG
media_image1.png
227
871
media_image1.png
Greyscale
Regarding claim 7, Abudayyeh teaches that the composition comprises two or more guide sequences capable of hybridizing two different target sequences (paragraph [0248]).
Regarding claim 8, Abudayyeh teaches that the guide sequence is capable of hybridizing to one or more target sequences in eukaryotes or prokaryotes (paragraph [0332], in order to use the composition to test for bacterial, or human, animal, or plant, materials, the guide sequences must be able to hybridize to prokaryotic or eukaryotic sequences).
Regarding claim 21, Abudayyeh teaches that the composition comprises a tracrRNA sequence (paragraph [0196]).
Regarding claim 22, Abudayyeh teaches that the Cas protein comprises two HEPN domains (paragraph [0159]).
Regarding claims 23, 52, Abudayyeh teaches nucleic acid sequences encoding a Cas protein, that are transcribed to mRNA (paragraph [0152]), and nucleic acids encoding guide sequences (claims 1, 4-6; paragraph [0189]).
Regarding claim 44, Abudayyeh teaches a polypeptide detection system comprising: a Cas protein (claims 2, 5-6, 10); one or more detection aptamers comprising a masked promoter binding site or a masked primer binding site (claim 2) and a trigger sequence template (paragraph [0144], the aptamer sequence serves as a trigger RNA template); and an oligonucleotide-based masking construct (claim 2) comprising a non-target sequence (paragraph [0013], [0014]: the RNA-based masking construct is not a target sequence, because the target sequences of claim 44 are polypeptide sequences, not polynucleotide sequences).
Regarding claim 45, Abudayyeh teaches that the system further comprises nucleic acid amplification reagents (claim 3).
Regarding claim 47, Abudayyeh teaches a nucleic acid detection system comprising: a Cas protein (claims 1, 5-6, 10); one or more guide RNAs designed to bind to target molecules; and an RNA-based masking construct comprising a non-target sequence (claim 1), wherein the Cas protein cleaves the RNA-based masking construct once activated by the one or more target sequences (paragraph [0146]).
Regarding claim 53, Abudayyeh teaches a vector comprising one or more vectors comprising: a first regulatory element operably linked to a nucleotide sequence encoding a Cas protein; and a second regulatory element operably linked to a nucleotide sequence encoding the guide sequence (paragraphs [0155], [0157]-[0158]).
Regarding claims 55 and 58, Abudayyeh teaches delivery vehicles comprising the CRISPR composition and a delivery vehicle or single vector (paragraph [0155]).
Regarding claim 59, Abudayyeh teaches that the delivery vehicle comprises one or more vectors encoding the Cas protein and the guide sequences (paragraphs [0155], [0157]-[0158]).
Regarding claim 60, Abudayyeh teaches that the delivery vehicle is an AAV viral vector (paragraphs [0155], [0157]-[0158]).
Regarding claim 65, Abudayyeh teaches that the CRISPR composition may be introduced into a cell, wherein the cell is a eukaryotic cell (paragraph [0153]).
Regarding claim 68, Abudayyeh teaches that the CRISPR systems can be used to detect therapeutically-relevant mutations in order to inform a therapeutic method of treatment (paragraphs [0365]-[0368], [0379]).
Regarding claims 69 and 74, Abudayyeh teaches that the CRISPR systems can be used in methods for modifying a target locus of interest, the method comprising contacting the target sequences with the CRISPR composition (paragraph [0441]).
Regarding claim 76, Abudayyeh teaches a method for detecting a target nucleic acid in a sample, comprising: contacting the sample with the nucleic acid detection CRISPR system, wherein activation of the CRISPR protein via binding of the guide RNAs to the target sequences results in modification of the RNA-based masking construct, producing a detectable positive signal; and detecting the detectable positive signal (claim 72).
Regarding claim 77, Abudayyeh teaches that the method further comprises contacting the sample with nucleic acid amplification reagents (claims 75-77).
Regarding claim 80, Abudayyeh teaches that the target nucleic acid is a DNA molecule, and the method further comprises contacting the target DNA with a primer comprising an RNA polymerase site (claim 74) and an RNA polymerase (paragraph [0240]).
Regarding claim 82, Abudayyeh teaches that the masking construct comprises:
a silencing RNA that suppresses generation of a gene product encoded by a reporting construct, wherein the gene product generates the detectable positive signal when expressed (claim 18);
a ribozyme that generates the negative detectable signal, and wherein the positive detectable signal is generated when the ribozyme is deactivated (claim 19);
a ribozyme that converts a substrate to a first color and wherein the substrate converts to a second color when the ribozyme is deactivated (claim 20);
an aptamer (claim 21);
an RNA oligonucleotide to which a detectable ligand and a masking component are attached (claim 27);
a nanoparticle held in aggregate by bridge molecules, wherein at least a portion of the bridge molecules comprises RNA, and wherein the solution undergoes a color shift when the nanoparticle is disbursed in solution (claim 28);
a quantum dot linked to one or more quencher molecules by a linking molecule, wherein at least a portion of the linking molecule comprises RNA (claim 31); or
RNA in complex with an intercalating agent, wherein the intercalating agent changes absorbance upon cleavage of the RNA (claim 32).
Regarding claim 85, Abudayyeh teaches that the one or more guide RNAs comprise a mismatch (claim 34).
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 1-2, 5, 21-24, 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14, 20 of U.S. Patent No. US 11618896 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims recite engineered, non-naturally occurring systems comprising a Cas13 protein less than 900 amino acids long and one or more guide RNAs (claims 1-5, 20) (required by instant claims 1-2, 5, 21-23). The issued claims also recite that the Cas13 protein is fused or linked to an adenosine or cytidine deaminase domain (claims 6-14) (required by claims 24, 27).
Claims 1-2, 5, 8, 21-23, 53, 55, 58-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. US 11773412 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims recite engineered compositions comprising a Cas protein comprising at least one HEPN domain, including Cas13 and encompassing Cas13 proteins less than 900 amino acids long, and one or more guide RNAs (claims 1-7). The issued claims further recite vector systems, including viral vector systems, comprising the compositions (claims 18-24); regulatory elements operably linked to nucleic acids encoding the components of the compositions (claims 11, 20); and configuration of the nucleic acids encoding the composition optimized for expression in eukaryotic cells (claim 8).
Claims 1-2, 5, 7-8, 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. US 11739308 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims recite an engineered composition comprising a Cas13b protein and one, two, or more guide RNAs (claims 1-5), wherein the guide RNA hybridizes to a target RNA sequence in a prokaryotic or eukaryotic cell (claims 6-7).
Claims 1-2 are sufficiently broad as to encompass any composition comprising a Cas13, or other Cas protein comprising one or more HEPN domains, that is less than 900 amino acids long, and at least one guide RNA. Claims 7 and 8 are sufficiently broad as to encompass any such composition that comprises more than one guide RNA (claim 7) and which can be used in prokaryotes or eukaryotes (claim 8). Claim 21 encompasses any guide RNA-Cas complex, as guide RNAs require a tracrRNA sequence in order to complex with a Cas protein. Claim 22 encompasses any Cas13 protein, as they inherently comprise two HEPN domains. Claim 23 encompasses any CRISPR system of claim 1 encoded in a nucleic acid. Applicants have numerous patents and patent applications filed whose claims encompass compositions comprising Cas proteins comprising one or more HEPN domains and comprising one or more guide RNAs, and which compositions are designed for use in prokaryotes or eukaryotes. The above nonstatutory double patenting rejections over US 11618896 B2, US 11773412 B2, and US 11739308 B2 are exemplary patents which encompass such broadly-recited compositions. The following is a list of issued patents and pending patent applications which encompass the broadly-recited compositions of claims 1-2, 7-8, 21-23:
US 10266887 B2, US 11021740 B2, US 11021740 B2, US 12037639 B2, US 11104937 B2, US 11104937 B2, 17/495219, US 11618896 B2, US 11685916 B2, US 11633732 B2, US 11702649 B2, US 11739308 B2, 18/349707, US 11767528 B2, US 12297433 B2, 19/171510, US 11788083 B2, 18/334046, 18/334074, US 11840711 B2, 18/480647, US 11898142 B2, 18/430788, US 12215318 B2, US 12234454 B2, US 12221636 B2, 19/049171, US 12350368 B2, US 12415000 B2, US 12421507 B2, US 12435330 B2, US 12522807 B2, 16/450699, 16/450852, 16/450825, US 11060115 B2, US 11421250 B2, US 11773412 B2, 18/235760, 16/623799, 16/626396, 16/756134, 16/617560, 17/065504, 16/955380, 16/756139, 17/273999, 16/961820, 17/372406, 17/439063, 17/610942, 17/264340, 18/965675, 17/288504, 17/772782, 17/807405, 17/779953, 18/251277, 18/023538, 18/701358, 18/814007, 18/906750, 18/965935, 18/579685.
Claims 1-2, 7-8, 21-23 of the instant application are rejected for nonstatutory double patenting over the above-listed patents and patent applications. Applicants are advised to examine the above-listed patents and patent applications and file appropriate terminal disclaimers.
Claims 1-2, 7-8, 19, 21-24, 27, 37, 40, 52-53, 55, 58-60, 65, 68-69, 71, 74, 87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-6, 8-12, 19, 24-26, 28, 31, 33-34, 36, 38, 40-42, 44 of copending Application No. 17610942 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims recite a composition comprising a Cas13, including the short Cas13d, and one or more guide RNAs (claims 1, 11-12, 19, 24), and further comprising a repair template for homology-directed repair (claims 11, 24). The copending claims also recite a dCas13 fused to a nucleotide deaminase (claim 19); vectors, including viral vectors comprising the compositions (claims 5-6, 8); nucleic acids encoding the composition (claim 10); regulatory elements operably linked to the nucleic acids encoding the components of the composition (claims 1, 25-26); methods of modifying target nucleic acids using the compositions, in eukaryotic cells (claims 1, 38, 40).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 7-8, 19, 21-23, 40, 65, 68-69, 71, 74, 87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 14, 16, 18, 20, 24, 28-32 of copending Application No. 17288504 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims recite a composition comprising a Cas13, including the short Cas13d, and one or more guide RNAs (claims 1, 5), and further comprising a repair template for homology-directed repair (claims 3-4, 28). The copending claims also recite methods of modifying target nucleic acids using the compositions, in eukaryotic cells (claims 28-31).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 7-8, 19, 21-24, 27, 37, 40, 52-53, 55, 58-60, 65, 68-69, 71, 74, 87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 11-36 of copending Application No. 17807405 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims recite a composition comprising a Cas13, including the short Cas13d, and one or more guide RNAs (claims 11, 16-17), and further comprising a repair template for homology-directed repair (claims 11). The copending claims also recite a dCas13 fused to a nucleotide deaminase (claim 11); vectors, including viral vectors comprising the compositions (claims 28); nucleic acids encoding the composition (claim 1); methods of modifying target nucleic acids using the compositions, in eukaryotic cells (claims 30-33).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 7-8, 21-24, 27, 37, 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. US 11685916 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims recite an engineered system comprising dCas13b of less than 900 amino acids and at least one guide RNA, wherein the dCas13b is fused or linked to a deaminase domain. The issued claims further recite methods of modifying bases in a target sequence using the composition (claims 1-6).
Claims 1-2 are sufficiently broad as to encompass any composition comprising a Cas13, or other Cas protein comprising one or more HEPN domains, that is less than 900 amino acids long, and at least one guide RNA. Claims 7 and 8 are sufficiently broad as to encompass any such composition that comprises more than one guide RNA (claim 7) and which can be used in prokaryotes or eukaryotes (claim 8). Claim 24 is sufficiently broad as to encompass any composition comprising a Cas13-deaminase fusion protein and guide RNA. Applicants have numerous patents and patent applications filed whose claims encompass compositions comprising Cas-deaminase fusion proteins comprising one or more HEPN domains and comprising one or more guide RNAs, and which compositions are designed for use in prokaryotes or eukaryotes. The above nonstatutory double patenting rejections over US 11618896 B2 and US 11685916 B2 are exemplary patents which encompass such broadly-recited compositions. The following is a list of issued patents and pending patent applications which encompass the broadly-recited compositions of claims 1-2, 7-8, 21-24, 27, 40:
US 11618896 B2, US 11685916 B2, US 11840711 B2, 18/480647, US 12221636 B2, 19/049171, US 12421507 B2, 16/623799, 16/756134, 16/617560, 16/756139, 17/372406, 17/610942, 17/264340, 18/965675, 17/807405, 17/779953, 18/334046, 18/349707, 18/965935, 18/579685.
Claims 1-2, 7-8, 21-24, 27, 40 of the instant application are rejected for nonstatutory double patenting over the above-listed patents and patent applications. Applicants are advised to examine the above-listed patents and patent applications and file appropriate terminal disclaimers.
Claims 1-2, 7-8, 21-23, 47, 76-77, 80, 82, 85 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US 10266887 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims recite methods for detecting target nucleic acids in samples, comprising: contacting the samples with reagents for amplifying the target sequences; a Cas 13 which comprises at least one HEPN domain; at least one guide sequence; an RNA-based masking construct; an RNA polymerase; a primer comprising an RNA polymerase site (claims 1-14).
Claims 1-2, 7-8, 21-23, 44-45, 47, 65, 76-77, 80, 82, 85 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. US 11898142 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims recite systems for detecting polypeptides, comprising: a Csm6 protein (which comprises at least one HEPN domain) or C2C2 or Cas13b (claims 2, 4-9), one or more guide RNAs designed to bind to trigger RNAs, one or more RNA-based masking constructs, and one or more polypeptide detection aptamers (claim 2). The issued claims recite methods for detecting nucleic acids in a sample, comprising contacting the sample with a system comprising a Cas protein comprising at least one HEPN domain (claims 1, 4-9), one or more guide RNAs designed to bind to corresponding target nucleic acids, and one or more RNA-based masking constructs (claims 1, 4-20, 23, 32-39, 43) and further comprising nucleic acid amplification reagents (claims 3).
Claims 44-45, 47, 76-77, 80, 82 recite compositions for and methods of detecting target nucleic acids or target polypeptides, comprising contacting samples with a Cas-gRNA composition, a detection aptamer, and nucleic acid amplification reagents. Applicants have numerous patents and patent applications filed whose claims encompass such compositions and methods for detecting target nucleic acids or polypeptides. The above nonstatutory double patenting rejections over US 10266887 B2 and US 11898142 B2 are exemplary patents which encompass such methods and compositions. The following is a list of issued patents and pending patent applications which encompass the broadly-recited compositions of claims 1-2, 7-8, 44-45, 47, 76-77, 80, 82:
US 10266887 B2, US 10266886 B2, US 12037639 B2, US 11021740 B2, US 11104937 B2, US 11174515 B2, 17/495219, US 11633732 B2, US 11702649 B2, US 11898142 B2, 18/430788, US 12221636 B2, 19/049171, US 12415000 B2, 16/450852, 16/450825, US 11421250 B2, 18/235760, 16/623799, 16/756134, 16/617560, 17/065504, 16/955380, 16/756139, 17/273999, 16/961820, 17/372406, 17/439063, 17/264340, 17/772782, 18/251277, 18/349707, 18/023538, 18/480647, 18/334074, 18/814007, 18/906750.
Claims 1-2, 7-8, 44-45, 47, 76-77, 80, 82 of the instant application are rejected for nonstatutory double patenting over the above-listed patents and patent applications. Applicants are advised to examine the above-listed patents and patent applications and file appropriate terminal disclaimers.
Claims 52-53, 55, 58-60 broadly recite vectors, including viral vectors and nucleic acids, comprising or encoding a Cas13-gRNA system. Applicants have numerous patents and patent applications filed whose claims encompass such viral vectors and nucleic acids. The above nonstatutory double patenting rejections over US 11773412 B2 and copending Application No. 17610942 are exemplary patents and copending applications which encompass such vector compositions. The following is a list of issued patents and pending patent applications which encompass the broadly-recited compositions of claims 52-53, 55, 58-60:
US 11685916 B2, US 11767528 B2, 19/171510, US 11788083 B2, 18/334046, US 11840711 B2, 18/480647, US 12215318 B2, US 12221636 B2, 19/049171, US 12350368 B2, US 12415000 B2, 16/450699, US 11060115 B2, US 11421250 B2, US 11773412 B2, 18/235760, 16/623799, 16/626396, 16/756134, 16/617560, 17/065504, 16/756139, 17/273999, 17/372406, 17/610942, 17/264340, 18/965675, 17/807405, 18/349707, 18/965935.
Claims 52-53, 55, 58-60 of the instant application are rejected for nonstatutory double patenting over the above-listed patents and patent applications. Applicants are advised to examine the above-listed patents and patent applications and file appropriate terminal disclaimers.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached on (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
For those applications where applicant wishes to communicate with the examiner via Internet communications, e.g., email or video conferencing tools, the following is a sample authorization form which may be used by applicant:
"Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file."
To facilitate processing of the internet communication authorization or withdraw of authorization, the Office strongly encourages use of Form PTO/SB/439, available at www.uspto.gov/patent/patents-forms. The form may be filed via EFS-Web using the document description Internet Communications Authorized or Internet Communications Authorization Withdrawn to facilitate processing. See MPEP 502.03(II).
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635