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 of Group I (claims 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, 33, 39-41, 45, 47-49, 54-56, 60, and 68-69, directed to a non-naturally occurring, engineered composition comprising an ISCB polypeptide) in the reply filed on January 26, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 18, 42, 50, 53, 57, 59, 70, and 72, directed to a method and an isolated cell or progeny comprising the modifications using the method withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim.
Accordingly, claims 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, 33, 39-41, 45, 47-49, 54-56, 60, and 68-69 are examined herein.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/105,177 filed on October 23, 2020.
Drawings
The drawings are objected for the following reasons: 37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” In the current case, the view numbers for the partial views for Figures 11, 12, 20, 32A, 32B, 33A, 33B, 33C, 38A, 43, 48, and 58 that appear on several sheets are followed by "Cont." instead of a capital letter such as FIG. 1A, FIG. 1B, etc. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
An incomplete sentence “C-terminal domain” is present at the end of [0135], and it is not clear whether this is intended to be the heading for [0136].
In [01035] - [01040] there are terms including "Applicantsperformed" "Applicantsfirst examined" and "Applicantsconfirmed" where a space is missing between the two words.
In [01040], there is the recitation of "Fig. 2C" but Figure 2C is not provided in the supplemental drawings.
In [01035], the specification disclosed Fig. 1A as an illustration of the architecture of IscB, but FIG. 1A is not provided in the supplemental drawings, and the instant FIG. 1 teaches IscB cleaving dsDNA encoding different spacers. If Applicant intends to cite Fig. 1A of the reference Kapitonov et al (ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs; Journal of Bacteriology, 2016, 198(5):797-807), it is recommended that Fig. 1A is cited within the same parenthesis of the reference.
Appropriate correction is required.
The use of the terms “9° N™ DNA Ligase” and “SplintR®Ligase”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: The specification fails to provide proper antecedent basis for “CRISPR-associated single guide molecule” recited in claims 45, 54, and 60. The specification discloses “CRISPR-associated ωRNAs” ([01086]) and “CRISPR-associated ncRNA” ([01128]), which are structurally different. The state of the art does not teach any “CRISPR-associated single guide molecule” that is “capable of forming a complex with the IscB protein of claim 22 and directing site-specific binding at a target sequence”.
Claim Objections
Claim 27 objected to because of the following informalities: the recitation of “and/or wherein comprising a CRISPR-associated guide molecule capable of forming a complex with the IscB protein and directing site-specific binding of the complex to a target sequence of a target polynucleotide” is duplicated within the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, and 39-41 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., law of nature, natural phenomenon, or product of nature) without significantly more. The inventor discloses and claims compositions comprising naturally occurring products. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See the subject matter eligibility test below:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter?
Claims 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, 33, 39-41, 45, 47-49, 54-56, 60, and 68-69 recite "a composition comprising…”. Thus, the claimed invention is directed to a process, machine, manufacturer or composition of matter.
Step 2A, Prong 1: Do the claims recite an abstract idea, product of nature, or natural phenomenon?
Claim 1 recites “a non-naturally occurring, engineered composition comprising…”, which is subject matter that falls within the product of nature exception. As MPEP 2106 states “…neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible."). Thus, a synthetic, artificial, or non-naturally occurring product such as a cloned organism or a human-made hybrid plant is not automatically eligible because it was created by human ingenuity or intervention. See, e.g., In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1337, 110 USPQ2d 1668, 1671-72 (Fed. Cir. 2014) (cloned sheep); cf. J.E.M. Ag Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U.S. 130-132, 60 USPQ2d 1868-69 (2001) (hybrid plant).” Accordingly, the broadest reasonable interpretation of “non-naturally occurring” encompass synthetically made products, and the recitation of “engineered” refers to a process of “genetic engineering”. Without more, merely reciting “non-naturally occurring” and “engineered” in the preamble of claim that is otherwise structurally and functionally identical to what occurs in nature will also not be interpreted as a markedly different characteristic.
Claim 1 encompasses an IscB protein comprising a Ruv-C nuclease domain, an HNH domain, or both. Kapitonov et al (ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs; Journal of Bacteriology, 2016, 198(5):797-807) teaches that Ktedonobacter racemifer naturally encodes IscB polypeptides, including an IscB2 protein that contains an HNH insertion within RuvC-like domain and an IscB1 protein that encodes only a RuvC-like domain (pg. 799, left-column, second paragraph). The specification also teaches the elected species for examination (SEQ ID NO: 2063) is encoded by OGEU01000025.1 (metagenome genome assembly, contig: NODE_25_length_150080_cov_8.882980, wholegenome shotgun sequence, NCBI reference sequence, Entrez Nucleotide Version date: Jan 23, 2018, 34 pages). The specification also discloses additional IscB polypeptide sequences (Tables 1-3), all of which are likewise encoded in natural genomes. Accordingly, the claimed IscB polypeptide is found in nature.
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Claim 1 further recites an ωRNA comprising a scaffold and a “reprogrammable” spacer sequence. Naturally occurring ωRNAs inherently contain both a scaffold and a spacer sequence capable of being reprogrammed; thus, the characterization of “reprogrammable” does not impart a structural distinction. Naturally occurring ωRNAs do not need to be pre-programmed to possess this property of “reprogrammable”. The claim additionally recites that the ωRNA is capable of forming a complex with the IscB polypeptide and directing the IscB polypeptide to a target polynucleotide. The specification teaches the elected species for examination (SEQ ID NO: 2064) is encoded by OGEU01000025.1 and encompasses the recited functions (FIG. 6A-6C, [01032]), and additional ωRNA sequences in Table 1, all of which are likewise encoded in the same natural genomes as the corresponding IscB polypeptide. Accordingly, the claimed ωRNA is also found in nature.
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Thus, claim 1 refers to a judicial exception because IscB polypeptide and ωRNA molecule are products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 2 recites “a PLMP domain”, which the specification teaches it is a conserved N-terminal domain referred as a PLMP domain or an X domain ([0133]). Table 2 further demonstrates that naturally occurring IscB polypeptides constitute an X domain. Thus, claim 2 refers to a judicial exception because the recited PLMP domain is a product of nature that lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 4 refers to a judicial exception because it merely recites structure of naturally occurring IscB polypeptides. As taught by Kapitonov, IscB contains a RuvC-like domain split by the insertion of a bridge helix and an HNH endonuclease domain, an architecture that is shared with Cas9 (FIG. 1, pg. 799). The specification also teaches the HNH domain is inserted between RuvC-II and RuvC-III subdomains (FIG. 9A). Thus, the IscB polypeptide recited in claim 4 lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 6 refers to a judicial exception because Kapitonov teaches the studied naturally occurring IscB protein is 1,594 base pairs long (about 531 amino acids), thus the recited IscB length in the instant claim is a property that lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 7 refers to a judicial exception because it encompasses naturally occurring ωRNAs that contain spacer sequences which lengths fall within the claimed range. Although claim recites a “reprogrammable spacer sequence”, it does not confer any markedly different characteristics as explained above and applied to claim 1. Thus, claim 7 recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 8 refers to a judicial exception because cells that naturally contain the composition of claim 1 necessarily include target sequence comprising a target adjacent motif (TAM) sequence 3’ of the target polynucleotide as this is the natural mechanism of action of IscB-mediated nuclease targeting. Thus, claim 8 recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 12 recites “a functional domain associated with the IscB protein”. Under the broadest reasonable interpretation, it broadly encompasses any functional domain associated with IscB protein, including those that act upstream, downstream, or in conjunction with IscB protein as the claim does not require that the functional domain be covalently linked to the IscB protein, nor does it recite any structural alteration of the IscB protein itself. Cells naturally containing IscB proteins also contains additional functional domains that are inherently present and act in concert with nucleases, including enzymes involved in DNA repair and processing following nuclease cleavage events. Thus, claim 12 refers to a judicial exception because it merely recites additional products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 14 refers to a judicial exception because the claim does not require any modification or functional alteration of the recombinase relative to its naturally occurring counterpart. Thus, claim 14 merely recites the presence of an additional naturally occurring enzyme, in combination with naturally occurring composition of claim 1, that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 16 refers to a judicial exception because the specification teaches “vectors include nucleic acid molecules that are…double-stranded...” ([0555]) and cells naturally containing IscB polypeptide and ωRNA molecule also naturally contains vectors that encode for them. Thus, claim 16 recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 17 refers to a judicial exception because there are cells that contain the naturally occurring composition of claim 1, as discussed above and applied to claim 1. Although claim recites a “engineered”, it does not confer any markedly different characteristics as explained above and applied to claim 1. Thus, claim 17 recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 22 recites “engineered” and “non-naturally occurring” which do not confer any markedly different characteristics as discussed above as applied to claim 1. The claim recites an IscB protein comprising an N-terminal X domain, a RuvC domain, a Bridge Helix domain, and a C-terminal Y domain, which architecture exhibits the same domain composition and structure as naturally occurring IscB1 proteins taught by Kapitonov (pg. 799). The specification teaches multiple examples of IscB proteins whose sequences are encoded in natural genomes and further identifies the presence of the recited domains (Table 2). The specification further discloses that Y domain is included within the X domain listed in Table 2 ([0261]). Accordingly, claim 22 refers to a judicial exception because the recited IscB protein is a product of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claims 23-25 refers to a judicial exception because IscB homologs in nature have diverse sequences with conserved functional domains, and the instant claims merely defines a subset of naturally occurring IscB proteins. The specification teaches examining “a cluster of CRISPR-associated IscBs similar to non-CRISPR associated IscBs (at ~50% amino acid identity)” ([01036]) with a representative IscB protein. This genomic sequence comparison demonstrates that sequences of naturally occurring IscB homologs can differ by more than 50%. The instant claims merely recite natural sequence variation within a protein family. Thus, the instant claims still correspond to products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 26 refers to a judicial exception because the specification teaches naturally occurring X domains are no more than 50 amino acids in length (Table 2); thus, claim 26 recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 27 refers to a judicial exception because the specification teaches the naturally occurring composition of claim 22 also further naturally comprises an HNH domain (Table 2, e.g., SEQ ID NO: 2043); thus claim 27 recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 29 refers to a judicial exception because it encompasses naturally occurring IscB proteins whose lengths fall within the claimed range. Accordingly, claim 29 recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claims 39-41 refers to a judicial exception because the recited limitations are products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart as discussed above and applied to claims 16-17.
Claim 33 pass the subject matter eligibility test because the nuclease domains of naturally occurring IscB proteins are catalytically active, and the specification teaches introduction of specific mutations (E157A on RuvC-II subdomain or H212A on HNH domain) abolish the nucleolytic activity of IscB protein ([01042]). Thus, this recited limitation is interpreted as imparting markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart, and claim 33 is NOT directed to judicial invention.
Claim 45 pass the subject matter eligibility test for the same reasons discussed above as applied to claim 33. The instant claim further recites a nucleotide deaminase associated with the IscB protein, which also confers as a markedly different structural or functional characteristics. Therefore, claim 45 is NOT directed to a judicial invention. Accordingly, its dependent claims 47-49 reciting “polynucleotides”, “vector”, and “cell” comprising the components of claim 45 are also NOT directed to a judicial invention.
Claim 54 pass the subject matter eligibility test for the same reasons discussed above as applied to claim 33. The instant claim further recites a reverse transcriptase associated with the IscB protein, which also confers as a markedly different structural or functional characteristics. Therefore, claim 54 is NOT directed to a judicial invention. Accordingly, its dependent claims 55-56 reciting “polynucleotides”, and “vector” comprising the components of claim 54 are also NOT directed to a judicial invention.
Claim 60 pass the subject matter eligibility test for the same reasons discussed above as applied to claim 33. The instant claim further recites a non-LTR retrotransposon associated with the IscB protein, which also confers as a markedly different structural or functional characteristics. Therefore, claim 60 is NOT directed to a judicial invention. Accordingly, its dependent claims 68-69 reciting “polynucleotides”, and “vector” comprising the components of claim 54 are also NOT directed to a judicial invention.
Step 2A, Prong 2: Do the claims recite additional elements that integrate the judicial exception into a practical application?
Claims 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, and 39-41 do NOT recite any additional elements, and therefore, they do not include recite additional elements that integrate the judicial exception into a practical application.
Step 2B: Do the claims recite additional elements that amount to significantly more than the judicial exception?
Claims 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, and 39-41 do NOT recite any additional elements, and therefore, they do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 112
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 39-41, 47-49, 55-56, and 68-69 are 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. 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.
Claims 39 and 41 recite “one or more components of the composition of claim 22”. Claim 22 recites a composition comprising an IscB protein, wherein the IscB protein comprises four different domains. A dependent claim must further limit the subject matter of the claim from which it depends and include all of the limitations of that claim. Claims 39 and 41 omit the required composition of claim 22, do not further limit the composition, and shift the scope of the invention to different subject matter (e.g., nucleic acids, vectors, and cells). Thus, claims 39 and 41 are of improper dependent form.
Claim 40 is dependent of claim 39 that is of improper dependent form (see discussion above). Further, claim 40 fails to include all of the limitations of the composition of claim 22 for the same reason discussed as applied to claims 39 and 41.
Claims 47, 55, and 68 recites “one or more polynucleotides encoding one or more components of the composition” of claims 45, 54, and 60, respectively. However, claims 45, 54, and 60 recite a composition comprising multiple structural components, including an IscB protein, specific enzymes, a CRISPR-associated single guide molecule, and optional functional and sequence limitations. A dependent claim must further limit the subject matter of the claim from which it depends and include all of the limitations of that claim. Claims 45, 54, and 60 require a multi-component composition that includes at a minimum, two proteins and an RNA molecule. However, dependent claims 47, 55, and 68 are directed only to one or more components of corresponding compositions. Accordingly, dependent claims 47, 55, and 68 omits essential structural limitations of claims from which they depend, changes the scope of the invention from a multi-component invention to polynucleotides, and do not further limit the claimed composition. Thus, claims 47, 55, and 68 are of improper dependent form.
Claims 48, 56, and 69 are dependent of claims 47, 55, and 68 that are of improper dependent form (see discussion above). Further, claims 48, 56, and 69 also fails to include all of the limitations of the compositions of 45, 54, and 60, respectively.
Claim 49 fails to include all of the limitations of the multi-component composition of claim 45 as discussed above as applied to claims 47, 55, and 68.
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 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, 33, 39-41, 45, 47-49, 54-56, 60, and 68-69 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 “an IscB polypeptide comprising a split Ruv-C nuclease domain comprising RuvC-I, RuvC-II, and RuvC-III subdomains, an HNH domain or both”, which renders the claim indefinite. It is not clear if the IscB polypeptide comprises i) a Ruv-C domain that itself comprises RuvC-I, RuvC-II, and RuvC-III subdomains, or ii) an HNH domain, or iii) both a Ruv-C nuclease domain and an HNH domain. It is not clear if the IscB polypeptide comprises i) a Ruv-C nuclease domain comprising RuvC-I, RuvC-II subdomains, and ii) Ruv-C III subdomain, an HNH domain, or both. It is not clear whether RuvC-I, RuvC-II, and RuvC-III subdomains are required in all embodiments, or only in embodiments comprising a Ruv-C nuclease domain. It is not clear whether the recitation “or both” refers to an Ruv-C nuclease domain and an HNH domain or to a Ruv-C III subdomain and an HNH domain.
Claim 22 recites “a C-terminal Y domain” which renders the claim indefinite. The specification teaches “the C-terminal domain (also referred to herein as a Y domain) may comprise one or more conserved residues or motifs as shown in FIG. 3 ([0136]), which illustrates a sequence alignment of various polypeptides. The structure of the C-terminal Y domain is not defined in the specification or known in the art. Accordingly, a person of ordinary skill in the art would not be able to determine the metes and bounds of a C-terminal Y domain with reasonable certainty.
Claims 23 recites “wherein the X domain has an amino acid sequence that share at least 50%...sequence identity with X domains in Table 2”, which renders the claims indefinite. MPEP 2173.05(s) states "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted)." It is unclear which sequences in Table 2 are intended as the reference for determining 50% sequence identity given that not all sequences in Table 2 contain an X domain. The claims do not specify whether sequences lacking the X domain are excluded from comparison. Accordingly, a person of ordinary skill in the art would not be able to determine the scope of the claim with reasonable certainty.
Claim 24 recites “wherein the Y domain has an amino acid sequence that share at least 50%...sequence identity with Y domains in Table 2”, which renders the claim indefinite. See MPEP 2173.05(s) citation above. None of the sequences recited in Table 2 are labeled to contain a Y domain. The specification teaches “in an embodiment, the X domain include Y domains in Table 2” ([0261]); however, it is unclear which amino acid sequences of the X domains encode Y domains. Thus, it is unclear which sequences in Table are intended as the reference for determining 50% sequence identity. Accordingly, a person of ordinary skill in the art would not be able to determine the scope of the claim with reasonable certainty.
Claim 25 recites “wherein the IscB protein shares at least 80%...sequence identity with a IscB protein selected from Tables 2 and 3”, which renders the claim indefinite. See MPEP 2173.05(s) citation above. It is unclear which specific features, domains, or combinations thereof define the scope of the claim. It is unclear whether the claim encompasses all entries in Tables 2 and 3, only certain embodiments in the tables, or any variants thereof. By reciting the relevant accession numbers, amino acid ranges, or domain compositions directly in the claim language would clearly identify which IscB sequences and structures are required.
Claim 33 recites the limitation “the nuclease domains”. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites “a split Ruv-C nuclease domain comprising RuvC-I, RuvC-II, and RuvC-II subdomains, an HNH domain, or both” (see indefiniteness discussion above for claim 1). It is unclear which nuclease domains (plural) are catalytically inactive. If the IscB polypeptide in claim 1 comprises only a split RuvC-nuclease domain, it is unclear whether all the subdomains are catalytically inactive or only two, and which two. Further, claim 33 recites “wherein the nuclease domains (plural) of the IscB proteins are catalytically inactive, optionally, wherein the nuclease domain (singular) has nickase activity or is engineered to have nickase activity”. This claim is indefinite because it recites mutually inconsistent limitations. A nuclease domain that exhibits nickase activity necessarily retains catalytic activity, and thus cannot reasonably be understood as catalytically inactive. Accordingly, it is unclear whether the scope of the claim constitutes a catalytically inactive nuclease domain, a partially active nickase domain, or both.
Claim 41 recites “a cell or progeny thereof”, which renders the claim indefinite. It is unclear if the progeny thereof is also genetically engineered to expresses the compositions of claim 22 or not because the claim does not specify whether the expression of the compositions of claim 22 is required in the progeny. Accordingly, a person of ordinary skill in the art would not be able to determine the scope of the claim with reasonable certainty.
Claims 45, 54, and 60 recites “CRISPR-associated single guide molecule” which renders the claims indefinite. The specification discloses “CRISPR-associated wRNAs” ([01086]) and “CRISPR-associated ncRNA” ([01128]), which are structurally different. The state of the art does not teach any “CRISPR-associated single guide molecule” that is “capable of forming a complex with the IscB protein and directing site-specific binding at a target sequence”. Accordingly, a person of ordinary skill in the art would not be able to determine the structure of the recited “CRISPR-associated single guide molecule” and the scope of the claim with reasonable certainty.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4, 6-8, 12, 14, 16-17, 22-27, 29, 33, 39-41, 45, 47-49, 54-56, 60, and 68-69 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Claims 1 is drawn to a composition comprising an IscB polypeptide and an ωRNA molecule. The claim further encompasses a genus of IscB polypeptide and ωRNA molecule with two functional relationships: (1) is capable of forming a complex with each other and (2) the ωRNA molecule is capable of directing the IscB polypeptide to a target polynucleotide.
The specification disclosed actual practice and complete structures of two single species: i) the elected species for examination, SEQ ID NO: 2063 and 2064 (FIG. 7A and 7B, FIG. 6A-6C, [01032-01033]), and ii) AwaIscB (FIG. 15E, [01041-01042]). The specification further discloses sequences of numerous naturally occurring IscB polypeptides and ωRNA molecules (Table 1) without actual reduction to practice. It is well-known to a person skilled in the art that functions and activity may vary greatly depending on the overall structures and subdomains that constitute an active enzyme. The specification supports this argument as activity of 57 of the 86 (66%) selected phylogenetically diverse IscB systems were identified by the identification of a target adjacent motif (FIG. 48), but of these 57 functional IscBs, only 5 could be reconstituted with the respective ωRNA molecule in vitro to achieve efficient target cleavage (one of them being AwaIscB) ([01041]). Thus, it is not specifically shown which IscB polypeptide and ωRNA molecule, other than the limited working examples, can form complexes with the required functional relationships. Without a recognized correlation between structure and function, one of skill in the art would not be able to identify without further testing which IscB polypeptide and ωRNA molecule combination constitutes the recited composition of claim 1.
The state of the art does not teach the complete structure of ωRNA molecules capable of performing the two required functional relationships as the specification discloses “despite its wide distribution across prokaryotes and shared domain composition and architecture with Cas9, the function of IscB remains unknown” ([01034]). Kapitonov et al (ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs; Journal of Bacteriology, 2016, 198(5):797-807) supports this argument with statement of “more complicated mechanisms of action of …IscB proteins cannot be ruled out, in particular those that would involve RNA binding via the arginine-rich helices of these proteins. Such a possibility seems particularly plausible for the IscB2 proteins, which might function analogously to Cas9 proteins, which employ the HNH nuclease domain to cleave the DNA strand paired with the CRISPR RNA and the RuvC-like domain to cleave the opposite strand” (pg. 806). Further, the specification teaches “the conserved region encodes an ncRNA containing functionally important hairpins, which Applicant named ωRNA” ([01039]). Accordingly, no prior art teaches the correlation between structure and function of ωRNA.
Further, dependent claims 2, 4, 6-8, 12, 14, 16-17, and 33 recite structural limitations of the IscB polypeptide including a PLMP domain and location of the NHN domain, length of the IscB polypeptide and ωRNA spacer sequence, characteristics of the target polynucleotide, and additional domains associated with the IscB polypeptide, all of which fail to remedy the lack of written description therein. Therefore, these dependent claims are also rejected for depending from a rejected claim.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of IscB polypeptide and ωRNA molecules, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of IscB polypeptides and ωRNA molecules with recited functions.
Claim 12 is drawn to a composition of claim 1 that further comprises “a functional domain associated with the IscB protein”. This claim encompasses a genus of any functional domain fused, operably coupled to, associated upstream or downstream, or in conjunction with the IscB protein.
The specification teaches the possible activities of the functional domain ([0211]), its possible location to the terminus of the IscB protein ([0212]), and additional suitable functional domains can be found to be associated with Cas13 proteins ([0213]). However, the specification fails to disclose actual reduction to practice of any species of this broad genus, any disclose of drawings or structures, sufficient relevant identifying characteristics including complete structure, partial structure (e.g., sequences of exemplary functional domains and residues of the IscB protein where the functional domain is fused to), and functional characteristics couples with a known or disclosed correlation between function and structure (i.e., capable of associating with each other), a method of making the claimed composition.
The state of the art does not teach any functional domains associated with the IscB protein in the composition of claim 1, which is required to be structurally functional to ωRNA molecules. Although functional domains associated with CRISPR-associated Cas13 proteins are known in the art, Kapitonov teaches that “IscB proteins, the closest homologs of cas9 not linked to CRISPR-Cas systems, are encoded by a distinct group of transposons” (pg. 804, right-column, second paragraph), and the specification supports this teaching by stating “no IscB has been reported to be associated with non-coding RNA or CRISPR assays ([01034]). Thus, without a recognized correlation between structure and function, one of skill in the art would not be able to identify without further testing which functional domain in the recited broad genus associates with the IscB protein.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of IscB protein and functional domains associated to it, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of functional domains in claim 12.
Claim 22 is drawn to a composition comprising an IscB protein that comprises an N-terminal X domain, a RuvC domain, a Bridge Helix domain, and a C-terminal Y domain. This claim is drawn to possession of any IscB protein that comprises these structures.
The specification teaches the N-terminal X domain comprises a conserved PLMP amino acid motif (FIG. 3, [0133]) and a Y domain as shown in Table 2 ([0261]). However, Table 2 does not identify or annotate any Y domain, nor does it delineate the boundaries of a Y domain within the listed IscB protein sequences. Accordingly, it is unclear whether any of the IscB proteins listed in Table 2 constitute species of the claimed genus. Additionally, the specification teaches that the C-terminal Y domain “may comprise one or more conserved residues or motifs as shown in FIG. 3” ([0136]), but the brief description of FIG. 3 identifies this figure as a sequence logo of an N-terminal domain. The specification does not clearly indicate whether the conserved motifs in FIG. 3, other than PLMP that constitutes the X domain, correspond to the Y domain. Although the specification teaches the “C-terminal domain is structurally homologous to a tudor domain” ([0137]), the correlation between the asserted structural homology with the conserved motif in FIG. 3 is not disclosed. Moreover, structural homology to a tudor domain does not by itself establish possession of a specific C-terminal Y domain, particularly where the Y domain is described to be within “a previously unidentified N-terminus that lacks clear homology to known domains and is absent in Cas9, which we denoted PLMP” or X domain ([01035]). The specification fails to disclose i) whether such conserved motifs are also located at the C-terminus, as required by the instant claim, ii) any species of IscB protein comprising the required C-terminal Y domain, iii) any species of IscB protein comprising the required complete structure, or iv) an actual reduction to practice.
The state of the art does not teach any IscB proteins comprising a N-terminal X domain and a C-terminal Y domain, supported by the specification that the N-terminal X domain was previously unidentified ([01035]).
Further, dependent claims 23-27, 29, 39-41, 45, 47-49, 54-56, 60, and 68-69 do not recite any limitations that support the possession of any species of IscB protein recited in claim 22; Thus, dependent claims are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and lack of prior art on IscB proteins comprising N-terminal X domain and C-terminal Y domain, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of IscB proteins comprising the recited structure of claim 22.
Claim 23 is drawn to the composition of claim 22 wherein the X domain has an amino acid sequence that shares at least 50% sequence identity with X domains in Table 2. This claim encompasses a broad genus of X domains sharing only 50% sequence identity.
The teachings of the specification regarding the X domain are discussed above as applied to claim 22. The specification teaches the X domain is characterized by a conserved PLMP four amino acid motif (FIG. 3, [0133]), which is a partial structure because all species of X domains identified in Table 2 comprises of more than 40 amino acids. The specification further teaches “truncation of more than 4 aa of the PLMP domain [X domain] of AwaIscB abolished cleavage activity (FIG. 49)” ([01043]), which indicates there is a correlation between structure and function; however, the recited AwaIscB protein is not included in Table 2. It is not clear whether this correlation applies to the IscB proteins in Table 2 as they contain X domains or it is applied to AwaIscB protein only. Nevertheless, the specification fails to disclose which residues within the remaining 50% of the X domain can be varied while retaining activity. Further, the X domains identified in Table 2 are limited to a small number of IscB proteins and are not representative species of the claimed genus. It is noted that Table 1 provides a comprehensive list of species for IscB protein but the X domains are not identified.
The state of the art does not teach any knowledge of an N-terminal X domain in IscB proteins, supported by the specification that this domain was previously unidentified and lacks clear homology to known domains and is absent in Cas9 ([01035]).
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and lack of prior art on IscB proteins comprising N-terminal X domain, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of IscB proteins wherein the X domain has an amino acid sequence that shares at least 50% sequence identity with X domains in Table 2.
Claim 24 is drawn to the composition of claim 22 wherein the Y domain has an amino acid sequence that shares at least 50% sequence identity with Y domains in Table 2. This claim encompasses a broad genus of Y domains sharing only 50% sequence identity.
The teachings of the specification regarding the Y domain are discussed above as applied to claim 22. The claim recites Y domains in Table 2, but the Y domain clearly is not identified or annotated in any of the sequences listed in Table 2. Although the specification teaches the Y domain shares a conservative motif in FIG. 3, this figure actually teaches motifs of an N-terminus domain, not C-terminal as required in claim 22. Therefore, the specification fails to disclose any structure of the C-terminal Y domain and which residue of the remaining 50% structure can be varied. Even if one or more IscB proteins in Table 2 comprises a Y domain in the X domain as taught by the specification ([0261]), this limited number of species are not representative of the claimed genus. Further, if the X domains in Table 2 comprises Y domains, the specification also fails to disclose any correlation between structure and function of the Y domain as truncation more than four amino acids in the X domain abolished IscB activity ([01043]).
The state of the art does not teach any knowledge of a C-terminal Y domain or any Y domain in IscB proteins.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and lack of prior art on IscB proteins comprising any Y domain, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of IscB proteins wherein the Y domain has an amino acid sequence that shares at least 50% sequence identity with Y domains in Table 2.
Claim 25 is drawn to the composition of claim 22 wherein the IscB protein shares at least 80% sequence identity with IscB proteins in Tables 2 and 3. This claim encompasses a broad genus of IscB proteins comprising the required structure recited in claim 22 and sharing 80% sequence identity with IscB proteins in Tables 2 and 3.
The teachings of Table 2 are discussed above as applied to claims 22-24. Table 2 provides only five protein species comprising all of the domains required by the claim. Of these five species, one species lacks an HNH domain, while the remaining four species comprise the required RuvC domain and an HNH domain (not required by the claim). The specification fails to teach whether deletion of an entire HNH domain is intended to represent the remaining 20% of the structure that can be varied. Further, with respect to the specie lacking an HNH domain (No. 1), the specification fails to teach which residues within the remaining 20% of sequence can be varied while retaining the claimed structure and function of the IscB protein. Thus, even where an IscB specie omits an entire HNH domain, the specification fails to provide guidance as to which portions of the sequence are structurally dispensable.
In addition, the only structural and functional characterization the specification provided for the RuvC and HNH domain is that a single amino acid substitution (E157A and H212A) in each domain abolishes specific nucleolytic activity ([01042]); However, this characterization is identified for AwaIscB protein, which is NOT included in Tables 2 and 3. The specification does not teach whether the same correlation between structure and function is applicable to species in Tables 2 and 3. Further, this teaching demonstrates that the RuvC and HNH domains are highly sensitive to mutations, yet the specification fails to teach which residues outside of the identified positions can be modified while preserving structure and function. Accordingly, the sequences disclosed in Tables 2 and 3 represent only partial structures and are not representative species across the claimed genus.
The state of the art, Kapitonov teaches IscB2 and Cas9 share relatively high sequence similarity in the RuvC and Bridge Helix domains (Fig. 1, 798, right-column, third paragraph), but Kapitonov does not teach the required N-terminal X domain and C-terminal Y domain, supported by the specification that the N-terminal X domain was previously unidentified ([01035]). Thus, the state of the art does not teach which residues of the remaining 20% of structure can be varied while preserving the required structure and function of IscB proteins.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and lack of prior art on IscB protein variants and domain structures, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of IscB proteins.
Claims 45, 54, and 60 are drawn to a composition comprising an IscB protein of claim 22, with all the required structures, a CRISPR-associated single guide molecule, and a nucleotide deaminase (claim 45), a reverse transcriptase (claim 54), a non-LTR retrotransposon (claim 60). The claims are drawn to a genus of CRISPR-associated single guide molecules with two functional properties: i) forming a complex with the IscB protein, and ii) directing site-specific binding at a target sequence. The claims are also drawn to a genus of enzymes, specific to each claim, with functional property either associates with or capable of forming a complex with the IscB protein.
For compact prosecution, the term “CRISPR-associated single guide molecules” is interpreted as ωRNA molecules because the specification teaches working examples of IscB and ωRNA complexes (FIG. 7A and 7B, FIG. 6A-6C, [01032-01033]; FIG. 15E, [01041-01042]). (see discussion above in 35.U.S.C. 112b). The lack of written description for a genus of ωRNA molecules with the same two functional relationships is discussed above as applied to claim 1 and equally applies here. The lack of written description for a genus of functional domains as discussed above and applied to claim 12 is also applied here for a genus of nucleotide deaminase (claim 45), a reverse transcriptase (claim 54), a non-LTR retrotransposon (claim 60).
Further, dependent claims 47-49, 55-56, and 68-69 do not recite any limitations that support the possession of any species of the two claimed genus; Thus, dependent claims are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-2, 4, 7-8, 16-17, and 33 provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-3, 8-10, 13, 15, and 16 of copending Application No. 18/712,779 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Regarding instant claims 1, 2, and 4, ‘779 recites identical subject matter in claims 1-3, respectively.
Regarding instant claims 7-8, ‘779 recites identical subject matter in claims 8-9, respectively.
Regarding instant claims 16-17, ‘779 recites identical subject matter in claims 15-16, respectively.
Regarding instant claim 33, under the broadest reasonable interpretation this instant claim encompasses the composition of the instant claim 1, wherein the nuclease domain (e.g., RuvC) has nickase activity and the other nuclease domain (e.g., HNH) is catalytically inactive, and vice versa. Accordingly, ‘779 recites same subject matter in claims 10 and 13, respectively.
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 6 and 12 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6, 22, 23, and 40 of copending Application No. 18/712,779 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim 1, ‘779 recites identical subject matter in claim 1.
Regarding instant claim 6, ‘779 wherein the IscB polypeptide comprises about 170 to 600 amino acids (claim 6), which anticipates the instant claimed range.
Regarding instant claim 12, ‘779 teaches an IscB polypeptide, an ωRNA molecule with the two instantly recited functions, and a functional domain selected from the group consisting of a nucleotide deaminase, a reverse transcriptase, a non-LTR retrotransposon, or an integrase protein (claim 22). ‘779 further teaches additional species of functional domain and IscB polypeptide (claim 23). The instant claim 12 depends on the composition of instant claim 1, which under the broadest reasonable interpretation encompasses an IscB polypeptide comprising a split Ruv-C nuclease domain without an HNH domain constituting an IscB polypeptide with nickase activity. Accordingly, the instant claim 12 comprises an IscB polypeptide having nickase activity and a functional domain associated to the IscB polypeptide, which is taught by ‘779 (claim 40).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 22, 27, 29, and 39-41 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, and 14-16 of copending Application No. 18/712,779 in view of Kapitonov et al (ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs; Journal of Bacteriology, 2016, 198(5):797-807).
Regarding instant claim 22, ‘779 teaches an IscB polypeptide comprising a RuvC domain, a PLMP domain, which is also referred as the N-terminal X domain in the instant claim ([0133]), and a C-terminal Y domain (claim 2). In respect to the instantly recited Bridge Helix domain, it is a conserved region naturally present in IscB polypeptides as taught by Kapitonov (Fig. 1). Accordingly, claim 2 of ‘774 teaches an IscB protein in the instant claim 22.
Regarding instant claim 27, the teachings of ‘779 claim 2 are discussed above as applied to instant claim 22. Further, ‘779 teaches the IscB polypeptide comprises an HNH domain (claim 1).
Regarding instant claim 29, the teachings of ‘779 claim 2 are discussed above as applied to instant claim 22. The instant claim recites the IscB protein no more than 800 amino acids in length. ‘779 teaches wherein the IscB polypeptide of claim 1 (a genus encompassing the species IscB protein in the instant claim 22) is about 170 to about 600 amino acids (claim 6). The instant specification, the PLMP and C-terminal Y domain are no more than 50 amino acids (Table 2); Accordingly, a species IscB protein comprising the PLMP and C-terminal Y domain would still fall within the instantly claimed range.
Regarding instant claims 39-41, the teachings of ‘779 claim 1 on the genus of IscB polypeptide encompassing a species comprising the instantly recited IscB protein are discussed above as applied to instant claim 29. Further, ‘779 teaches a polynucleotide, a vector system, and a cell comprising the instantly recited IscB protein (claims 14-16, respectively).
Claims 45, 47-49, 54-56, 60, and 68-69 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22, and 25-27of copending Application No. 18/712,779 in view of Kapitonov et al (ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs; Journal of Bacteriology, 2016, 198(5):797-807) as applied to instant claim 22, and further in view of Jinek et al (A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity, Science, 2012, 337:816-821)
The teachings of ‘779 and Kapitonov are discussed above as applied to instant claim 22.
Regarding instant claims 45, 54, and 60, ‘779 teaches an IscB polypeptide, an ωRNA molecule with the two instantly recited functions, and a functional domain selected from the group consisting of a nucleotide deaminase (as recited in instant claim 45), a reverse transcriptase (as recited in instant claim 54), or a non-LTR retrotransposon (as recited in instant claim 60) (claim 22).
However, ‘779 does not teach wherein the IscB polypeptide is catalytically inactive as recited in the instant claims 45, 54, and 60.
Kapitonov denoted the catalytic amino acid residues in RuvC I, RuvC II, and RuvC III subdomains of the RuvC nuclease domain in IscB and Cas9 (Fig. 1), and IscB1 comprises the RuvC-like domain only, without the HNH domain (pg. 799). In addition, Jinek teaches point mutation D10A inactivates catalytic activity of the RuvC nuclease domain of Cas9 (Fig. 2).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified ‘779 IscB polypeptide to be catalytically inactive because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of expanding genome editing applications using catalytically inactive nuclease domains that preserve specific target binding while prevent cleavage. One would have had a reasonable expectation of success in doing so because Kapitonov teaches conserved catalytic residues in both Cas9 and IscB and Jinek teaches successful catalytically inactive Cas9 variants.
Regarding instant claims 47-49, 55, 56, and 68-69, the obviousness to modify ‘779 IscB polypeptide to be catalytically inactive is discussed above as applied to instant claims 45, 54, and 60. ‘779 further teaches a polynucleotide (claim 25), vectors (claims 26), and cell (claim 27) comprising the composition of instant claims 45, 54, and 60.
This is a provisional nonstatutory double patenting rejection.
Claims 45, 47, and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 18 of copending Application No. 19/271,555 (reference application) in view of Kapitonov et al (ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs; Journal of Bacteriology, 2016, 198(5):797-807) as applied to instant claim 22, and further in view of Jinek et al (A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity, Science, 2012, 337:816-821). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim 45, ‘555 teaches a composition comprising an IscB nickase, one or more ωRNA (i.e., CRISPR-associated single guide molecule) capable of forming a complex with the IscB nickase and directing sequence-specific binding of the complex to one or more targeted nick sites (i.e., the target sequence within the target polynucleotide) (claim 5).
However, ‘555 does not teach wherein the IscB protein is catalytically inactive.
Kapitonov denoted the catalytic amino acid residues in RuvC I, RuvC II, and RuvC III subdomains of the RuvC nuclease domain in IscB and Cas9 (Fig. 1), and IscB1 comprises the RuvC-like domain only, without the HNH domain (pg. 799). In addition, Jinek teaches point mutation D10A inactivates catalytic activity of the RuvC nuclease domain of Cas9 (Fig. 2).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified ‘555 IscB nickase to be catalytically inactive because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of a catalytically inactive nuclease domains that preserve specific target binding while prevent cleavage. One would have had a reasonable expectation of success in doing so because Kapitonov teaches conserved catalytic residues in both Cas9 and IscB and Jinek teaches successful catalytically inactive Cas9 variants.
Regarding instant claims 47 and 48, the obviousness to modify ‘555 IscB nickase to be catalytically inactive is discussed above as applied to instant claim 45. ‘555 also teaches a vector system comprising one or more polynucleotides encoding the programmable nickase and deaminase (claim 18).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 12, 16, and 17 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 62, and 65 of copending Application No. 18/956,654 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1 and 12, instant claim 1 recites an IscB polypeptide comprising the recited structure, and one exemplary sequence of IscB polypeptide is SEQ ID NO: 2063 which is SEQ ID NO: 12780 of ‘654. Further, claim 1 of ‘654 teaches an ωRNA molecule comprising the two functions recited in the instant claim 1. Thus, ‘654 teaches the composition of claim 1. In addition, claim 1 of ‘654 teaches an IscB polypeptide comprising one or more insertions of a heterologous polypeptide which (i.e., a functional domain in the instant claim 12).
Regarding instant claims 16 and 17, ‘654 teaches a vector system and a cell comprising the composition of claim 1 (claims 62 and 65).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 60, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8, 40, and 41 of copending Application No. 19/333,523 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim 60, ‘523 claim 8 teaches a composition of claim 1 which comprises a) programmable DNA-binding protein, b) a non-long terminal repear (non-LTR) retrotransposon capable of associating with the programmable DNA-binding protein, and c) a donor construct comprising a donor polynucleotide for insertion into the target polynucleotide and an engineered binding element capable of forming a complex with the non-LTR retrotransposon polypeptide. ‘523 further teaches wherein the DNA-binding protein is an OMEGA protein that is an IscB protein, and one or more ωRNA (i.e., CRISPR-associated single guide molecule) capable of forming a complex with the IscB protein and directing sequence-specific binding of the complex to the target sequence within the target polynucleotide (claim 8). Accordingly, claim 8 of ‘523 teaches the composition of the instant claim 60.
Regarding instant claims 68 and 69, ‘523 teaches one or more polynucleotides (claim 40) and vectors (claim 41) comprising the composition of the instant claim 60.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 60 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18/276,471 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim 60, ‘523 claim 2 teaches a composition of claim 1 which comprises a) first site-specific nuclease, b) a non-LTR) retrotransposon polypeptide capable of forming a complex with the first site-specific nuclease, and c) a donor construct comprising a donor polynucleotide for insertion into the target polynucleotide and comprising one or more elements capable of forming a complex with the non-LTR retrotransposon polypeptide. ‘523 further teaches wherein the first site-specific nuclease is an IscB polypeptide, and the composition further comprises a nucleic acid component capable of forming a complex with the IscB polypeptide and directing binding of the complex to the target sequence (claim 2). Accordingly, claim 2 of ‘523 teaches the composition of the instant claim 60.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowable.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636