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 .
Claim Interpretation
Claim 5 recites SpCas9, VRER SpCas9, VQR SpCas9, EQR SpCas9, xCas9-3.7, eSpCas9 (1.0), eSpCas9 (1.1), Cas9-HF1, HypaCas9, evoCas9, HiFi Cas9, ScCas9, StCas9, NmCas9, SaCas9, CiCas9, CasX, and Cascade/Cas3. The meaning of these terms, including as abbreviated, have a known meaning in the prior art as the field of CRISPR and associated nucleases has matured. As such, these terms are excepted as having a reasonably certainty in scope as to not be indefinite.
Claim Objections
Claims 1, 4, 5 and 8 are objected to because of the following informalities:
In claim 1, since Sequence Identifiers are recited for SEQ ID NOS: 2-4, long sequences should not be recited in the claims.
In claim 1, “SEQ.ID.NO.” for reference to sequence identifiers must be “SEQ ID NO:”.
In claim 1, line 2, “the cytidine deaminase protein” should be amended to “a cytidine deaminase protein.” While the later recitation of sequence identifiers is considered to provided antecedent basis, the claims should use an indefinite article upon first recitation of a cytidine deaminase.
In claim 1, the conjunction “and” should appear between SEQ ID NO: 3 and SEQ ID NO: 4 in the recited Markush group.
In claim 1, “the cytidine deaminase” in line 2 should be “a cytidine deaminase.” This term is not considered indefinite since the following Markush group defines the cytidine deaminase; regardless, grammatically a definite article “the” should not be recited.
In claim 4, “a protein capable of carrying a mutant of APOBEC1 on a nucleic acid” should be restated as a “nucleic acid binding protein.” Any protein is capable of carrying (i.e. being fused) to a cytidine deaminase protein. “Capable of carrying . . . on a nucleic acid” is an unconventional statement that that the protein is capable of binding a nucleic acid and the claim should directly state the function of the protein recited. Further, in claim 4, the recited “a mutant of APOBEC1” is not required to be a cytidine deaminase as encoded in claim 1 and is not a structural part of the claim and should therefore be removed as extraneous language. For example, part (b) of claim 4 can be restated as “a protein capable of binding a nucleic acid when fused of the cytidine deaminase protein.” Regarding recitation of “a function domain thereof” at end of claim 4, any protein capable as recited is a functional domain thereof such that ““a function domain thereof” is duplicate unnecessary claim language and should be removed.
In claim 5, an extraneous parenthesis appears to be present in “CasX).”
In claim 8, consistent claim terminology should be used throughout the claims such that “encoding a polypeptide” should be “encoding a cytidine deaminase protein of claim 1” wherein claim 1 does not recite a polypeptide.
In claim 10, the preamble should be amended to recite “A base editing process comprising the following steps.” The recitation of two transitional phrases “comprising” in the preamble and a generic “A method” followed by a specific “base editing process” is redundant.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 5, 8 and 10-11 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 3 recites: (a) an mRNA transcribed by a nucleotide sequence of claim 1, (b) splicing variants of (a) comprising at least one of the mutations F66L+V1791, 1195N, and C82R. Specification, page 9, sets forth: “Within the meaning of the present invention, splicing (assembly) is understood to be the process of modifying transcribed mRNA by which intronic sequences are removed and exons are joined together, whereby splicing variants are understood to be all sequences, even intermediate sequences, which are produced during the splicing process.”
An ” mRNA transcribed by a nucleotide sequence of claim 1” is understood as an RNA molecule that can be made by action of a RNA polymerase acting on any of SEQ ID NOS: 2, 3 or 4 as recited in claim 1, wherein such RNA molecule will be identical to SEQ ID NO: 2, 3 or 4 except for substitution of T with U. However, none of SEQ ID NOS: 2, 3 and 4 have any intron sequences. A direct translation of SEQ ID NO: 4 yields the following sequence:
MSSETGPVAVDPTLRRRIEPHEFEVFFDPRELRKETCLLYEINWGGRHSIWRHTSQNTNKHVEVNFIEKFTTERYFCPNTRRSITWFLSWSPCGECSRAITEFLSRYPHVTLFIYIARLYHHADPRNRQGLRDLISSGVTIQIMTEQESGYCWRNFVNYSPSNEAHWPRYPHLWVRLYVLELYCIILGLPPCLNILRRKQPQLTFFTIALQSCHYQRLPPHILWATGLKC.
The above is identical to the protein APOBEC1 from Rattus norvegicus except for a point mutation C82R, as evidenced by Uniprot, Accession No. A6ILF2, 2023, www.uniprot.org. SEQ ID NOS: 2 and 3 are also identical to APOBEC1 from R. norvegicus except for the presence of one or two point mutations. As such, an mRNA transcribed from SEQ ID NO: 2, 3 or 4 of claim 1 does not contain any introns such that it is unclear as to what sequence may constitute a “splicing variant” such that an ordinarily skilled artisan cannot determine how to avoid infringement of claim 1. The recitation of “splicing variants of (a)” is understood that at least one embodiment of splicing variant is expressly encompassed by claim 3. However, since SEQ ID NO: 2, 3 and 4 of claim 1 do not contain any introns, it is unclear what sequence or structure that may constitute a splicing variant as recited.
Further, claim 3, recites “splicing variants of (a) comprising at least one of the mutations F66L+V1791, I195N, and C82R.” All embodiments of claim 3 are understood to be nucleic acids as recited in the preamble of claim 3, and F66L+V1791, I195N, and C82R is understood to be nomenclature of amino acid substitutions. Since nucleic acids do not comprise nor contain amino acids, it is unclear how a polynucleotide can comprise “at least one of the mutations F66L+V1791, I195N, and C82R” such that an ordinarily skilled artisan cannot determine how to avoid infringement. In particular, for example, position 66 of all of SEQ ID NOS: 2, 3 or 4 is G wherein it is unclear how a substitution F66L is to be affected at this position.
Claim 10 recites “a desired genomic mutation is obtained.” “When a subjective term is used in the claim, the examiner should determine whether the specification supplies some objective standard for measuring the scope of the term. Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite.” MPEP 2173.05(b)(IV). Claim 10 does not require a generic genomic mutation but specifically a “desired genomic mutation.” However, what genomic mutation that may be “desired” is a subjective term wherein the specification appears to provide no objection standard in order to allow the public to determine the scope of the claim. As such, claim 10 is indefinite for this reason.
Claim 8 recites “comprising or having contained therein.” The transitional phrase “comprising” is fully open. See MPEP 2111.03(I). “[T]erm "having" in transitional phrase "does not create a presumption that the body of the claim is open." MPEP 2111.03(IV). Since “comprising” and “having” do not necessarily have the same meaning as a transitional phrase, it is unclear if the recited transition phrase ““comprising or having” is equivalent to comprising or is a transitional phrase intermediate between comprising and having that is not fully open in the same manner as “comprising.” “Comprising or having” is not considered to be a Markush group since “comprising or having” is not structural limitations of the claims but only the transitional phrase whose purpose is to define how open claim 8 is to unrecited claim elements. As such, “comprising or having” is understood as a compound transitional phrase with unclear meaning, with no definition in the specification, such that an ordinarily skilled artisan cannot understand how to avoid infringement.
Claims 10 and 11 recites the limitation "the selection with antibiotic" in lines 8 and 5, respectively. There is insufficient antecedent basis for this limitation in the claim. There is no recitation or claim limitation that provides a literal antecedent basis for “the selection with antibiotic” in claims 10 and/or 11 and claims from which claims 10 and 11 depend, nor any claim limitation that provides a reasonable inherent antecedent basis. As such, it is not clear what claim element or act of a method “the selection” references such that an ordinarily skilled artisan cannot understand how to avoid infringement.
Claim 11 recites the limitation "all the elements necessary" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of claim features that provides an explicit nor reasonable inherent antecedent basis for “all the elements necessary.” While specific components of the recited kit are recited, the open transitional phrase “comprising” is recited such that unrecited elements are included in the scope of claim 11 wherein it cannot be assumed that “all the elements necessary” are only those explicitly recited later in the claim. As such, it is unclear as to what claim features “the elements necessary” references such that an ordinarily skilled artisan cannot determine how to avoid infringement. It is recommended that claim 11 recite a transitional phrase “A kit comprising” followed by specific claim limitations required for infringement of the claim.
Claim 5 recites the phrase “its lab created variants” at least twice in the claim, particularly “Cas9 and its lab-created variants” and “Cas12a and its lab-created variants.” Recitation of “its lab created variants” is understood to extend the scope of claim 5. That is, a variant of Cas9 and Cas12a can be considered to fall outside of the scope of Cas9 or Cas12a, which can be considered to only encompass proteins to which the label Cas9 or Cas12a is associated in the art. In this view, “its lab-created variants” is not a redundant term but that “Cas9 and its lab-created variants” is broader is scope that a simple recitation of “Cas9” and same with respect to Cas12a. Further, “lab-created variant” is considered to have a different scope than “variant.” As such, in order to understand how to avoid infringement, an ordinarily skilled artisan must be able to determine a structural difference between a “lab-created variant” and a “variant” and/or to what extent variation can exist and still be a lab-created variant of Cas9 or Cas12a. It is noted that as far as “is lab created variant” is understood as a product-by-process limitation (see MPEP 2113(I)), “lab-created variants” are not required to be produced by any particular process. However, the specification provides for no guidance regarding differentiating between a “lab-created variant” and a “non-lab-created variant” such that an ordinarily skilled artisan at the time of filing cannot determine how to avoid infringement.
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.
Claims 2, 3, 4, 5, 6, 8 and 10-13 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.
Claims 2 and 4 depend from claim 1 and can be infringed without infringing claim 1. As such, claims 2 and 4, and claims depending therefrom, do not require all of the limitations of the claim from which they depend.
Claims 2 and 4 recite proteins/polypeptides that can be prepared by solid phase peptide synthesis without the use any recombinant/isolated nucleotide sequence including any of those recited in claim 1. Claims 2 and 4 recite products and are not required to be made by any specific method. That is, claims 2 and 4 and not limited by any step of a method. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." MPEP 2113(I). That is, even if claims 2 and 4 directly recited that the polypeptide/protein be produced by expression of a nucleotide of claim 1, as far as claims 2 and 4 are stated as products rather than as methods claims 2 and 4 do not require embodiments thereof to be made using any of the polynucleotides of claim 1. For example, an embodiment of claim 2 or 4 can be made by expressing a polynucleotide comprising SEQ ID NO: 2 in a recombinant cell except the codon at positions 3-6 being AGT encoding Serine replaced with ATC also encoding Serine (i.e. encoding the same polypeptide as encoded by SEQ ID NO: 2 but different from and of SEQ ID NOS: 2, 3 and 4). As such, claims 2 and 4 and claims depending therefrom (including claim 11) can be infringed without infringing claim 1 such that claims 2 and 4, and claims depending therefrom, do not require all of the limitations of the claim 1 from which they depend.
Regarding claims 6 and 10 and claim 12, since claims 6 and 10 and 12 depend from claims 4 and 5, respectively, a nucleotide sequence comprising SEQ ID NO: 2 except having the codon at positions 3-6 being AGT encoding Serine replaced with ATC also encoding Serine (with additional sequence to encode the remainder of the recited fusion protein) would read on the broadest reasonable interpretation of a “nucleotide coding for the fusion protein of claim 4 [or claim 5].” As such a coding nucleotide as recited in claims 6, 10 and 12 is not required to comprise any of SEQ ID NOS: 2, 3 or 4 as required by claim 1. It is noted that this rejection can be overcome by amending claims 6, 10 and 12 to be a polynucleotide expressly comprising SEQ ID NO: 2, 3 or 4.
Regarding claim 3, claim 3 recites: (a) an mRNA transcribed by a nucleotide sequence of claim 1; or (b) splicing variants of (a) comprising at least one of the mutations F66L+V1791, 1195N, and C82R. Specification, page 9, sets forth: “Within the meaning of the present invention, splicing (assembly) is understood to be the process of modifying transcribed mRNA by which intronic sequences are removed and exons are joined together, whereby splicing variants are understood to be all sequences, even intermediate sequences, which are produced during the splicing process.” Claim 3 depends from claim 1. While it is unclear if any of SEQ ID NOS: 2, 3 or 4 contains an intron sequence, a “splicing variant” is understood as sequence that is other than SEQ ID NO: 2, 3 or 4 such that an isolated/recombinant nucleic acid that does not comprise SEQ ID NO: 2, 3 or 4 being a splicing variant can be an embodiment of claim 3. As such, claim 3 and further dependent claim 13 fail to include all the limitations of the claim upon which it depends, such limitation being the requirement of claim 1 that a recombinant/isolated nucleic acid comprise one of SEQ ID NOS: 2, 3 or 4.
Regarding claim 8, claim 8 depends from claim 1 and recites “a nucleotide sequence encoding a polypeptide of claim 1.” Claim 8 does not recite “a nucleotide sequence of claim 1.” Rather, claim 1 recites a generic “a nucleotide sequence” that encodes a polypeptide of claim 1 wherein such nucleotide sequence is not required to be one of SEQ ID NOS: 2-4. As such, claim 8 does not require a nucleotide sequence of one of SEQ ID NOS: 2-4 and fails to include all the limitations of the claim upon which it depends. It is recommended that claim 8 be amended to require “the nucleotide sequence of claim 1.”
In addressing the rejections above, it is recommended that claims intended to have a polynucleotide requiring one of SEQ ID NOS: 2-4 as a structural limitation be in one independent claim and claims dependent therefrom, and claims intended to have a protein as encoded by one of SEQ ID NOS: 2-4 be in another independent claim and claims dependent therefrom.
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.
Allowable Subject Matter
Claims 1 and 7 are objected to as above or as being dependent upon an objected to base claim, but would be allowable upon addressing such rejections.
The following is a statement of reasons for the indication of allowable subject matter:
SEQ ID NO: 2, 3 and 4 embody a rat-derived cytidine deaminase, also known as APOBEC-1, having substitutions F66L+V179I, I195N and C82R, respectively. Anant et al. (An AU-Rich Sequence Element (UUUN[A/U]U) Downstream of the Edited C in Apolipoprotein B mRNA Is a High-Affinity Binding Site for Apobec-1: Binding of Apobec-1 to This Motif in the 39 Untranslated Region of c-myc Increases mRNA Stability, Mol. Cell. Biol. 20, 2000, 1982-92) describes APOBEC-1 having substitutions F66L and F87L. However, the other required substitutions do not appear to be taught in the prior art of record.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TODD M EPSTEIN whose telephone number is (571)272-5141. The examiner can normally be reached Mon-Fri 9:00a-5:30p.
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652