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 with traverse of the species election requirement mailed 04/16/2026 in the reply filed on 06/15/2026 is acknowledged. The traversal is on the ground(s) that the “claimed inventions in Groups A-C share the same or corresponding special technical features within the meaning of PCT Rule 13.2” (page 9). This is not found persuasive because the instant application is a domestic application, and as such, restriction of the instant application was not performed under PCT Rule 13.2; restriction of the instant application was performed under 35 USC 121.
The requirement is still deemed proper. However, the species election requirements have been withdrawn.
Applicant marked claims 9, 14, 20, 24-25 as withdrawn pursuant to the species election requirement. However, these claims read on the elected species, and thus it is not proper to withdraw these claims. Furthermore, the species election requirement has been withdrawn.
Claims Status
Claims 1-31 is/are currently pending and under examination.
Priority
Instant claims 11-13 require that the gRNA be linked covalently or through base pairing to a donor/repair template. However, Provisional Application 62108064 and Applications 15006131, 15950268, and 17194312, which the instant application claims priority to, do not teach donor/repair templates. As such, the priority date for claims 11-13 is 07/06/2023, the date of the first set of claims of the instant application which recite a guide RNA associated with a DNA repair template.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
The claims contain limitations preceded by the term “optional”. All claim limitations recited as “optional” are interpreted as not required. As such, prior art can be applied to teach these limitations, but does not need to be applied.
Claim 17 recites that the internal non-nucleotide linker “maintains or improves one or more functions of said ribonucleoprotein”. The specification does not describe specific types, structures, or features of internal non-nucleotide linkers which would maintain, improve, or worsen one or more functions of a Cas-gRNA ribonucleoprotein complex. As such, the claim is interpreted to encompass any internal non-nucleotide linker.
Claim Objections
Claims 1, 7, 28 are objected to because of the following informalities:
Claim 1 is missing a hyphen in line 10: “target specific sequence” should read “target-specific sequence”.
Claim 7 recites “CRSPR” in line 1, which should read “CRISPR”.
Claim 28 recites the term “comprises” in line 3. For grammatical correctness, this must either be amended to read “wherein the method comprises” or “comprising”.
Claim 28 recites “to modify sequence” in line 1. This should read “to modify the sequence”.
Claim 28 recites steps “c” and “d”, but does not recite steps “a” or “b”, and does not depend on any claim that recites steps “a” or “b”. The examiner suggests amending “c” and “d” to be “a” and “b”, respectively.
Appropriate correction is required.
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 1-27 and 30-31 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 the limitation "their preformed ribonucleoprotein" in line 8. There is insufficient antecedent basis for this limitation in the claim. “Their preformed ribonucleoprotein” implies an earlier reference to a preformed ribonucleoprotein; however, no such earlier reference is found in the claim.
Claim 1 recites that expression of the polypeptide is “optionally under control”, but the claim does not recite what is meant by “under control”; it is unclear what or who controls expression and how expression is controlled. If what is intended is that the expression of the polypeptide is under the control of a transcriptional regulator or promoter or other sequence element, this structure should be recited (e.g., “under the control of a promoter”). As currently presented, this limitation of claim 1 renders the metes and bounds of claim 1 unclear, and thus renders claim 1 indefinite. Claims 2-27 and 30-31 depend on claim 1 but do not clarify this indefiniteness, and so are rendered indefinite. For further examination, claim 1 is interpreted to encompass polypeptides whose expression is under the control of a transcription regulatory sequence element, including but not limited to a promoter sequence.
Claim 16 recites “bound regions of said guide RNA by said polypeptide”. It is unclear, based on the claims and specification, what is meant by “bound regions of said guide RNA”, and as such, claim 16 is rendered indefinite. This limitation is interpreted to mean “the regions of said guide RNA which are bound by said polypeptide” for the purposes of further examination.
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.
Claims 22 and 25 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 22 and 25 recite that “said polypeptide comprises absent, one or more nuclear localization sequences” with no additional limitations. A given polypeptide can only have 0, 1, or more nuclear localization sequences, and thus, claims 22 and 25 do not further limit claims 1 and 24, respectively. 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.
Claims 11-13 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.")."
Claims 11-13 require that the gRNA be associated, covalently or through base pairing, to a DNA repair template. Claim 15 requires that a DNA repair/donor template be administered. However, the instant specification does not teach or suggest any DNA repair or donor template, and furthermore, does not teach or suggest a DNA repair or donor template associated, covalently or through base pairing, with a gRNA. The instant drawings do not provide depictions of such gRNA associated with DNA repair or donor templates. As such, the specification lacks written support for the limitations of claims 11-13 and 15, and it cannot be determined whether the applicant was in possession of the invention as claimed in claims 11-13 and 15.
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) 1-5, 7-10, 14-18, 20-29, 31 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ravinder (US20160102322A1, EFD 10/09/2014).
Regarding claim 1, Ravinder teaches a method of directing a Cas protein to a target nucleic acid in a cell using a guide RNA, comprising delivering to the cell a Cas protein and gRNA and binding the gRNA to the target nucleic acid (claims 19, 21). Ravinder teaches that the components of the CRISPR system may be delivered simultaneously or sequentially (paragraphs [0218]-[0221]). Ravinder teaches that the polypeptide and gRNA may be delivered as a ribonucleoprotein complex or encoded on nucleic acids (paragraph [0221]). Ravinder teaches that the gRNA may comprise at least one internal non-nucleotide linker (paragraphs [0146]-[0160]; claim 15).
Regarding claims 2-3 and 16, Ravinder teaches that the non-nucleotide linker may be positioned between the crRNA and the tracrRNA (paragraphs [0146]-[0148], [0151]; Fig. 11). As it is the tracrRNA that the Cas protein binds (paragraph [0078]), the Cas protein would inherently not bind the non-nucleotide linker if not positioned within the tracrRNA.
Regarding claim 4, Ravinder teaches that the tracrRNA portion of the gRNA may comprise one or more non-nucleotide linkers (paragraphs [0151], [0155]-[0160]).
Regarding claims 5, 7-8, Ravinder teaches that the Cas protein is a Cas9 comprising endonuclease domains (paragraphs [0089]-[0090]; claims 19, 21-23).
Regarding claim 9, Ravinder teaches that the protein may be a fusion protein, comprising a Cas domain and an heterologous domain, which heterologous domain may be FokI (a nuclease) (paragraph [0092]). Ravinder teaches that the Cas protein may be fused to protein domains having methylase, demethylase, transcription activation, transcription repression, transcription release factor, histone modification, RNA cleavage, or nucleic acid binding activity (paragraph [0176]).
Regarding claim 10, Ravinder teaches that the CRISPR system may be delivered packaged in a viral vector (paragraph [0193]).
Regarding claim 14, Ravinder teaches that the gRNA may be covalently linked with a “hybridization tag” (an oligonucleotide) (paragraphs [0172]-[0174]).
Regarding claim 15, Ravinder teaches that the method further comprises delivery of a DNA repair template (DNA donor template) (paragraphs [0218]-[0223]) and that delivery of the DNA repair template may be simultaneous with delivery of the Cas9 protein and gRNA or separately (paragraph [0220]).
Regarding claim 17, Ravinder teaches that ligation of RNA segments with non-nucleotide linkers “is advantageous” because it is “fast, modular, efficient, often [does]not produce toxic waste products, can be done with water as a solvent, and can be set up to be stereospecific” (paragraph [0151]). Ravinder teaches that ligation with non-nucleotide linkers is a method of producing functional gRNAs (paragraphs [0146]-[0160]). As described in Claim Interpretation above, any non-nucleotide linker is considered to be encompassed by claim 17. Thus, the teachings of Ravinder—that gRNAs may comprise internal non-nucleotide linkers within the tracrRNA and/or between the tracrRNA and crRNA—encompass the limitations of instant claim 17.
Regarding claim 18, Ravinder teaches that in the process of synthesizing gRNAs, mutations are naturally introduced (paragraphs [0292], [0294], [0329]).
Regarding claim 20, Ravinder teaches that the gRNA may be linked covalently at either terminus (including the terminus of the tracrRNA) with a “hybridization tag” (an oligonucleotide) (paragraphs [0172]-[0174]).
Regarding claim 21, Ravinder teaches that the CRISPR system may be packaged in a non-viral carrier (paragraph [0193]).
Regarding claim 22, Ravinder teaches that the Cas9 protein may further comprise a nuclear localization signal (paragraph [0117]).
Regarding claim 23, Ravinder teaches that the gRNA may comprise one or more modified nucleotides (paragraph [0165]).
Regarding claim 24, Ravinder teaches that the Cas9 protein may be fused to a fluorescent protein (GFP) (paragraph [0043]).
Regarding claim 25, Ravinder teaches that the Cas9 protein may further comprise a nuclear localization signal (paragraph [0117]).
Regarding claim 26, Ravinder teaches that the method may comprise delivering more than one gRNA (paragraphs [0253], and teaches that any of the gRNAs may comprise internal non-nucleotide linkers (paragraphs [0146]-[0160]).
Regarding claim 27, Ravinder teaches that the gRNA may be attached to a solid support (paragraphs [0169]-[0173]).
Regarding claim 28, Ravinder teaches a method of directing a Cas protein to a target nucleic acid in a cell using a guide RNA, comprising delivering to the cell a Cas protein and gRNA and binding the gRNA to the target nucleic acid (claims 19, 21). Ravinder teaches that the components of the CRISPR system may be delivered simultaneously or sequentially (paragraphs [0218]-[0221]). Ravinder teaches that the polypeptide and gRNA may be delivered as a ribonucleoprotein complex or encoded on nucleic acids (paragraph [0221]). Ravinder teaches that the gRNA may comprise at least one internal non-nucleotide linker (paragraphs [0146]-[0160]; claim 15).
Regarding claim 29, Ravinder teaches that the method comprises delivering more than one gRNA (paragraph [0253]; Fig. 4), wherein the gRNAs target non-overlapping target regions (Fig. 4). Ravinder also teaches that the Cas9 proteins may be modified to be nickase Cas9 proteins (claim 23; paragraphs [0008], [0023]).
Regarding claim 31, Ravinder teaches that the Cas9 protein may further comprise a nuclear localization signal (paragraph [0117]).
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.
Claim(s) 1-10, 14-18, 20-29, 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US20160102322A1, EFD 10/09/2014), in view of Maheshri (WO2014127287A1).
Regarding claim 1, Ravinder teaches a method of directing a Cas protein to a target nucleic acid in a cell using a guide RNA, comprising delivering to the cell a Cas protein and gRNA and binding the gRNA to the target nucleic acid (claims 19, 21). Ravinder teaches that the components of the CRISPR system may be delivered simultaneously or sequentially (paragraphs [0218]-[0221]). Ravinder teaches that the polypeptide and gRNA may be delivered as a ribonucleoprotein complex or encoded on nucleic acids (paragraph [0221]). Ravinder teaches that the gRNA may comprise at least one internal non-nucleotide linker (paragraphs [0146]-[0160]; claim 15).
Regarding claims 2-3 and 16, Ravinder teaches that the non-nucleotide linker may be positioned between the crRNA and the tracrRNA (paragraphs [0146]-[0148], [0151]; Fig. 11). As it is the tracrRNA that the Cas protein binds (paragraph [0078]), the Cas protein would inherently not bind the non-nucleotide linker if not positioned within the tracrRNA.
Regarding claim 4, Ravinder teaches that the tracrRNA portion of the gRNA may comprise one or more non-nucleotide linkers (paragraphs [0151], [0155]-[0160]).
Regarding claims 5, 7-8, Ravinder teaches that the Cas protein is a Cas9 comprising endonuclease domains (paragraphs [0089]-[0090]; claims 19, 21-23).
Regarding claim 9, Ravinder teaches that the protein may be a fusion protein, comprising a Cas domain and an heterologous domain, which heterologous domain may be FokI (a nuclease) (paragraph [0092]). Ravinder teaches that the Cas protein may be fused to protein domains having methylase, demethylase, transcription activation, transcription repression, transcription release factor, histone modification, RNA cleavage, or nucleic acid binding activity (paragraph [0176]).
Regarding claim 10, Ravinder teaches that the CRISPR system may be delivered packaged in a viral vector (paragraph [0193]).
Regarding claim 14, Ravinder teaches that the gRNA may be covalently linked with a “hybridization tag” (an oligonucleotide) (paragraphs [0172]-[0174]).
Regarding claim 15, Ravinder teaches that the method further comprises delivery of a DNA repair template (DNA donor template) (paragraphs [0218]-[0223]) and that delivery of the DNA repair template may be simultaneous with delivery of the Cas9 protein and gRNA or separately (paragraph [0220]).
Regarding claim 17, Ravinder teaches that ligation of RNA segments with non-nucleotide linkers “is advantageous” because it is “fast, modular, efficient, often [does]not produce toxic waste products, can be done with water as a solvent, and can be set up to be stereospecific” (paragraph [0151]). Ravinder teaches that ligation with non-nucleotide linkers is a method of producing functional gRNAs (paragraphs [0146]-[0160]). As described in Claim Interpretation above, any non-nucleotide linker is considered to be encompassed by claim 17. Thus, the teachings of Ravinder—that gRNAs may comprise internal non-nucleotide linkers within the tracrRNA and/or between the tracrRNA and crRNA—encompass the limitations of instant claim 17.
Regarding claim 18, Ravinder teaches that in the process of synthesizing gRNAs, mutations are naturally introduced (paragraphs [0292], [0294], [0329]).
Regarding claim 20, Ravinder teaches that the gRNA may be linked covalently at either terminus (including the terminus of the tracrRNA) with a “hybridization tag” (an oligonucleotide) (paragraphs [0172]-[0174]).
Regarding claim 21, Ravinder teaches that the CRISPR system may be packaged in a non-viral carrier (paragraph [0193]).
Regarding claim 22, Ravinder teaches that the Cas9 protein may further comprise a nuclear localization signal (paragraph [0117]).
Regarding claim 23, Ravinder teaches that the gRNA may comprise one or more modified nucleotides (paragraph [0165]).
Regarding claim 24, Ravinder teaches that the Cas9 protein may be fused to a fluorescent protein (GFP) (paragraph [0043]).
Regarding claim 25, Ravinder teaches that the Cas9 protein may further comprise a nuclear localization signal (paragraph [0117]).
Regarding claim 26, Ravinder teaches that the method may comprise delivering more than one gRNA (paragraphs [0253], and teaches that any of the gRNAs may comprise internal non-nucleotide linkers (paragraphs [0146]-[0160]).
Regarding claim 27, Ravinder teaches that the gRNA may be attached to a solid support (paragraphs [0169]-[0173]).
Regarding claim 28, Ravinder teaches a method of directing a Cas protein to a target nucleic acid in a cell using a guide RNA, comprising delivering to the cell a Cas protein and gRNA and binding the gRNA to the target nucleic acid (claims 19, 21). Ravinder teaches that the components of the CRISPR system may be delivered simultaneously or sequentially (paragraphs [0218]-[0221]). Ravinder teaches that the polypeptide and gRNA may be delivered as a ribonucleoprotein complex or encoded on nucleic acids (paragraph [0221]). Ravinder teaches that the gRNA may comprise at least one internal non-nucleotide linker (paragraphs [0146]-[0160]; claim 15).
Regarding claim 29, Ravinder teaches that the method comprises delivering more than one gRNA (paragraph [0253]; Fig. 4), wherein the gRNAs target non-overlapping target regions (Fig. 4). Ravinder also teaches that the Cas9 proteins may be modified to be nickase Cas9 proteins (claim 23; paragraphs [0008], [0023]).
Regarding claim 31, Ravinder teaches that the Cas9 protein may further comprise a nuclear localization signal (paragraph [0117]).
However, while Ravinder teaches that the Cas9 protein may be fused to heterologous protein domains to provide additional activities (paragraph [0176]), Ravinder does not teach that such additional protein activity may be deaminase activity, requiring fusion of the Cas9 protein to a deaminase domain.
Maheshri teaches that a Cas9 protein may be fused to a deaminase domain.
Regarding claims 6 and 9, Maheshri teaches that Cas9 proteins may be fused to deaminase domains to provide RNA-directed DNA deamination activity and to promote mutations (claim 46; page 26 lines 9-20).
It would have been obvious to an artisan at the time of filing that the Cas9 fusion protein of Ravinder could comprise any effector domain described in the art as fused to a Cas9 domain. Furthermore, Ravinder teaches that the intention of the methods is to introduce mutations (paragraphs [0004], [0335]; claim 19), and as such, it would have been obvious to such an artisan that effector domains which provide benefits to the capacity to introduce mutations would be beneficial to include in a Cas9 fusion protein. As such, it would have been obvious to an artisan the time of filing that the Cas9-deaminase fusion of Maheshri should be used in the methods of Ravinder to promote introduction of mutations into the targeted nucleic acids.
Claim(s) 11-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US20160102322A1, EFD 10/09/2014) and Maheshri (WO2014127287A1), as applied to claim 1 above, and further in view of Lee (2017; see explanation of priority date of claims 11-13 above under Priority).
The teachings of Ravinder and Maheshri are discussed above and render obvious the limitations of claim 1.
Regarding claim 11, Ravinder teaches that a donor template (repair template) may be co-delivered with the Cas9 and gRNA, and that the donor template may be single-stranded and linear (paragraphs [0228]; claim 20).
Regarding claims 12-13, the phrase “comprises an oligonucleotide sequence of” one stop codon or of one transcription cis-regulatory element is sufficiently broad to encompass a sequence of one nucleotide comprised in a stop codon or a transcription cis-regulatory element. As the Ravinder does teach a donor template with 80 nucleotides homologous to the target sequence (paragraph [0228]), such a donor template will inherently comprise more than one of adenosine, cytidine, thymidine, and guanosine, and thus will comprise a 1-nucleotide-long oligonucleotide sequence of any stop codon or transcription cis-regulatory element. Furthermore, the target sequence of Ravinder is not limited to sequences which do not include transcription cis-regulatory elements or stop codons. It would have been obvious to an artisan that any nucleic acid sequence could be a target sequence, including sequences comprising stop codons or transcription cis-regulatory elements. As the donor template of Ravinder shares 80-nucleotide homology to a targeted sequence, it would have been obvious to an artisan that, as any sequence could be a targeted sequence in the method of Ravinder, any sequence, including ones comprising stop codons or transcriptional cis-regulatory elements, could be comprised in the donor sequence.
However, Ravinder and Maheshri do not teach that a donor or repair template is linked covalently or through base pairing to a guide RNA.
Lee teaches that covalently linking a DNA repair template to a guide RNA increases editing efficiency (see Abstract; page 2).
Regarding claim 11, Lee teaches that fusion (covalent linkage) of the gRNA and donor (repair) template enhances homology-directed repair (HDR) efficiency (Fig.1b; page 2). It would have been obvious to an artisan, based on the teachings of Lee, that the gRNA and donor templates of Ravinder should be covalently linked in order to enhance the efficiency of HDR.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US20160102322A1, EFD 10/09/2014) and Maheshri (WO2014127287A1), as applied to claim 1 above, and further in view of Brown (US20130046084A1).
The teachings of Ravinder and Maheshri are described above and render obvious the limitations of claim 1.
However, Ravinder and Maheshri do not teach which nucleotide component is replaced by the non-nucleotide linker.
Brown teaches methods of linking RNA segments with non-nucleotide linkers.
Regarding claim 19, Brown teaches that the non-nucleotide linker covalently linking two RNA molecules may replace a phosphodiester linkage (claim 1).
Brown teaches methods of chemically ligating RNA oligonucleotides (claim 1). Ravinder explicitly teaches that the methods taught by Brown should be used to chemically ligate RNA segments to create a guide RNA (paragraph [0151]). Based on the teachings of Brown and Ravinder, it would have been obvious to an artisan that non-nucleotide linkers linking gRNA segments should be formed by methods known in the art (such as Brown), which would result in non-nucleotide linkers replacing phosphodiester linkages.
Claim(s) 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US20160102322A1, EFD 10/09/2014) and Maheshri (WO2014127287A1), as applied to claim 1 above, and further in view of Duchateau (WO2014191128A1).
The teachings of Ravinder and Maheshri are described above and render obvious the limitations of claim 1.
Regarding claim 30, Ravinder teaches that the Cas9 protein may be delivered using a cell-penetrating peptide (paragraph [0270]).
However, Ravinder does not teach that the cell-penetrating peptide (CPP) is covalently linked to the Cas9 protein.
Duchateau teaches that CPPs may be covalently linked to Cas9 proteins.
Regarding claim 30, Duchateau teaches that a CPP may be covalently linked to a Cas9 protein (page 21).
Both Ravinder and Duchateau teach that CPP molecules may be used to facilitate introduction of the CRISPR system into targeted cells. While Ravinder does not provide teachings on the mechanisms by which the CPP is associated with the CRISPR system, Duchateau does. It would have been obvious to an artisan at the time of filing that the methods of linking a CPP to CRISPR system components, including the Cas9 protein, should be used in the methods of Ravinder in order to deliver the CRISPR system to cells using a CPP, as taught by Ravinder.
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.
16994660:
Claims 1-10, 14-25, 28-29, 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 38-56, 58-70 of copending Application No. 16994660 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims recite a method of editing a target gene (claim 55) and encompasses methods of delivering a nucleic acid encoding a Cas protein and a guide RNA to a cell (claim 56), delivered in any order. The copending claims recite that the gRNA comprises at least one internal non-nucleotide linker (claim 38) anywhere in the gRNA (claim 38). The copending claims recite that the Cas protein may be fused to a deaminase domain (claim 58). The copending claims recite that the encoding nucleic acid may be packaged in a viral vector or a non-viral vector (claims 56, 67). The copending claims recite that a single-stranded nucleic acid template is also comprised in the gene editing composition (claims 38, 47, 55).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
US 11667914 B2:
Claims 1-5, 7-8, 14, 16-17, 19-20, 22-26, 28, 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11667914 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims recite methods of gene editing in cells, comprising delivering a Cas protein and an lgRNA (claim 1). The issued claims recite that the lgRNA comprises internal non-nucleotide linkers (claim 1) and modifications (claims 3-4). The issued claims recite a species of the broader genus claims of the instant application.
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.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
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