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 .
Priority
The instant application is a CON of application 17/972,885 filed 10/25/2022, which is a CON of application 16/851,360 filed 04/17/2020, which is a CON of application 16/441,209 filed 06/14/2019, which is a CON of application 14/319,530 filed 06/30/2014, which is a CON of PCT US2014/040868 filed on 06/04/2014 that claims priority to US provisional 61/830,787 filed 06/04/2013.
Information Disclosure Statement
The information disclosure statements filed 01/29/2024, 03/21/2024, and 03/31/2025 have been considered.
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 1-28 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.
Claims 1 and 11 requires an aptamer that comprises a target of an RNA binding domain. The claim also requires that the effector domain has an RNA binding domain and that the RNA binding domain binds to the target of the RNA binding domain (i.e., aptamer). The claim also further recites that the guide RNA is connected to the effector domain; however, the claim is silent in regards to how this connection occurs in order to localize the effector domain to the target nucleic acid or edit a target gene in a eukaryotic cell. It is unclear if the effector domain directly binds the gRNA or is indirectly connected to the gRNA. The instant specification teaches that the gRNA bears MS2 binding cites [pg. 10, para 2]. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims.
Claims 1 and 11 recite “the effector domain having the RNA binding domain” in lines 12 and 11, respectively. It is unclear what it means for an effector domain to ‘have’ a RNA binding domain. It is unclear if a portion of the effector domain contains a domain that binds a RNA or something else. The lack of clarity renders the claims indefinitely.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein
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 11-20 and 25-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain 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 pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP 2163.I1.A.3.(b) states, "when filing an amendment an applicant should show support in the original disclosure for new or amended claims" and "[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description". According to MPEP § 2163.1.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117".
The current claims require a method of editing a target gene in a eukaryotic cell, comprising providing to the cell a nucleic acid encoding a nuclease null or nickase Cas9 protein that interacts with the guide RNA having the aptamer attached to the 3' end or the 5' end and an effector domain having the RNA binding domain, wherein the guide RNA including the effector domain connected thereto and the Cas9 protein colocalize to the target DNA sequence and thereby edit the target gene. The application as-filed does not disclose using a nuclease null Cas9 protein to editing a target gene. No basis for this limitation was identified in the specification for editing a target gene using a nuclease null Cas9 protein or to support the claims as currently written.
The current specification as originally filed, discloses the use of an RNA guided nuclease null DNA binding protein for a method of modulating expression of a nucleic acid [pg. 2, para 3-4; pg. 4, para 4; pg. 24, last paragraph]. The specification, throughout, also teaches a nucleic acid encoding an RNA guided nuclease-null DNA binding protein that further encodes the transcriptional regulator protein or domain fused to an RNA guided nuclease-null DNA binding protein, which suggest using the protein for modulating expression and not editing of a gene.
A search was conducted for “edit” in the specification, and in no case was there any disclosure of using a nuclease null Cas9 protein to edit a target gene. The specification teaches that TALE (nucleases)-FokI dimers are used as genome editing tools, wherein the TALE is similar to a Cas9(WT)-gRNA complex [pg. 20-21]. The specification also teaches that off-set nicks (i.e. nickases) are used in methods of genome-editing [pg. 23, para 3; pg. 35, Example XIII]. Moreover, in the method recited in claim 11, a nuclease null Cas9 protein, a guide RNA having the aptamer and an effector domain having the RNA binding domain appear to serve no purpose. That is, using a guide RNA to guide the nuclease null Cas9 protein to a target site, only to have it “there”, when it cannot cut the target site to allow for gene editing, appears to be superfluous, since the application as filed does not indicate how the gene can be edited without cutting the site. And even if that were the case, there is no explanation of what role would be played by a nuclease null Cas9 or other players that might be involved in this situation.
Taken together, the specification does not provide sufficient written description for the claims, as currently recited. Since no basis has been identified, the claims are rejected as incorporating new matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Doudna et al. (US20140068797 A1, 01/28/2013, cited on the information disclosure statement filed 04/20/2020).
Regarding claims 1 and 11, Doudna teaches a method genome targeting and editing, comprised of providing a cell with a guide RNA that is complementary to the target nucleic acid sequences on genomic DNA or exogenous DNA, and the null Cas9 protein (same as Cas9 having inactive nuclease domain) [136,137, 0163, 0409-0410, 0608, 0775]. Doudna teaches that a guide RNA is also referred to a "DNA-targeting RNA" [0130]. Doudna teaches that the DNA-targeting RNA comprises an additional segment at either the 5' or 3' end that comprises a modification or sequence that provides for a binding site for proteins (e.g., proteins that act on DNA, including transcriptional activators, transcriptional repressors, DNA methyltransferases, DNA demethylases, histone acetyltransferases, histone deacetylases, and the like); thereby teaching where the guide RNA can be connected to an effector domain [0133, 0385, 0425, 0443]. Additionally, Doudna teaches that the activator-RNA and/or the targeter-RNA (of the DNA-targeting RNA) can comprise an RNA aptamer sequence [0173]. Doudna teaches that aptamers can bind a small molecule [0174]. Doudna teaches that the aptamer allows for regulated stability and/or regulated accessibility by proteins and/or protein complexes [0425].
While Doudna does not teach that the effector domain is directly tethered to the aptamer via the RNA binding domain and target of the RNA binding domain, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the DNA-targeting RNA such that the effector domain is connected to the DNA-targeting RNA via the aptamer. Doudna teaches that the 5’ or 3’ end of the DNA-targeting RNA comprises an additional segment upon which a protein, such as an aptamer, can bind. This modification would simply amount to an rearrangement of parts, where a DNA-targeting RNA attached to a effector domain is still produced. One of ordinary skill would be motivated to make the modification for the advantage of allowing the DNA-targeting RNA to have regulated stability and/or regulated accessibility by effector proteins.
Regarding claims 2-3 and 12-13, Doudna teaches that suitable hosts include human cells [324-328].
Regarding claims 4-6 and 14-16, Doudna teaches that the DNA-targeting RNA" or "DNA targeting RNA polynucleotide" (also referred to herein as a "guide RNA" or "gRNA") can have a length of from about 12 nucleotides to about 100 nucleotides [0130, 0428].
Regarding claims 7 and 17, Doudna teaches the target DNA may be, for example, naked DNA in vitro, chromosomal DNA in cells in vitro, chromosomal DNA in cells in vivo, etc.[0254].
Regarding claims 10 and 20, Doudna teaches the use of two gRNAs to enable with distinct complementary regions to enable multiplex control of multiple genes simultaneously [0765].
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 Langi, 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 §§ 706.02(1)(1) - 706.02(1)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-l.isp.
Claims 1-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over allowed claims 1-32 of U.S. Patent 10640789 B2. The instant application and the ‘789 patent have a common assignee.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is anticipated by or nearly rendered obvious over the claims of the patent.
The patented claims all the limitations of the instant claims to include a method of modulating expression of a target nucleic acid in a eukaryotic cell comprising providing to the cell a nucleic acid encoding a guide RNA complementary to the target nucleic acid sequence and an aptamer comprising a target of an RNA binding domain, wherein the aptamer is attached to the 3′ end or the 5′ end of the guide RNA, wherein the guide RNA is a tracrRNA-crRNA fusion, providing to the cell a nucleic acid encoding a transcriptional activator or repressor (i.e. types of effector domains) and an RNA binding domain, wherein the RNA binding domain binds to the target of the RNA binding domain, providing to the cell a nucleic acid encoding a nuclease null Cas9 protein that interacts with the guide RNA, and wherein the cell expresses the guide RNA having the aptamer attached to the 3′ end or the 5′ end of the guide RNA, the transcriptional activator or repressor having the RNA binding domain and the Cas9 protein, and wherein the guide RNA including the transcriptional activator or repressor connected thereto and the Cas9 protein co-localize to the target nucleic acid sequence and wherein the transcriptional activator or repressor modulates expression of the target nucleic acid (i.e. by being localized to the target nucleic acid) [claims 1, 8, and 19].
Regarding claim 2, the patented claims teach wherein the cell is a yeast cell, a plant cell or a mammalian cell [claims 2, 10, 20].
Regarding claim 3, the patented claims teach wherein the cell is a human cell [claims 3, 11, and 21].
Regarding claim 4, the patented claims teach wherein the guide RNA is between about 10 to about 250 nucleotides [claims 4, 12, and 22].
Regarding claim 5, the patented claims teach wherein the guide RNA is between about 20 to about 100 nucleotides [claims 5, 13, and 23].
Regarding claim 6, the patented claims teach wherein the guide RNA is between about 100 to about 250 nucleotides [claims 6, 14, and 24].
Regarding claim 7, the patented claims teach wherein the target nucleic acid is genomic DNA, mitochondrial DNA, viral DNA or exogenous DNA [claim 7].
Regarding claim 8, the patented claims teach wherein the aptamer comprises two copies of MS2 bacteriophage coat-protein binding RNA stem-loop [claims 15, 17 and 25].
Regarding claim 9, the patented claims teach wherein the RNA binding domain comprises MS2 bacteriophage coat-protein [claims 16, 18 and 26].
Regarding claim 10, the patented claims teach wherein multiple guide RNAs are introduced to the cell with each guide RNA being complementary to a different target nucleic acid sequence and having an aptamer comprising a target of an RNA binding domain, wherein the aptamer is attached to the 3' end or the 5' end of the guide RNA, wherein each guide RNA is a tracrRNA-crRNA fusion, and wherein multiple guide RNAs have the effector domain connected thereto [claims 27-32].
Claims 1-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over allowed claims 1-20 of U.S. Patent US11981917B2. The instant application and the ‘917 patent have a common assignee.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is anticipated or is nearly rendered obvious by the claims of the patented application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is anticipated by or nearly rendered obvious over the claims of the patent.
Regarding claims 1, 11, 21-22 and 25-26he patented claims all the limitations of the instant claims to include method of localizing an effector domain to a target nucleic acid sequence in a eukaryotic cell (or a method of editing a target gene in a eukaryotic cell) comprising providing to the cell a nucleic acid encoding a guide RNA complementary to the target nucleic acid sequence and an aptamer comprising a target of an RNA binding domain, wherein the aptamer is attached to the 3′ end or the 5′ end of the guide RNA, wherein the guide RNA is a tracrRNA-crRNA fusion, providing to the cell a nucleic acid encoding the effector domain and an RNA binding domain, wherein the RNA binding domain binds to the target of the RNA binding domain, providing to the cell a nucleic acid encoding a nuclease null or nickase Cas9 protein that interacts with the guide RNA, and wherein the cell expresses the guide RNA having the aptamer attached to the 3′ end or the 5′ end of the guide RNA, the effector domain fused to the RNA binding domain and the Cas9 protein, and wherein the guide RNA including the effector domain connected thereto and the Cas9 protein co-localize to the target nucleic acid sequence [claims 1 and 11].
Regarding claim 2 and 12, the patented claims teach wherein the cell is a yeast cell, a plant cell or a mammalian cell [claims 2, 12].
Regarding claim 3 and 13, the patented claims teach wherein the cell is a human cell [claims 3, 13].
Regarding claim 4 and 14, the patented claims teach wherein the guide RNA is between about 10 to about 250 nucleotides [claims 4, 14].
Regarding claim 5 and 15, the patented claims teach wherein the guide RNA is between about 20 to about 100 nucleotides [claims 5, 15].
Regarding claim 6 and 16, the patented claims teach wherein the guide RNA is between about 100 to about 250 nucleotides [claims 6, 16].
Regarding claim 7 and 17, the patented claims teach wherein the target nucleic acid is genomic DNA, mitochondrial DNA, viral DNA or exogenous DNA [claims 7, 17].
Regarding claim 8 and 18, the patented claims teach wherein the aptamer comprises two copies of MS2 bacteriophage coat-protein binding RNA stem-loop [claims 8, 18].
Regarding claim 9 and 19, the patented claims teach wherein the RNA binding domain comprises MS2 bacteriophage coat-protein [claims 9, 19].
Regarding claim 10, 20, 23-24 and 27-28, the patented claims teach wherein multiple guide RNAs are introduced to the cell with each guide RNA being complementary to a different target nucleic acid sequence and having an aptamer comprising a target of an RNA binding domain, wherein the aptamer is attached to the 3' end or the 5' end of the guide RNA, wherein each guide RNA is a tracrRNA-crRNA fusion, and wherein multiple guide RNAs have the effector domain connected thereto [claims 10 and 20].
Allowable Subject Matter
Claims 8-9, 18-19, and 21-28 are allowable over the prior art. The closest prior art, Doudna, as discussed above. Doudna nor the prior teaches that the aptamer comprises two copies of MS2 bacteriophage coat-protein binding RNA stem-loop or where the RNA binding domain comprises MS2 bacteriophage coat-protein. Doudna nor the prior links MS2 to a CRISPR-Cas9 complex. Additionally, Doudna, nor the prior art, teaches or provides a reasonable rational on where to connect the aptamer to the guide RNA. Doudna, nor the prior art, teaches a method wherein the gRNA/aptamer contains a target of an RNA binding domain which binds to an RNA binding domain/ RNA binding domain complex.
Furthermore, the instant specification teaches that a chimeric gRNA retain functionality when, and only tolerates, sequences are attached to the 5' end of the crRNA portion or the 3' end of the tracrRNA portion [pg. 18, para 3-4; Fig. 5].
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1636