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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The foreign priority applicant was filed on 12/25/20.
Claim Interpretation
The limitation in the pre-amble “for ADA-depending editing of a target RNA” of instant claim 1 is an intended use of the claimed gRNA. The broadest reasonable interpretation of claim 1 is a guide comprising an sequence that is complementary to a portion of a target RNA that comprises a polyadenylation signal sequence.
The limitation in claim 5 is not required to be taught by the prior art because it is directed to a an intended use of the claimed product.
Claim 4 requires that the gRNA forms a base pair with an adenosine in the polyadenylation signal sequence of the target RNA.
The limitation ‘A host cell into which the expression vector according to claim 8 is introduced’ in Claim 10 embraces a cell not comprising the expression vector of claim 8 because there is no limitation requiring the cell having the vector. In other words the gRNA was not introduced into the cell.
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 1-3, 5-7 and 10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to product found in nature (a mammalian cell) without significantly more. The claims recite a guide RNA comprising a sequence that is complementary to a target RNA, wherein the target RNA has a polyadenylation signal sequence. The limitation in the pre-amble “for ADA-depending editing of a target RNA” of instant claim 1 is an intended use of the claimed gRNA. The broadest reasonable interpretation of claim 1 is a guide sequence from either a microRNA or a siRNA comprising the guide sequence, wherein the guide sequence is complementary to a mRNA; or the guide sequence is a natural antisense RNA transcript found in a mammalian cell. The prior art teaches that miRNA comprise a sequence that is complementary to mRNA. See Alfonso-Grunz et al. (Cell Mol Life Sci 2015, 72:3127-3141). The prior art further teaches that natural antisense RNA sequences that are complementary to a mRNA are found in mammalian (human) cells. See WO 2007087113. Sheets et al. (Nucleic Acid Research 18, pages 5799-5805) teach that the base sequence AAUAAA is a conserved sequence that is located in the vicinity of the cleavage site of vertebrate mRNA to which the poly A tail is added. This indicate that all cells from a vertebrate, including humans, would have the base sequence. In addition, the limitation ‘a modified sequence of the base sequence’ in claim 2 reads on a poly A tail found in any mRNA found in nature. See Sheets (supra). Furthermore, the limitation in instant claim 5 is not required to be taught by the prior art because it is directed to an intended use of the claimed product in claim 1. This judicial exception is not integrated into a practical application because there are no additional structural limitations in the claims that would exclude the product from reading on a guide RNA in a mammalian cell found in nature. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because as set forth above the additional limitations do not add patentable weight to the claims because they do not add any additional structural limitations to the claims.
With respect to claim 6 directed to a system of editing as target RNA comprising the guide RNA of claim 1 and an ADAR, the broadest reasonable interpretation of the system reads on a mammalian cell comprising a natural antisense RNA transcript and an endogenous ADAR. See paragraph 60 of US 20190040383 (cited on an IDS) that discloses that ADAR are found in mammals (humans). A skilled artisan would possess the knowledge that any mammalian cell in a mammal expresses ADAR and a natural antisense RNA transcript are also found in the same mammalian cells.
The nucleic acid recited in instant claim 7 would embrace a genomic sequence found in mammalian cell because the genomic sequence would encode the guide RNA according to claim 1.
The broadest reasonable interpretation of claim 10 is any cell found in nature because there is no active limitation requiring the cell to comprise the expression vector of claim 8.
Thus, claims 1-3, 5-7 and 10 are patent ineligible.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 10 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). The broadest reasonable interpretation of a host cell not comprising the expression vector of claim 10 and reads on a human having the cell because the term “a” embraces one or more cells and is not limited to one cell. The specification embraces editing a target RNA in a human. Thus, any human having this cell would be embraced by the claimed product.
Claim Rejections - 35 USC § 112
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.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of producing an expression vector comprising a step of culturing a host cell comprising the expression vector, does not reasonably provide enablement for producing an expression vector in a host cell that does not comprise the vector. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The broadest reasonable interpretation of the claimed method embraces culturing a cell to produce an expression vector, wherein the cell does not comprise the vector. The claim embraces the host cell according to claim 10, but claim 10 does not require that the host cell comprises the vector. The claim just recites a host cell that would eventually have the vector. There is no nexus between the pre-amble and the method step to complete the pre-amble of the claimed method. The vector has to be in the host cell for the method to be enabled.
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.
NOTE: The limitation ‘A host cell into which the expression vector according to claim 8 is introduced’ in Claim 10 embraces a cell not comprising the expression vector of claim 8 because there is no limitation requiring the cell having the vector.
Claims 1, 2, 3, 5, 7, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alfonso-Grunz et al. (Cell Mol Life Sci 2015, 72:3127-3141). Alfonso-Grunz teaches that miRNA comprise a sequence that is complementary to mRNA comprising a polyadenylation sequence, wherein the sequence is AAUAAAA (pages 3128-3133, and Figures 1-3). A genomic sequence comprising a miRNA would read on the limitation in claim 7 (see Figures 1-3). Alfonso-Grunz et al. teach a cell (Figure 1).
Claims 1-3. 5, 7, 10, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by The Scripps Research Institute (WO2007087113) as evident by Sheets et al. (Nucleic Acid Research 1990, 18, pages 5799-5805).
‘113 discloses natural antisense transcripts comprise a sequence that is complementary to a mRNA (pages 7, 24-35, 48, 74, 78, and 100-103 and Figures 12A-D). Furthermore, ‘113 discloses a delivering a siRNA to a cell wherein the siRNA comprises a sequence that is complementary to an antisense transcript or a sense transcript (pages 45-48). Antisense transcripts contain a cap structure and a poly A tail (page 7). A genomic sequence comprising the natural antisense transcript would read on the limitation in claim 7 (see Figures 1-3). ‘113 teaches a cell (pages 18 and 20).
‘113 does not teach that the an antisense transcript or mRNA would inherently have a sequence consisting of AAUAAA. Sheets et al. teach that the base sequence AAUAAA is a conserved sequence that is located in the vicinity of the cleavage site of vertebrate mRNA to which the poly A tail is added.
Thus, in view of Sheets, a siRNA that targets an antisense transcript or mRNA would embrace a target RNA including a polyadenylation signal sequence consisting of AAUAAA because the signal sequence would be inherent in the sequence having a poly A tail or any mRNA (sense transcript).
Claims 1-3, 5-10 and 14 are rejected under 35 U.S.C. 102(a)(1) or (2) as being anticipated by Yeo et al. (CA3062595, published 11/15/18 and EFD 5/10/17) as evident by Sheets et al. (Nucleic Acid Research 1990, 18, pages 5799-5805).
Yeo teaches a cell comprising a vector comprising an nucleotide comprising ADAR and a vector comprising a guide RNA comprising a region of homology capable of near-perfect RNA-RNA base pairing to a target RNA (page 58). The target RNA can be mRNA.
Yeo also teaches a method “Cas9-directed RNA editing” or “CREDIT” to provide reversible alteration of genetic information in a temporal manner (abstract and pages 8, 46-49, 60-63, and 145-149). CREDIT comprises using a system comprising (A) a nucleic acid sequence encoding a CRISPR/Cas RNA editing fusion protein comprising a nuclease-dead CRISPR associated endonuclease (dCas) fused to a catalytically active deaminase domain of Adenosine Deaminase acting on RNA (ADAR); and (B) a nucleic acid sequence encoding an extended single guide RNA (esgRNA) comprising: (i) a short extension sequence of homology to the target RNA comprising a mismatch for a target adenosine in the target RNA, and (ii) a dCas scaffold.
Yeo does not teach that the mRNA would inherently have a base sequence consisting of AAUAAA. However, Sheets et al. teach that the base sequence AAUAAA is a conserved sequence that is located in the vicinity of the cleavage site of vertebrate mRNA to which the poly A tail is added.
In view of Sheets, a mRNA targeted in the working examples on pages 60-63 of Yeo would embrace a target RNA including a polyadenylation signal sequence consisting of AAUAAA because the signal sequence would be inherent in the mRNA sequence.
Thus, Yeo as evident by Sheets teach CREDIT for editing mRNA in a cell comprising contacting the cell comprising the mRNA with an expression vector comprising (A) a nucleic acid sequence encoding a CRISPR/Cas RNA editing fusion protein comprising a dCas fused to a catalytically active deaminase domain of ADAR; and (B) a nucleic acid sequence encoding an esgRNA comprising: (i) a short extension sequence of homology to the mRNA comprising a polyadenylation signal sequence, and (ii) a dCas scaffold. See pages 60-63.
Sequences A) and B) can be in the same vector or different vectors (page 145 of Yeo).
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.
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 4 and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Yeo et al. (CA3062595, published 11/15/18 and EFD 5/10/17) taken with Sheets et al. (Nucleic Acid Research 18, pages 5799-5805, 1990) as applied to claims 1-3, 5-10 and 14 above.
Yeo teaches a method of using a system termed “Cas9-directed RNA editing” or “CREDIT” to provide reversible alteration of genetic information in a temporal manner (abstract and pages 28-29, 46-49, 60-64, and 145-149). The CREDIT system provides the ability to target any adenosine in the transcriptome to direct conversion to inosine. Yeo teaches a vector comprising an nucleotide comprising ADAR and a vector comprising a guide RNA comprising a region of homology capable of near-perfect RNA-RNA base pairing to a target RNA (Figure 2). The target RNA can be mRNA and the target RNA can be involved in pathogenesis or a therapeutic target for conditions (page 49).
Yeo does not specifically teach the gRNA having a sequence that is complementary to a portion of the target RNA, wherein the sequence comprises a nucleotide that is complementary with an adenosine in the polyadenylation signal sequence of the target RNA.
However, Sheets et al. teach studying point mutations in AAUAAA and the poly A addition and the effects on the accuracy and efficiency of cleavage and polyadenylation in vitro (pages 5799-5805, Figure 2).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Yeo taken with Sheets to make a gRNA comprising a sequence that is complementary to a nucleotide sequence comprising a polyadenylation signal sequence comprising AAUAAA to edit poly A signals and study accuracy and efficiency of cleavage and polyadenylation in vivo, namely to arrive at the claimed invention. It would have been a simple substitution for one ordinary skill in the art to use the RNA editing method taught by Yeo in a cell comprising a target RNA comprising a polyadenylation signal sequence to edit a target RNA having the poly adenylation signal with a reasonable expectation of success. The method of using the vector in a cell would embrace culturing the vector in a cell because the broadest reasonable interpretation of claim 11 embrace delivering a vector to a cell. There are no method steps for culturing the vector in the cell in claim 11, nevertheless, one of ordinary skill in the art would have been motivated to culture the cells to maintain the vector in the cells for research purposes. It would have been obvious to one of ordinary skill in the art to make a pharmaceutical composition comprising the vectors and a pharmaceutically acceptable carrier for storage or for delivering to a cell (page 56 of Yeo).
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 8 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over The Scripps Research Institute (WO2007087113) as evident by Sheets et al. (Nucleic Acid Research 1990, 18, pages 5799-5805) as applied to claims 1-3. 5, 7, 10, and 14
‘113 discloses natural antisense transcripts comprise a sequence that is complementary to a sense transcript (mRNA) or an antisense transcript comprising a polyadenylation sequence (pages 7, 24-35, 48, 74, 78, and 100-103 and Figures 12A-D). Furthermore, ‘113 discloses a siRNA comprising a sequence that is complementary to an antisense transcript or a sense transcript (pages 45-48). Antisense transcripts contain a cap structure and a poly A tail (page 7). Pages 17-18 disclose a pharmaceutical composition. Pages 19-22 discloses using a vector to deliver the siRNA.
‘113 does not specifically teach a vector comprising the siRNA targeting an antisense transcript comprising a poly adenylation signal sequence.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to use a vector comprising the siRNA to assist in delivery of the siRNA to a cell. One of ordinary skill in the art would have been motivated to place the siRNA in a pharmaceutical composition comprising a vector and a pharmaceutically acceptable carrier to store or for delivery to a cell.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 5, 7, 8, 10-12, and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 115-127 of copending Application No. 18853514 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a gRNA targeting a RNA sequence comprising a polyadenylation signal sequence. Claim 124 of ‘514 recites a pharmaceutical composition comprising a viral vector comprising an antisense oligonucleotide that is complementary to a region of a protein-encoding mRNA transcript, which would embrace a mature mRNA that has a poly A tail and read on instant claims 1, 4, 5, 7, 8, 10, and 12. Claim 126 of ‘514 embraces delivering the composition to a cell and would read on or make obvious instant claims 11 and 14.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
See attached PTO-326 for disposition of claims.
Claims 1-4 and 6-23 of copending Application No. 17783591 do not appear to embrace a gRNA targeting a sequence comprising a polyadenylation signal sequence.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WO 2019005886 (published 1/3/2019 and EFD 6/26/17). Paragraph 643 of WO 2019005886 discloses using CRISPR system to edit poly A signals.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571)-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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