DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 23, 2026 has been entered.
Applicants previously canceled claims 1-38, 51, and 53-58. Applicants make no amendments, but add new claim 59. Claims 39-50, 52, and 59 are pending in this application, and are under examination. In addition, due to the previous cancellation of claims 51 and 58, claims 39-50 and 52 are deemed to have a priority filing date of June 17, 2013, the filing date of U.S. Provisional Patent Application No. 61/836,123.
Any objection or rejection of record in the previous Office Action, mailed October 27, 2025, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments.
Information Disclosure Statement
The Information Disclosure Statement filed April 27, 2026 has been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 39-50 are rejected under 35 U.S.C. 103 as being unpatentable over Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021).
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478]).
While Doudna does not explicitly disclose that expression of an altered gene product results in a phenotypic change, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the method of Doudna could be used to produce a phenotypic change in the organism because, as disclosed by Doudna, the Cas9 system can be used to target brain/neuronal cells and can be used to study the modulation of transcription and/or modification of DNA and/or modification of polypeptides associated with DNA. Thus, Doudna’s disclosure that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied provides one of ordinary skill in the art the motivation to target neuronal cells in order to alter a phenotype in a mammalian organism. This would also be useful for the treatment of diseases by altering a phenotype associated with a specific disease, which is desirable in treating mammalian organisms for genetically associated diseases and conditions, such as those associated with a neurological/neuronal disease or disorder.
Claims 52 and 59 are rejected under 35 U.S.C. 103 as being obvious over Doudna, as applied to claims 39-50 above, and in view of Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021). This rejection is modified as necessitated by Applicants’ amendments.
Doudna discloses a method of modifying brain/neuronal cells in a mammalian organism, as discussed above.
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Doudna fails to explicitly disclose or suggest that the AAV vector is AAV1, AAV2, AAV4, AAV5, or AAV8.
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the Doudna’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian, because Doudna’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success. Further, it would be well within the purview of one with ordinary skill in the art before the effective filing date of the claimed invention to optimize the level of Doudna’s indel formation to 20% or more, or any desirable level of indel formation. It would also have been obvious to one with ordinary skill in the art that Doudna’s viral vector could be used to treat any particular disease or condition that is genetically based because, as taught by Doudna, the viral vector system can be tailored by altering the sequences of the guides. Thus, one of ordinary skill in the art would have a predictable and reasonable expectation of success in targeting any particular gene in a eukaryotic system, where it was desirable to make a modification of the genetic material.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
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 39-50, 52, and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-41 of U.S. Patent No. 9,840,713 in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘713 patent and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism.
While the ‘713 patent does claim that the vector can be an adeno-associated viral (AAV) vector, the ‘713 patent does not claim the specific AAV serotypes, nor specific conditions that can be targeted.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Doudna fails to explicitly disclose or suggest that the AAV vector is AAV1, AAV2, AAV4, AAV5, or AAV8.
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the Doudna’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian for use in the ‘713 patent, because Doudna’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success. It would also have been obvious to one with ordinary skill in the art that the ‘713 patent’s method could be practiced with Doudna’s viral vector could be used to treat any particular disease or condition that is genetically based because, as taught by Doudna, the viral vector system can be tailored by altering the sequences of the guides. Thus, one of ordinary skill in the art would have a predictable and reasonable expectation of success in targeting any particular gene in a eukaryotic system, where it was desirable to make a modification of the genetic material.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
Claims 39-50, 52, and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,577,630 in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021). This rejection is the same as the previous provisional non-statutory double patenting rejection over U.S. Patent Application No. 14/971,356, now U.S. Patent No. 10,577,630.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘630 patent and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism in vivo using an AAV vector having the same serotypes. Both the ‘630 patent and the instant application claim methods of targeting specific organs/tissues in order to target a disease or condition relating to those organs, which include liver disorders.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, would target those specific organs for treatment of diseases associated with those organs instead of the hepatic disorders of the ‘630 patent.
Claims 39-50, 52, and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,407,985 in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘985 patent and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism in vivo using an AAV vector having the same serotypes. Both the ‘985 patent and the instant application claim methods of targeting specific organs/tissues in order to target an ocular disease or condition.
The ‘985 patent fails to claim targeting brain/neuronal cells or treating an associated disease.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, would target those specific organs for treatment of diseases associated with those organs instead of the ocular disorders of the ’985 patent.
Claims 39-50, 52, and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,018,275 in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘275 patent and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism in vivo using an AAV vector having the same serotypes. Both the ‘275 patent and the instant application claim methods of targeting specific organs/tissues in order to target a disease or condition relating to those organs, which include liver disorders.
The ’275 patent does not claim an AAV vector, nor the AAV serotypes.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the ‘275 patent’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian because the ‘275 patent’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, would target those specific organs for treatment of diseases associated with those organs instead of the ocular disorders of the ’275 patent.
Claims 39-50, 52, and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4 of U.S. Patent No. 12,252,707 in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021). This rejection is the same as the previous provisional non-statutory double patenting rejection over U.S. Patent Application No. 17/245,952, now U.S. Patent No. 12,252,707.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims a method of modifying a eukaryotic organism by administration of a CRISPR/Cas9 system in vivo and the ‘707 patent claims an animal/organism comprising a cell transformed with a vector comprising a CRISPR/Cas9 system. Both the instant application and the ‘707 patent claim an S. pyogenes Cas 9 and the use of two nuclear localization signals. Absent evidence to the contrary, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that any eukaryotic organism produced by the instant method would result in a eukaryotic organism that is the same as that claimed by the ‘707 patent.
While the ‘707 patent does claim that the vector can be an adeno-associated viral (AAV) vector, the ‘707 patent does not claim the specific AAV serotypes, nor specific conditions that can be targeted.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Doudna fails to explicitly disclose or suggest that the AAV vector is AAV1, AAV2, AAV4, AAV5, or AAV8.
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the Doudna’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian for use in the ‘707 patent, because Doudna’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success. It would also have been obvious to one with ordinary skill in the art that the ‘707 patent method could be practiced with Doudna’s viral vector could be used to treat any particular disease or condition that is genetically based because, as taught by Doudna, the viral vector system can be tailored by altering the sequences of the guides. Thus, one of ordinary skill in the art would have a predictable and reasonable expectation of success in targeting any particular gene in a eukaryotic system, where it was desirable to make a modification of the genetic material.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-5, 7, 10-13, 32-35, 37-38, 40, 45, and 54-58 of copending Application No. 14/971,169 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘169 application and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism in vivo using an AAV vector having the same serotypes. Both the ‘169 application and the instant application claim methods of targeting specific organs/tissues in order to target a disease or condition relating to those organs, which include neuronal and ocular disorders. Therefore, the claims are not deemed to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-21 of copending Application No. 15/230,161 (reference application) Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims a method of modifying a eukaryotic organism by administration of a CRISPR/Cas9 system in vivo and the ‘161 application claims an animal/organism comprising a cell transformed with a vector comprising a CRISPR/Cas9 system. Absent evidence to the contrary, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that any eukaryotic organism produced by the instant method would result in a eukaryotic organism that is the same as that claimed by the ‘161 application.
The ‘161 application fails to claim modification of a brain/neuronal cell in the organism.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, would target those specific organs for treatment of diseases associated with those organs instead of the ocular disorders of the ‘161 application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 22 of copending Application No. 17/034,754 (reference application) in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims a method of modifying a eukaryotic organism by administration of a CRISPR/Cas9 system in vivo and the ‘754 application claims an animal/organism comprising a cell transformed with a vector comprising a CRISPR/Cas9 system. Absent evidence to the contrary, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that any eukaryotic organism produced by the instant method would result in a eukaryotic organism that is the same as that claimed by the ‘754 application.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, would target those specific organs for treatment of diseases associated with those organs instead of the ocular disorders of the ‘754 application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-48 of copending Application No. 18/107,108 (reference application) in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims a method of modifying a eukaryotic organism by administration of a CRISPR/Cas9 system in vivo and the ‘108 application claims a CRISPR/Cas9 system for in vivo administration to animal/organism. Both the instant application and the ‘108 application claim an S. pyogenes Cas 9 and the use of two nuclear localization signals. Absent evidence to the contrary, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the CRISPR/Cas9 system of the ‘108 application could be administered to a eukaryotic organism produced by the instant method would result in a eukaryotic organism that is the same as that claimed by the ‘108 application.
While the ‘108 application does claim that the vector can be an adeno-associated viral (AAV) vector, the ‘108 application patent does not claim the specific AAV serotypes, nor specific conditions that can be targeted.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Doudna fails to explicitly disclose or suggest that the AAV vector is AAV1, AAV2, AAV4, AAV5, or AAV8.
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the Doudna’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian for use in the ‘108 application, because Doudna’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success. It would also have been obvious to one with ordinary skill in the art that the ‘108 application’s method could be practiced with Doudna’s viral vector could be used to treat any particular disease or condition that is genetically based because, as taught by Doudna, the viral vector system can be tailored by altering the sequences of the guides. Thus, one of ordinary skill in the art would have a predictable and reasonable expectation of success in targeting any particular gene in a eukaryotic system, where it was desirable to make a modification of the genetic material.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 56-74 of copending Application No. 18/740,453 (reference application) in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘453 application and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism in vivo using an AAV vector having the same serotypes. Both the ‘453 application and the instant application claim methods of targeting specific organs/tissues in order to target a disease or condition relating to those organs, which include liver disorders.
The ‘453 application does not claim an AAV vector, nor the AAV serotypes, nor modification of brain or neuronal cells.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the ‘453 application’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian because the ‘453 application’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 21 of copending Application No. 19/025,611 (reference application) in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘611 application and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism in vivo using an AAV vector having the same serotypes. Both the ‘453 application and the instant application claim methods of targeting specific organs/tissues in order to target a disease or condition relating to those organs, which include liver disorders.
The ‘611 application does not claim an AAV vector, nor the AAV serotypes or modification of brain neuronal cells.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the ‘611 application’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian because the ‘611 application’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34-52 of copending Application No. 19/079,848 (reference application) in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021). This rejection is modified as necessitated by Applicants’ amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘848 application and the instant application claim methods of modifying a eukaryotic organism by administering a CRISPR/Cas9 system to the organism in vivo using an AAV vector having the same serotypes. Both the ‘848 application and the instant application claim methods of targeting specific organs/tissues in order to target a disease or condition relating to those organs, which include liver disorders.
The ‘848 application does not claim an AAV vector, nor the AAV serotypes or modification of brain or neuronal cells.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the ‘848 application’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian because the ‘848 application’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-50, 52, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of copending Application No. 19/342,889 (reference application) in view of Doudna et al. (U.S. Patent Application Publication No. 2014/0068797, published March 6, 2014, claiming priority to U.S. Provisional Patent Application No. 61/757,640, filed January 28, 2013, and cited in the Information Disclosure Statement filed March 17, 2021), Asuri et al. (20(2) Molecular Therapy 329-338 (November 22, 2011), and cited in the Information Disclosure Statement filed March 17, 2021) and Damian et al. (21(4) Molecular Therapy 720-722 (April, 2013), and cited in the Information Disclosure Statement filed March 17, 2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims a method of modifying a eukaryotic organism by administration of a CRISPR/Cas9 system in vivo and the ‘889 application claims a CRISPR/Cas9 system for in vivo administration to animal/organism. Both the instant application and the ‘889 application claim an S. pyogenes Cas 9 and the use of two nuclear localization signals. Absent evidence to the contrary, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the CRISPR/Cas9 system of the ‘889 application could be administered to a eukaryotic organism produced by the instant method would result in a eukaryotic organism that is the same as that claimed by the ‘108 application.
While the ‘108 application does claim that the vector can be an adeno-associated viral (AAV) vector, the ‘108 application patent does not claim the specific AAV serotypes, nor specific conditions that can be targeted.
Regarding claims 39 and 59, Doudna discloses vectors comprising heterologous nucleic acids encoding CRISPR-Cas9 systems, including one or more guides, tracr mate sequences, and tracr sequences (paragraph [0137]). Doudna discloses that the vectors can be adeno-associated (AAV) virus vectors (paragraph [0302]). Doudna discloses that the CRISPR-Cas9 nucleic acids can be heterologous to the viral vector (paragraph [0117]). Doudna discloses that expression of the CRISPR-Cas9 nucleic acids can be driven by the T7 promoter and expression of T7 polymerase (paragraph [00106]). Doudna discloses cells, organisms and tissues, where the organism is a eukaryotic organism, such as a mammal, which is interpreted as delivering the system to an organism in vivo (paragraph [0017]). Doudna discloses targeting brain cells in genetically modified organisms, using a Cas9 molecule, which can be naturally-occurring or modified/chimeric (paragraph [0361]). Doudna discloses that the DNA of the targeted cells can be modified (paragraph [0361]). Doudna discloses that neurons (neuronal cells) can be targeted (paragraph [0362]). Doudna discloses that Cas9 can be used to modulate transcription and/or modify DNA and/or modify polypeptides associated with DNA, and that the properties of any gene of choice, expression product of choice or genomic locus of choice can be studied (paragraph [0790]).
Regarding claim 40, Doudna discloses that the system guides can be chimeric RNA (paragraph [0015]).
Regarding claim 41, Doudna discloses that multiple DNA-targeting RNAs can be used to simultaneously modify different locations on a target DNA (paragraph [0271]).
Regarding claim 42, Doudna further discloses that the heterologous molecule encodes a homologous recombination template for homology-directed repair (paragraph [0150]).
Regarding claims 43-44, Doudna discloses that the Cas9 can be from a variety of bacterial sources, including Streptococcus pyogenes, Staphylococcus, and Campylobacter (paragraphs [0013], [0596], and [0719]).
Regarding claim 45, Doudna discloses that the Cas9 can direct cleavage of both strands at the target sequence (paragraphs [0014], [0085], and [0127]).
Regarding claim 46, Doudna discloses that the Cas9 can contain mutations that provide for the Cas9 being a nickase or a double nickase (paragraphs [0014], [0085], and [0127]). Doudna further discloses that the mutations can be in the RuvC domain of Cas9, and/or one or more of D10A and H840A (paragraphs [0014] and [0085]).
Regarding claims 47-48, Doudna discloses that the vector can comprise a nuclear localization signal (NLSs), and because Doudna discloses that “a” can be plural, this encompasses two or more NLSs (paragraphs [0160] [0241]).
Regarding claim 49, Doudna discloses that the vector can further comprise additional functional domains (paragraph [0418]).
Regarding claim 50, Doudna discloses that the function domain can be a transcriptional activation domain, such as VP64 (paragraph [0418]).
Regarding claim 52, Doudna discloses use of a promoter that drives expression in neurons (paragraph [0478])
Doudna fails to explicitly disclose or suggest that the AAV vector is AAV1, AAV2, AAV4, AAV5, or AAV8.
Asuri discloses several adeno-associated virus vectors that can be used to deliver genetic material to a cell (abstract). Specifically, Asuri discloses AAV1.9, AAV2 and AAV6 vectors carrying zinc finger nucleases (page 334, paragraph bridging columns 1 and 2).
Damian discloses that AAV vectors could be used to deliver CRISPR-Cas9 systems to cells instead of TALENs and ZFNs because the CRISPR-Cas9 system is smaller, and thus could more easily be packaged into AAV vectors (page 720, paragraph bridging columns 2 and 3 and column 3, first full paragraph and page 721, column 3, second full paragraph).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any known AAV serotype vector according to Asuri to deliver the Doudna’s CRISPR-Cas9 systems using AAV systems according to Asuri and Damian for use in the ‘889 application, because Doudna’s CRISPR-Cas9 system will fit better inside any of the AAV vector systems according to Asuri and Damian, and thus have a predictable and reasonable expectation of success. It would also have been obvious to one with ordinary skill in the art that the ‘889 application’s system could be practiced with Doudna’s viral vector could be used to treat any particular disease or condition that is genetically based because, as taught by Doudna, the viral vector system can be tailored by altering the sequences of the guides. Thus, one of ordinary skill in the art would have a predictable and reasonable expectation of success in targeting any particular gene in a eukaryotic system, where it was desirable to make a modification of the genetic material.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to target neurological/neuronal diseases with the CRISPR/Cas system of Doudna, Asuri, and Damian because, as disclosed by Doudna, these diseases relate to specific organs of the organism, and one of ordinary skill in the art would have known that such cells and promoters of Doudna, which are able to target brain and neuronal cells, along with the vectors disclosed by Doudna, Asuri, and Damian would target those specific organs for treatment of diseases associated with those organs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Amendments and Arguments
Regarding the rejections under 35 U.S.C. § 103, Applicants’ arguments have been fully considered and are not deemed to be persuasive.
Applicants again assert that Doudna fails to disclose or suggest that the CRISPR-Cas9 systems can be used to target brain or neuronal cells, which provides for altered expression of a gene product by the CRISPR-Cas9 system in the brain or neuronal cell, and in turn produces a phenotypic change in the mammalian organism.
To begin, it appears that Applicants are attacking each reference individually. However, one cannot show nonobviousness by attacking references individually where rejections are based on combinations of references. In re Keller, 642, F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Here, it is the combination of Doudna with Asuri and Damien taken together and as a whole that would lead one of ordinary skill in the art directly to the claimed invention. While Applicants assert that, while the instant specification discloses in vivo editing of the meCP2 gene and multiplexed in vivo editing of the Dnmt1, Dnmt3a, and Dnmt3b genes, Doudna does not provide such disclosure. Applicants further assert that Doudna does not disclose phenotypic effects in the brain of a subject.
However, contrary to Applicants assertion, Doudna does indeed disclose targeting brain and/or neuronal cells in a mammalian organism, as discussed above. Doudna discloses that the targeting the brain/neuronal cells can be used to study the modification of DNA and the transcription and expression of gene products in the CRISPR-Cas9 targeted cells. And while Doudna does not specifically disclose that the modifications of the cells results in a phenotypic change in the organism, one of ordinary skill in the art, given the disclosure of Doudna, would understand that the targeting of brain and/or neuronal cells in the mammalian organism with a CRISPR-Cas9 system could result in altering the transcription and expression of a gene product, and that alteration of a gene product expression would naturally result in the production of a phenotypic change in a mammalian organism. Further, it would have been obvious to one with ordinary skill in the art that Doudna, by disclosing the modification of brain/neuronal cells, which would alter the phenotype of those cells, could be used to treat neurological/neuronal disorders and conditions.
Further, in response to Applicants’ assertion that Doudna’s disclosure does not bridge the gap to the claimed method and does not provide a single successful example of in vivo alteration of gene expression, it is noted that such an example is not required. In addition, Doudna’s specification provides clear guideposts to show that, not only is in vivo administration of CRISPR-Cas9 systems contemplated, but delivery to neuronal cells is disclosed as well. Therefore, one of ordinary skill in the art, knowing that use of CRISPR-Cas9 un brain/neuronal cells could result in organismal phenotypic changes, would find it at least obvious to try. Given the finite experimental requirements to determine that in vivo editing of brain/neuronal cells leads to a phenotypic change in the subject, one of ordinary skill in the art would have been able to design and carry out experimental protocols to show that the disclosure of Doudna provides sufficient evidence would result in the claimed method of modifying a brain or neuronal cell of an organism in vivo to achieve a phenotypic change in the organism. (See KSR International Co. v. Teleflex Inc., (550 U.S. 398; 127 S.Ct. 1727; 82 USPQ2d 1385).
Applicants further assert that neither Asuri nor Damian cure the deficiencies of Doudna. However, both Asuri and Damian are cited for the use of AAV delivery systems, which can be used to deliver Doudna’s CRISPR-Cas9 system to the brain/neuronal cells of a mammalian organism. The cited prior art references, when taken together and as a while provide for targeting the brain and/or neuronal cells of a mammalian organism using Doudna’s CRISPR-Cas9 system and delivering the system to the cells of the organism using Asuri’s and Damian’s AAV systems. Applicants have still not provided any objective, factually-based evidence that Asuri’s and Damian’s AAV systems would not be able to deliver Doudna’s CRISPR-Cas9 system to brain and neuronal cells in vivo in order to produce a phenotypic change in those cells. Applicants have again provided only arguments of counsel, and arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135,139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
Thus, one of ordinary skill in the art, having Doudna (with and without Asuri and Damian) would be led directly to the claimed invention. For all these reasons, and those listed above, the rejections as set forth above are maintained.
Regarding the non-statutory double patenting rejections, Applicants again request that they be held in abeyance until the claims at issue are deemed otherwise allowable. Therefore, these rejections, as modified above due to Applicants’ amendments, are maintained. In addition, the rejections of the claims over the claims of U.S. Patent Application Nos. 14/971,356 and 17/245,952 are no longer provisional, given the issuance of U.S. Patent Nos. 10,577,630 and 12,252,707, respectively. An additional provisional non-statutory double patenting rejection is made over U.S. Patent Application No. 19/342,889.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
The following patents and patent applications each disclose the same limitations as Zhang I above, and are therefore considered to be duplicative, commensurate in scope, and cumulative. Each of the following was cited in the Information Disclosure Statement filed March 17, 2021.
U.S. Patent Application Publication No. 2016/0281072;
U.S. Patent No. 8,945,839;
U.S. Patent No. 8,993,233;
U.S. Patent No. 8,871,445;
U.S. Patent Application Publication No. 2015/0247150; and
U.S. Patent Application Publication No. 2015/0291965.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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