DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The preliminary amendment filed April 25, 2024 is acknowledged. Claims 1-5, 13, 26 and 29-36 are pending and under examination.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 9. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Additionally, the use of the terms SYBR®, Nucleofector®, LeukoPakTM, EasySep®, ImmunoCult®, NanoDrop®, Äkta Go®, HiScribe®, and Monarch®, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 5 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. Claim 4 is a also multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claim 5 has not been further treated on the merits.
Claim Interpretation
The claims are directed to modified crRNAs or methods using modified crRNAs. Although the Specification teaches that crRNAs bind to Cas13 enzymes, it does not define a “crRNA” as only being Cas13 crRNAs, CRISPR type VI crRNAs, or limited in function to only binding Cas13. The specification defines the abbreviation “crRNA” as “CRISPR RNAs” (page 1, line 13). CRISPR systems use at least one CRISPR RNAs which are abbreviated crRNA (Makarova et al., Nature Reviews Microbiology (2020), 18: 67-83). In the art “crRNA” is used to mean CRISPR RNAs from all classes and type. As such “crRNA” is interpreted to encompass crRNAs from any CRISPR system, including types I, II, III, IV, V and VI, and the crRNA portion of a single guide RNA (sgRNA) for a Type II Cas9 system.
If Applicant intends the crRNA to be limited to Type VI (Cas13) systems, it is suggested that the claims be amended to recite “A modified Cas13 crRNA” or “A modified type VI crRNA”.
Claim Rejections - 35 USC § 102 - Rahdar
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4 and 13 are rejected under 35 U.S.C. 102(a)(1) as being rejected by Rahdar (Rahdar et al., PNAS (2015), 112: E7110-E7117).
Regarding claim 1, Rahdar teaches a crRNA molecule comprising a DNA recognition sequence (i.e., a spacer sequence) and a tracrRNA recognition sequence (i.e., a direct repeat sequence) and having three 2’-O-methyl modified nucleotides (Fig 3).
Regarding claim 4, Rahdar teaches the 2’-O-methyl nucleotides are at position 1 and 5 from the 5’ end (Fig 3B).
Regarding claim 13, Rahdar teaches the crRNA comprising the 2’-O-methyl nucleotides enhances the gene disruption compared to non-modified crRNAs (Fig 3B). Rahdar teach using the 2’-O-methyl nucleotides enhances stability of the oligonucleotides (page E7112, ¶3).
Claim Rejections - 35 USC § 102 - McMahon
Claims 1, 3-4 and 13 are rejected under 35 U.S.C. 102(a)(1) as being rejected by McMahon (McMahon et al., Molecular Therapy (2018), 26: 1228-1240).
Regarding claim 1, McMahon teaches a crRNA molecule called “MPD-43-01”, which comprises a direct repeat sequence and a DNA specificity sequence (i.e., a spacer sequence) and having 2’-O-methyl modified nucleotides and phosphorothioate linkages (Supp Fig 5B).
Regarding claim 3, McMahon teaches the direct repeat sequence is 5’ of the DNA specificity sequence (i.e., the spacer sequence) (Sup Fig 5B).
Regarding claim 4, McMahon teaches the 2’-O-methyl nucleotides are at position 1 at the 5’ end and the last two nucleotides on the 3’ end (Fig 5B).
Regarding claim 13, McMahon teaches the MPD-43-01 crRNA enhances the gene disruption compared to a non-modified crRNA (Fig 5B). McMahon teach using the 2’-O-methyl nucleotides enhances stability of the crRNAs (page 1129, ¶2).
Claim Rejections - 35 USC § 103 – Anderson in view of Moon
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 13, 26 and 29-33 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson (US 20220267773 A1, priority to at least July 23, 2020) in view of Moon (Moon et al., Trends in Biotechnology (2019), 37: 870-881).
Regarding claims 1-2, 13, 29 and 30, Anderson teaches a crRNA molecule comprising a direct repeat sequence (i.e., the hairpin in Fig 18A) and a spacer sequence that is 39 nucleotides long and complementary to the SARS-CoV-2 leader sequence (Fig 17A-B). Anderson teaches combining the crRNA targeting the leader sequence with a Cas13 expression construct (i.e., a recombinant expression vector encoding a Cas13 polypeptide) for destruction (i.e., knockdown) of the SARS-CoV-2 RNA ([0457]-[0468]). Anderson teaches the Cas13/crRNA directed to the SARS-CoV-2 leader sequence can be used for development of a therapy to treat coronavirus infections (i.e., a method of treating COVID-19 infection in a subject) ([0457]). Anderson also teaches that nucleic acid molecules can have modifications that increase their serum stability and resistance to nucleases including 2’-O-methyl and phosphorothioate linkages ([0267], [0271]). Anderson also teaches pharmaceutical compositions and formulations comprising the Cas13 and crRNA ([0326], [0332], [0335]-[0366]).
Anderson does not teach in the working examples delivering Cas13 enzymes with the crRNA comprising the chemically modified nucleotides.
Moon reviews the state of the art of improving CRISPR guide RNAs (i.e., crRNAs) in 2019. Moon teaches there are multiple ways of producing guide RNAs including synthetic production, which has the benefit of combining the guide RNAs in vitro with the CRISPR enzyme to form a ribonucleoprotein complex (RNP) (page 871, ¶1). Moon teaches RNPs provide more specific sequence targeting than using a vector system (page 871, ¶1; page 876, ¶2-3). Moon also teaches synthetic guide RNAs can be produced with modified nucleotides and linkages, such as 2’-O-methyl groups and phosphorothioate bonds, and is a routine practice (¶ spanning pages 871-872). Moon teaches such modifications render the guide RNAs resistant to nucleases that are present in the blood (¶ spanning pages 871-872). Moon teaches that chemical modifications to guide RNAs were exemplified with Cas9 guide RNAs, “but can be identically applicable to Type V and VI gRNAs” (Fig 1, legend). Moon teaches Cas13 is a type VI Cas nuclease (Glossary).
Regarding claims 1-2, 13, 29 and 30, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Anderson’s crRNA targeting the SARS-CoV-2 leader sequence by using 2’-O-methyl nucleotides and/or phosphorothioate linkages when delivering the crRNAs with Cas13 for the purpose of treating a COVID-19 infection. It would have amounted to modifying crRNAs in known ways and delivering the crRNAs with Cas13 by known ways to yield predictable results. The skilled artisan would have predicted that the leader sequence-targeting crRNA could be modified with 2’-O-methyl groups and/or phosphorothioate linkages because 1) Anderson teaches those are known modifications, and 2) Moon teaches that such modifications on CRISPR guide RNAs are “routine”. One would have been motivated to do so and deliver the Cas13/crRNA as an RNP because Moon teaches RNPs have increased specificity over vector-based therapeutics and the modified crRNA has increased stability over non-modified nucleic acids.
Regarding claim 26, the Specification does not define or described what is encompassed by “modulation of gene transcripts” or “regulation of the target RNA” except for page 21, which recites “modulation comprises down regulation of protein expression of the target mRNA”. Anderson teaches using the leader sequence-targeting crRNA and Cas13 for destruction of the SARS-CoV-2 RNA as indicated above for claims 1, 29 and 30, which is interpreted as being encompassed by “a method of modulating the SARS-CoV-2 gene transcript” and “crRNA induces regulation of the target RNA” by down regulating the transcript. The obviousness of modifying Anderson’s crRNA with 2’-O-methyl nucleotides and/or phosphorothioate linkages is recited above as for claims 1, 29 and 30.
Regarding claims 31-33, as indicated above for claim 21, Anderson teaches using the leader sequence-targeting crRNA and Cas13 for destruction of the SARS-CoV-2 RNA as indicated above for claims 1, 29 and 30, which is interpreted as being encompassed by “a method of modulating the SARS-CoV-2 gene transcript” and “crRNA induces regulation of the target RNA” by down regulating the transcript. Anderson also teaches delivery of Cas13/crRNA systems to subjects via a variety of routes of administration and to cells in vivo and ex vivo (i.e., to primary cells) ([0302], [0360]). Moon teaches that CRISPR technologies have been used to manipulate cells ex vivo and in vivo (i.e., primary cells) (page 879, ¶3). The obviousness of modifying Anderson’s crRNA with 2’-O-methyl nucleotides and/or phosphorothioate linkages is recited above as for claims 1, 29 and 30.
Claim Rejections - 35 USC § 103 – Yin in view of Moon
Claims 1-3, 13, 26, 31 and 33-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yin (Yin et al., Molecular Therapy (2020), 21: 147-155), published September 4, 2020) in view of Moon (Moon et al., Trends in Biotechnology (2019), 37: 870-881).
Regarding claims 1-3 and 13, Yin teaches delivering Type VI Cas13a enzymes and crRNAs targeted to HIV-1 RNA for the purpose of treating HIV-1 infection (Abstract). Yin teaches a crRNA molecule comprising a direct repeat sequence (i.e., the hairpin in Fig S7) and a spacer sequence that is 28 nucleotides long and complementary to the long terminal repeat (LTR), gag, tat or rev regions of the HIV RNA (page 148, ¶3; Fig 1, Fig S7). Yin teaches the direct repeat sequence is 5’ of the spacer sequence (Fig S7). Yin teaches combining a crRNA expression cassette with a Cas13a expression cassette (i.e., a recombinant expression vector encoding a Cas13a polypeptide) for destruction (i.e., knockdown) of the HIV-1 RNA (page 151, ¶4).
Moon reviews the state of the art of improving CRISPR guide RNAs (i.e., crRNAs) in 2019. Moon teaches there are multiple ways of producing guide RNAs including synthetic production, which has the benefit of combining the guide RNAs in vitro with the CRISPR enzyme to form an RNP (page 871, ¶1). Moon teaches using RNPs provides more specific sequence targeting than using a vector system (page 871, ¶1; page 876, ¶2-3). Moon also teaches synthetic guide RNAs can be produced with modified nucleotides and linkages, such as 2’-O-methyl groups and phosphorothioate bonds, and is a routine practice (¶ spanning pages 871-872). Moon teaches such modifications render the guide RNAs resistant to nucleases that are present in the blood (¶ spanning pages 871-872). Moon teaches that chemical modifications to guide RNAs were exemplified with Cas9 guide RNAs, “but can be identically applicable to Type V and VI gRNAs” (Fig 1, legend). Moon teaches Cas13 is a type VI Cas nuclease (Glossary).
Regarding claims 1-3 and 13, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Yin’s method of targeting HIV-1 RNAs to inhibit HIV-1 replication by using crRNAs with 2’-O-methyl nucleotides and/or phosphorothioate linkages and delivering the crRNAs with Cas13a as an RNP for the purpose of treating an HIV-1 infection. It would have amounted to modifying crRNAs in known ways and delivering the crRNAs with Cas13a by known ways to yield predictable results. The skilled artisan would have predicted that the HIV-1-targeting crRNA could be modified with 2’-O-methyl groups and/or phosphorothioate linkages because Moon teaches that such modifications are “routine”. One would have been motivated to do so and deliver the Cas13/crRNA as an RNP because Moon teaches RNPs have increased specificity over vector-based therapeutics and the modified crRNA has increased stability over non-modified nucleic acids.
Regarding claim 26, the Specification does not define or described what is encompassed by “modulation of gene transcripts” or “regulation of the target RNA” except for page 21, which recites “modulation comprises down regulation of protein expression of the target mRNA”. Yin teaches using the LTR, Gag, Tat and Rev-targeting crRNA and Cas13 reduced HIV-1 gene expression (Fig 1C, legend), which is interpreted as being encompassed by “a method of modulating the HIV-1 gene transcript” and “crRNA induces regulation of the target RNA” by down regulating the transcript. The obviousness of modifying Yin’s crRNAs with 2’-O-methyl nucleotides and/or phosphorothioate linkages is recited above as for claims 1 and 13.
Regarding claims 31 and 33-36, Yin also demonstrates Cas13a/crRNA can target HIV RNA and disrupt HIV replication in Jurkat cells (i.e., immortalized immune lymphocyte cells) (Figs 3A-B), and concludes that “Cas13a suppresses HIV replication in CD4+ T cells.” (page 149, ¶1). Yin also teaches Cas13a/crRNAs can reduce HIV-1 RNA expression from latent HIV-1 DNA in Jurkat cells (Fig 5C; page 149, ¶2).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have delivered the obvious composition of Cas13a and modified crRNAs to primary T-cells for the purpose of treating HIV-1 infections. The skilled artisan would have been motivated to have done so and with a reasonable expectation of success because Yin suggests that Cas13a/crRNA can be used to treat HIV-1 infections in subjects and demonstrates successful HIV-1 RNA downregulation in a CD4+ T-cell line.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-14 and 16-17 of copending Application No. 16621085 in view of Moon (Moon et al., Trends in Biotechnology (2019), 37: 870-881). Claim 4 is rejected further in view of McMahon (McMahon et al., Molecular Therapy (2018), 26: 1228-1240). Claim 29 is rejected further in view of Anderson (US 20220267773 A1, priority to at least July 23, 2020).
Copending claim 1 recites a method for making guide sequences comprising… synthesizing a set of guide molecules comprising the set of guide sequence each guide molecule thereby capable of complexing with a CRISPR-Cas system (i.e., the guide molecules are or comprise a crRNA)…”. Copending claim 14 recites wherein the CRISPR-Cas system is a CRISPR-Cas Type II, Type V or Type VI system. Copending claim 17 recites wherein the guide sequence are… chemically modified guide sequences.
The copending claims do not recite specific chemical modifications. The copending claims do not recite specific spacer lengths or orientations of the crRNA. The copending claims do not recite specific targeting sequences.
Moon reviews the state of the art of improving CRISPR guide RNAs (i.e., crRNAs) in 2019. Moon also teaches synthetic guide RNAs can be produced with modified nucleotides and linkages, such as 2’-O-methyl groups and phosphorothioate bonds, and is a routine practice (¶ spanning pages 871-872). Moon teaches such modifications render the guide RNAs resistant to nucleases that are present in the blood (¶ spanning pages 871-872). Moon teaches that chemical modifications to guide RNAs were exemplified with Cas9 guide RNAs, “but can be identically applicable to Type V and VI gRNAs” (Fig 1, legend). Moon teaches in Type VI Cas13a crRNAs and Type V crRNAs, the direct repeat is 5’ of the spacer sequence and the spacer sequence hybridizes to (i.e., is complementary to) a target RNA. Moon teaches the spacer sequences in crRNAs can be 20-72 nucleotides (page 872, ¶3). Moon teaches Cas13a proteins target and cleave RNA molecules (Glossary).
Regarding claims 1-3, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the generic Type VI guide RNAs of the copending claims to include 2’-O-methyl nucleotides and/or phosphorothioate linkages. It would have amounted to modifying crRNAs in known ways by known means to yield predictable results. The skilled artisan would have predicted that the copending crRNAs could be modified specifically with 2’-O-methyl groups and/or phosphorothioate linkages because Moon teaches that such modifications are “routine”. One would have been motivated to do so to render the crRNAs nuclease resistant. The skilled artisan would also have been motivated to have the direct repeat 5’ of the spacer sequence that was at least 23 nucleotides and is complementary to a target RNA, with reasonable expectation of success because Moon teaches those features are standard for type V and VI Cas13a crRNAs.
Regarding claim 4, McMahon teaches a Type V crRNA molecule comprising a direct repeat sequence and a DNA specificity sequence (i.e., a spacer sequence) and having 2’-O-methyl modified nucleotides and phosphorothioate linkages (Supp Fig 5B). McMahon teaches the direct repeat sequence is 5’ of the DNA specificity sequence (i.e., the spacer sequence) (Sup Fig 5B). McMahon teaches the 2’-O-methyl nucleotides are at position 1 at the 5’ end and the last two nucleotides on the 3’ end (Fig 5B). McMahon teaches the MPD-43-01 crRNA enhances the gene disruption compared to a non-modified crRNA (Fig 5B). McMahon teach using the 2’-O-methyl nucleotides enhances stability of the crRNAs (page 1129, ¶2). It also would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the generic Type V guide RNAs of the copending claims to include 2’-O-methyl nucleotides and/or phosphorothioate linkages at the 5’ and 3’ ends. It would have amounted to modifying crRNAs in known ways by known means to yield predictable results. The skilled artisan would have predicted that the copending crRNAs could be modified at the 5’ and 3’ ends because McMahon demonstrates such a modified crRNA. One would have been motivated to do so to render the crRNAs nuclease resistant.
Regarding claim 29, Anderson teaches a Cas13 crRNA molecule comprising a direct repeat sequence (i.e., the hairpin in Fig 18A) and a spacer sequence that is 39 nucleotides long and complementary to the SARS-CoV-2 leader sequence (Fig 17A-B). Anderson teaches the Cas13/crRNA directed to the SARS-CoV-2 leader sequence can be used for development of a therapy to treat coronavirus infections ([0457]). Anderson also teaches that nucleic acid molecules can have modifications that increase their serum stability and resistance to nucleases including 2’-O-methyl and phosphorothioate linkages ([0267], [0271]).
It also would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have specifically designed the obvious variant of the type VI crRNA having 2’-O-methyl nucleotides and/or phosphorothioate linkages to target the SARS-CoV-2 leader sequence as taught in Anderson. It would have amounted to designing the obvious crRNAs to recognize a known RNA sequence in known ways to yield predictable results. The skilled artisan would have predicted that the obvious variants of the copending crRNAs could target the SARS-CoV-2 leader sequence because Anderson teaches the sequence. One would have been motivated to do so to use the nuclease-resistant crRNAs in a method to treat COVID-19 as taught in Anderson.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/CATHERINE KONOPKA/Examiner, Art Unit 1635