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
Applicant’s amendments filed July 20, 2026, amending claims 1, 4 and 5 is acknowledged. Claims 1-5, 13, 26 and 29-36 are pending and under examination.
The amendment to claim 5 overcomes the objection for improper dependent form. Claim 5 is now treated on the merits. All rejections of claim 5 are new and necessitated by amendment.
The amendment to claim 1 overcomes the §102 rejections of claims 1, 3 and 4. However, “type VI” was not added to claim 13, which still reads on Cas9 or Cas12 crRNAs.
In their remarks, Applicant states “A substitute specification removing the hyperlinks and adding generic terminology… is provided herewith” (page 5). However, no substitute specification was filed. As such, the objection to the Specification is maintained below.
Application 16/621,085 is now patent 12,548,638. The nonstatutory double patenting rejection is updated to reflect the patent claim numbering.
Any other rejections or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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 Interpretation
Claim 1 recites “A modified type VI crRNA”. Claim 13 recites “modifying a crRNA comprising a spacer sequence and a direct repeat.” 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. (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; of record). In the art “crRNA” is used to mean CRISPR RNAs from all classes and type. As such “crRNA” in claim 13 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. The remaining claims are limited to a type VI crRNA.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by amendment.
Claim 5 recites “the modified crRNA of claim 1, comprising chemically modified nucleotides throughout the crRNA.” Claim 5 is indefinite because it is not clear how many or what percentage of nucleotides and/or internucleotide linkages must be modified for the crRNA to be considered “modified throughout”. Thus, “throughout” is considered a term of degree, but the Specification does not provide a standard to determine for ascertaining the decree of modification for “throughout”. The Specification does not define “throughout” or provide an example of a crRNA with modifications “throughout”. According to the plain meaning of the word “throughout” can be used to mean “in every part”. However, Applicant’s own data indicates that a crRNA having all nucleotides chemically modified, renders the crRNAs unoperable (FIG. 1D). Consider the following everyday usage: “the museum had paintings throughout”. One would imagine paintings in every room and gallery, but not on every inch of wall available. As such, it is unclear whether every nucleotide in the crRNA is to be chemically modified, or if there is to be chemically modified nucleotides in each part, as in at least one chemically modified nucleotide in the spacer and at least one in the direct repeat.
Claim Rejections - 35 USC § 112(a) - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 5 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new rejection necessitated by amendment. It is directed to the interpretation that “throughout” means every nucleotide is modified in the crRNA.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of Claims
Claim 5 is drawn to a Cas13 crRNA having 100% chemically-modified nucleotides, wherein the chemical modification is 2’-O-methyl (M), 2’-O-methyl-3’-phosphorothioate (MS), and/or inverted thymine (invT). Accordingly, enablement of the method requires one skilled in the art to be able to use the fully modified crRNA having M, MS, and/or invT residues.
Guidance in the Specification
The specification provides several working examples with partially and fully modified crRNAs and tests their ability to target the targeted mRNA, as dictated by the spacer/guide sequence (pages 22-26). While the specification teaches that crRNAs having only 3 modified nucleotides at the 3’ end of the spacer sequence have improved Cas13-mediated target cleavage, a crRNA wherein all the nucleotides had 2’-O-methyl modifications, completely abrogated Cas13a activity (FIG 1D; ¶ spanning pages 23-24). The specification speculates that the 2’-O’methyl groups throughout the crRNA disrupted Cas13-crRNA interactions (page 24, ¶1). Therefore, in light of the specification, it is highly unpredictable how the skilled artisan would use a fully-modified crRNA wherein every nucleotide either had an M, MS or invT modification.
State of the Prior Art
There is no working example in the prior art of a fully chemically modified Cas13a crRNA. Moon reviews the state of the art of improving CRISPR guide RNAs (i.e., crRNAs) in 2019 (Moon et al., Trends in Biotechnology (2019), 37: 870-881; of record. 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). However, typically only the 5’ and/or 3’ terminal residues are chemically modified since the modifications protect against exonucleases – nucleases that cleave off terminal nucleotides. Indeed, McMahon demonstrates that a type V crRNA having all phosphorothioate linkages resulted in a 70% loss of activity (McMahon et al., Molecular Therapy (2018), 26: 1228-1240; page 1232, ¶2; Fig 3A). Thus, in view of the prior art, it would have been highly unpredictable how one skilled in the art would use a fully modified Cas13a crRNA with M, MS or invT residues.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples of a fully-modified functional crRNA, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed since all evidence points to an inoperable fully modified 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.
Claim 13 is rejected under 35 U.S.C. 102(a)(1) as being rejected by Rahdar (Rahdar et al., PNAS (2015), 112: E7110-E7117). This is a maintained rejection.
Regarding claim 13, 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). 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
Claim 13 is rejected under 35 U.S.C. 102(a)(1) as being rejected by McMahon (McMahon et al., Molecular Therapy (2018), 26: 1228-1240). This is a maintained rejection.
Regarding claim 13, 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). 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 § 102 - Khera
Claims 1, 3-4 and 13 are rejected under 35 U.S.C. 102(a)(1) as being rejected by Khera (US 20190017119 A1). This is a new rejection necessitated by amendment.
Regarding claims 1 and 13, Khera teaches reducing the susceptibility of the Cas13 guide molecules (i.e., a type VI crRNA) to RNA-cleaving enzymes (i.e., a method of enhancing the stability) by incorporating modified nucleotides in the guide RNA, including 2’-O-methyl analogs (M) and 2’-O-methyl-3'-phosphorothioate (MS) nucleotides ([0154]). Khera teaches Cas13 crRNAs comprise a guide sequence (i.e., a spacer sequence) and a direct repeat sequence ([0160]).
Regarding claim 3, Khera teaches in some Cas13 crRNAs the direct repeat is 5’ to the spacer sequence ([0160]).
Regarding claim 4, Khera teaches incorporating the modified nucleotides in the 3-5 nucleotides at either the 3’ end or the 5’ end of the guide sequence of the crRNA.
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). This is a new rejection necessitated by amendment. It is modified to state that the Cas13 crRNA is a type VI crRNA.
Regarding claims 1-2, 13, 29 and 30, Anderson teaches that Cas13 enzymes and the crRNAs are type IV CRISPR systems ([0439]). 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, [0048]). 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). This is a maintained rejection.
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.
Response to Arguments - §103
Applicant provides one set of arguments to traverse the rejection of Anderson in view of Moon (Remarks, pages 6-7) and then reiterates them to traverse the rejection of Yin in view of Moon (page 8, ¶3-4). Examiner will address the arguments as they apply to both Anderson or Yin in view of Moon.
Applicant argues that while Moon mentions type VI systems, there is no data presented in Moon to show that type VI systems are amenable to chemical modifications. Applicant argues that the guide architecture, target recognition, nuclease activation and sequence requirements of Type VI systems differ from Cas9 systems (page 6, ¶4 to page 7, ¶1). Applicant cites to Wessels et al., who showed that activity of Cas13d guide RNAs depends on specific sequence features such that design principles for DNA-targeting CRISPR effectors would not be expected to apply directly to Cas13 crRNAs (page 7, ¶2). These arguments have been fully considered but are not persuasive. First, Moon discusses the differences in guide RNAs between Cas9 and Cas13 systems, including attempts to engineer guide RNAs (e.g., truncation, page 82, ¶4). Yet, Moon still teaches that the chemical modifications that have been extensively used for Cas9 systems are applicable to Cas13. Additionally, McMahon demonstrates that the modifications taught in Moon and suggested to work in type V systems, are indeed able to increase stability and gene targeting by type V CRISPR system (see §102 rejection above). Thus, the skilled artisan would have concluded that it was more likely than not the 2’-O-methyl and phosphorothioate linkages that render Cas9 exonuclease resistant, could also be used to render Cas13 crRNAs exonuclease resistant. Second, in the Wessels article, the authors found similarities between Cas13/gRNA complex and Cas9/gRNA complexes (e.g., gRNAs may allow extension and further stabilization of the stem loop, page 724, ¶2). There is nothing in Wessels to contradict Moon or persuade the skilled artisan that Moon’s assertion that chemical modifications routinely used in Cas9 gRNAs “can be identically applicable to Type V and VI gRNAs” is unfounded.
Applicant argues that Cas13 activation depends on RNA:RNA recognition that activates the catalytic domain, and therefore guide RNA characteristics may influence Cas13-sepcific process (page 7, ¶3, emphasis added). This argument has been full considered but is not persuasive because it is merely argument of counsel without supporting evidence. MPEP 716.01(c) makes clear that arguments of counsel cannot take the place of evidence in the record.
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 1-5 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US Patent 12548638 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). This is maintained rejection. It is modified to reflect the claim numbering changes upon patenting of the application.
Patented 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)…”. Patented claim 13 recites wherein the CRISPR-Cas system is a CRISPR-Cas Type II, Type V or Type VI system. Patented claim 15 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.
Response to Arguments - NSDP
Applicant argues that the patented claims are directed to a computer-implemented method of designing guide RNAs, not crRNAs having modifications. Applicant references the arguments used to traverse the §103 rejections are applied to the NSDP rejection (page 8, ¶6). This argument has been fully considered but is not persuasive. First, patented claims recite “synthesizing guide RNAs”, wherein the guide RNA are for a CRISPR-Cas VI system, which are known in the art as crRNAs. The patented claims also recite the guide sequences (i.e., the crRNAs) are chemically modified. Thus, the patented claims are directed, at least partially, to synthesizing chemically modified type VI crRNAs. Based on the teachings of Moon and McMahon it would have been obvious to specifically use M or MS modifications in the patented synthesized chemically modified type VI crRNAs. Response to Applicant’s arguments regarding Moon are recited above in paragraphs 47 and 48.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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