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 .
Claims 1-3, 5-14, 16-20, and 22 are pending. Claims 5-14 and 16-18 are withdrawn from consideration as being drawn to nonelected inventions.
Status of the Application
Applicant’s response and amendment filed 04 November 2025 are acknowledged and entered.
Applicant has amended Claims 1-2 and 19. Applicant has cancelled Claim 21.
Response to Amendment
Applicant has amended Claims 1 and 19 and canceled Claim 21 to overcome the 103 rejection; the 103 rejection is not withdrawn.
Applicant has amended Claim 2 to overcome the 112b rejection; the previous 112b rejection is withdrawn.
The NSDP rejections are maintained.
Claims 1-3, 19-20, and 22 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Claim Interpretation
The claims recite a CasΩ nuclease. The term CasΩ is not common in the art. Applicant’s Specification discloses (p. 3 L20-21): US9790490B2 describes Cas12a (Cpf1) enzymes, including Cas12a (type V), which corresponds to CasΩ according to the present invention. Therefore CasΩ is interpreted as being the same thing as what is described in the reference as Cpf1.
Claims 1 and 19 recite wherein the complex further comprises a label… or wherein the complex comprises a label in the target RNA. Applicant’s 22 July 2024 remarks (pp. 7-8) indicate that “label” means only moieties that are attached, either covalently or non-covalently and that “labels” specifically refers to visual labels such as dyes or fluorophores.
Claim 2 recites said guide RNA that specifically hybridizes with the single stranded target RNA molecule. In the art guideRNA is understood to be specific to a target; therefore the recited guideRNA in is understood to specifically hybridize with the single stranded RNA target molecule.
REJECTIONS NECESSITATED BY AMENDMENT
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 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 rejection is necessitated by the claim amendments.
Claim 2 recites the limitation "…wherein the single-stranded target RNA molecule having a sequence that is at least 90% complementary to said guide RNA that specifically hybridizes with the single stranded target RNA molecule" in L1-3. There is insufficient antecedent basis for this limitation in the claim because Claim 2 depends from Claim 1 which doesn’t recite any single-stranded target RNA molecule having a sequence that is at least 90% complementary to said guide RNA.
In the interest of compact prosecution the claim is interpreted as reciting: …wherein the single-stranded target RNA molecule has a sequence that is at least 90% complementary to said guide RNA that specifically hybridizes….
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-3, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WO996 (published 27 May 2021; of record), US Patent No. 9790490 (issued 17 October 2017, “US490”, of record), and Wikipedia (2021. “Negative-strand RNA virus” [p. archived 29 May 2021] and “Positive-strand RNA virus” [p. archived 11 April 2021]. Available online at Wikipedia.org. Accessed on 30 July 2025, “Wikipedia”, of record). This rejection is maintained and has been updated in response to the 04 November 2025 claim amendments.
WO996 teaches most of the limitations of Claims 1-3, 20, and 22 and the other reference teaches the remaining limitations. WO996 is drawn to antibacterial CRISPR compositions and methods. WO996 teaches nucleic acids encoding Cms1 polypeptides that (PDF p. 7 L5-20):
…act without the use of tracrRNAs, requiring on [sic] a single gRNA for sequence specificity… a Cms1-gRNA complex can perform an initial hybridization event to target a particular sequence... the Cms1 protein is then able to perform a secondary collateral activity directed against double-stranded DNA (dsDNA) or RNA without any sequence specificity… In general, Cms1 polypeptides comprise at least one RNA recognition and/or RNA binding domain. RNA recognition and/or RNA binding domains interact with guide RNAs.
WO996 teaches (p. 6 L 5-15) guide RNAs that are capable of interacting or that are designed to interact with a Cms1 polypeptide can bind, associate with, or otherwise form a complex with the Cms1 polypeptide.
WO996 also teaches (p. 7 L30-32) without being limited by theory, the RuvC endonuclease domain may also exhibit secondary, collateral activity directed against dsDNA and/or RNA in a non-sequence specific manner.
WO996 teaches (p. 7 L5-15) the term Cms1 endonucleases or Cms1 polypeptides refers to…sequences set for [sic] in SEQ ID NOs 41-160… The instant Spec. teaches on p. 15 L20-25 that:
the subgroup of ca40CasΩ nucleases according to the present invention, in particular as shown in SEQ ID Nos. 1-15, as one distinguishing feature exhibits a unique AA composition between the RuvC-II and RuvC-III catalytic motifs, comprising a deletion of AAs compared to nonCasΩ nucleases, such as Cas12a.
Instant SEQ ID NO. 1 is identical to WO996 SEQ ID NO 153, as shown by the following AA sequence alignment:
Query Match 100.0%; Score 6184; DB 33; Length 1180;
Best Local Similarity 100.0%;
Matches 1180; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSDKNQSFSQFTNLYELSKTLRFELKPSEITFEKLENNKLFKVKDVESKIFSKNENGEIS 60 SEQ ID NO 1
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSDKNQSFSQFTNLYELSKTLRFELKPSEITFEKLENNKLFKVKDVESKIFSKNENGEIS 60 SEQ ID NO 153
Qy 61 EAEKKVKNYLFDINETELNNLVKKCDEKIEEIKKIKDFLEKNPDKLWQVWIDNEKIKIID 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EAEKKVKNYLFDINETELNNLVKKCDEKIEEIKKIKDFLEKNPDKLWQVWIDNEKIKIID 120
[truncated for brevity]
Qy 1081 IQRIEDIKELQKEDKKGGQLGNLIFVDPENTSKQCPNCLEIGQRKHSRPTHDFVKCKKCG 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 IQRIEDIKELQKEDKKGGQLGNLIFVDPENTSKQCPNCLEIGQRKHSRPTHDFVKCKKCG 1140
Qy 1141 FDTRNDDTKKGFDFIDGGDTLAAYNIAKRGLKFLKEKNNL 1180
||||||||||||||||||||||||||||||||||||||||
Db 1141 FDTRNDDTKKGFDFIDGGDTLAAYNIAKRGLKFLKEKNNL 1180
Since the instant Spec. identifies SEQ ID NO 1 as a CasΩ and SEQ ID NO 1 is identical to WO996 SEQ ID NO 153, SEQ ID NO 153 has the same structure as a CasΩ nuclease, is a CasΩ nuclease and therefore inherently encompasses all the properties of a CasΩ nuclease.
As described in §Claim interpretation, the instant claims recite a CasΩ nuclease which is not a term that is common in the art. Applicant’s Specification discloses (p. 3 L20-21): US9790490B2 describes Cas12a (Cpf1) enzymes, including Cas12a (type V), which corresponds to CasΩ according to the present invention. Therefore Applicant’s Spec. indicates that CasΩ is the same thing as Cpf1. As described in the preceding ¶, the instant Spec. (p. 15 L20-25) identifies SEQ ID NO 1 as a CasΩ. Since SEQ ID NO 1 is identical to WO996 SEQ ID NO 153, SEQ ID NO 153 has the same structure as a CasΩ nuclease, is a CasΩ nuclease and inherently encompasses all the properties of a CasΩ nuclease. Since the Spec. discloses (p. 3 L20-21) CasΩ is Cpf1, that means that WO996 SEQ ID NO 153 (called Cms1) is the same thing as Cpf1. Altogether, Cms1 = CasΩ = Cpf1.
US490, drawn to non-naturally occurring or engineered DNA or RNA-targeting systems comprising a novel DNA or RNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA, provides evidence that Cpf1 was, before the effective filing date of the claimed invention, a known RNA-targeting Cas enzyme.
US490 teaches (Col 2 L25-41) their invention includes RNA-targeting systems. US490 teaches their system includes Cas enzymes that target RNA:
(Cols 28-29 L54-11) the term “nucleic acid-targeting system”, wherein nucleic acid is DNA or RNA… In general, a RNA-targeting system is characterized by elements that promote the formation of a RNA-targeting complex at the site of a target RNA sequence. In the context of formation of a DNA or RNA-targeting complex, “target sequence” refers to a DNA or RNA sequence to which a DNA or RNA-targeting guide RNA is designed to have complementarity, where hybridization between a target sequence and a RNA-targeting guide RNA promotes the formation of a RNA-targeting complex. [emphasis added]
That passage clearly indicates that the US490 target sequence is an RNA sequence to which an RNA-targeting guide RNA has complementarity, and the RNA-targeting guide RNA hybridizes to the RNA target sequence. US490 teaches (Col 33 L24-44) the guide sequence can be selected to target any RNA sequence, including mRNA, which an artisan knows is one kind of single-stranded RNA. US490 teaches (Col 34-35 L64-5) their invention includes a nucleic acid-targeting system that is derived from an organism comprising an endogenous RNA-targeting system and that in preferred embodiments, the RNA-targeting system is a Type V CRISPR system and the type V Cas enzyme is Cpf1.
WO996 teaches (p. 20 L10-15) that “predetermined” or “targeted sequence” means a DNA or RNA of interest. WO996 teaches (p. 19 L12-14) the target site has no sequence limitation except that the sequence is immediately preceded (upstream) by a consensus sequence. This consensus sequence is also known as a protospacer adjacent motif (PAM). WO996 teaches (p. 6 L9-11) that guideRNAs may be designed. A designed guideRNA is non-naturally occurring. An artisan understands that RNA is typically single-stranded. Therefore the WO996 disclosure encompasses the complex comprising a CasΩ nuclease, a non-naturally occurring guideRNA designed for binding to at least one single-stranded target RNA, and teaches that the target RNA is flanked by at least one PAM. Therefore WO996 teaches some limitations of Claim 1.
Since US490 teaches Cpf1 targets RNA, and WO996 teaches a “targeted sequence” is a nucleotide that can be RNA (“e.g., DNA or RNA”). Therefore, an artisan would have readily recognized that the Cpf1 of US490 (a.k.a. WO996’s Cms1) would possess the property of targeting RNA.
WO996 teaches (pp. 20-21 L12-12) the targeted sequence can be a sequence that is part of an antibiotic resistance gene. WO996 (pp. 20-21 L12-12) teaches:
In some embodiments, the Cms1 protein, or Cms1 protein-encoding polynucleotide, and guide RNA(s), or DNA encoding the guide RNA(s), are introduced into a plurality of bacterial cells with the guide RNA(s) designed to target sequences that are present only in a certain fraction of the cells. In some embodiments, this will result in the elimination or reduction of those cells that comprise the targeted sequence(s) that the guide RNA(s) are designed to hybridize with.
By “predetermined” or “targeted sequence” is intended a nucleotide (e.g., DNA or RNA) sequence in the microbe of interest that is unique to that microbe… In some embodiments, a targeted sequence of interest is a sequence that is part of an antibiotic resistance gene. Antibiotic resistance gene sequences are known in the art and include, for example and without limitation… [a list].
Therefore WO996 teaches that there can be a marker of antibiotic resistance in the target RNA. Since WO996 teaches the guideRNA targets the antibiotic resistance gene sequence, it contains the marker of antibiotic resistance as well.
WO996 teaches (p. 6 L15-30) the specificity of the initial hybridization event is provided by the guide RNA, the Cms1 polypeptide is universal and can be used with different guide RNAs to target different genomic sequences. Pp. 16-17 L30-10 teach about the guideRNA:
[The guide RNA can be] from about 8 nt to more than about 30 nt. For example, the region of base pairing between the first region of the guide RNA and the target site in the nucleotide sequence can be about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 22, about 23, about 24, about 25, about 27, about 30 or more than 30 nucleotides in length. In an exemplary embodiment, the first region of the guide RNA is about 20, 21, 22, 23, 24, or 25 nucleotides in length.
If the guideRNA is 8 nt long and the base pairing region of the target is 8 nt long, that would comprise 100% complementarity between the guideRNA and the target. If the guideRNA is 10 nt long and the base pairing region is 9 nt long, or if the guideRNA is 9 nt long and the target is 10 nt long, that would comprise 90% complementarity to the target. Therefore the teachings of WO996 describe an embodiment wherein or make obvious that the target RNA molecule has a sequence that is at least 90% complementary to said guideRNA, which are some limitations of Claim 2.
WO996 does not teach that the nuclease comprises a nuclear localization sequence (NLS) or is fused to any additional signaling domain (Claim 1).WO996 does not disclose ample details about the kinds of RNA that can be targeted with its compositions (Claim 1). WO996 does not disclose a guide RNA that comprises a modified nt (Claims 1 and 20). WO996 does not disclose pharmaceutical compositions (Claim 22).
However, US490, cited above as evidence, teaches CRISPR enzymes comprising Cpf1 that target RNA. Regarding the NLS or other functional domains (Claim 1), US490 teaches (Col 7 L4-15) the Cpf1 (which it calls an effector protein) can comprise heterologous functional domains such as one or more NLS domains. US490 teaches (Col 7 L35-40) the heterologous functional domain can be fused to the effector protein. US490 teaches other functional domains: (Col 76 L20-47) a CRISPR complex comprising a cell penetrating peptide or a peptide for targeting the complex to the chloroplast of a plant. Therefore US490 teaches limitations of Claim 1 (i.e., the NLS or additional domain fused to the nuclease).
Regarding the non-naturally occurring guide RNA (Claim 1): US490 teaches (Col 33 L24-44) the guide RNA can be selected to target any RNA sequence. US490 teaches (Col 43 L24-54) the target RNA of an RNA-targeting complex can be any RNA endogenous or exogenous to a eukaryotic cell, including an RNA residing in the eukaryotic cell’s nucleus or any disease-associated RNA. An artisan of ordinary skill would know that CRISPR systems are bacterial immune systems (this fact is taught by US490 Col 2 L4-10) and would therefore readily recognize that guide RNAs described by US490 as encompassing any RNA endogenous or exogenous to [a] eukaryotic cell would necessarily be non-naturally occurring guide RNAs designed for binding at least one target RNA (i.e., a limitation of Claim 1) because there is no evidence a bacterial immune system would ever evolve a guideRNA that targets a eukaryotic nucleic acid.
Regarding the modified guide RNA (Claims 1 and 20): US490 teaches (Col 57 L29-51; Col 58 L44-67) guide RNAs that comprise modifications that increase stability or activity. US490 teaches (same §) modified nt such as 2’-O-methyl and LNA nts.
Regarding the pharmaceutical composition (Claim 22): US490 teaches (Col 6 L24-31) compositions comprising their components for use in therapeutic treatments and (Col 65 L5-12) methods of using their engineered Cpf1 to treat viral infections including HBV. As discussed above, US490 teaches guideRNAs that target any RNA, including mRNA, disease-associated RNA, or RNA that resides in a eukaryotic cell’s nucleus. US490 also teaches (Col 109-110 L37-25) delivering the Cpf1 effector protein complex and pharmaceutically acceptable ingredients and (Col 284 L20-35 and Col 285 L39-45) delivering pharmaceutical compositions comprising components of the invention. Therefore US490 teaches pharmaceutical compositions comprising the CRISPR-Cas system.
Regarding the PAM sequence, US490 teaches (Col 9 L4-6) in some embodiments of their invention, a PAM directs binding of the effector protein complex to the target locus of interest (which, as discussed, may be an RNA including an mRNA). US490 teaches (Col 180 L38-63) the target polynt of a CRISPR complex can be any polynt endogenous or exogenous to the eukaryotic cell and the target sequence should be associated with a PAM that is recognized by the CRISPR complex. Therefore, the teachings of US490 indicate the target RNA should comprise a PAM.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compositions comprising a Cms1/Cpf1/CasΩ enzyme and a designed, non-naturally occurring guideRNA that binds and specifically hybridizes to a target sequence of WO996 with the teachings about guideRNA that targets an RNA target being used with the Cpf1 enzyme, an NLS being fused to the nuclease, guide RNAs comprising modified nts, guide RNA that can target any RNA comprising a PAM (including mRNA disease-associated RNA, viral RNA, or RNA that resides in a eukaryotic cell’s nucleus), and pharmaceutical compositions of US490 for the benefit of using the compositions to treat eukaryotic cells. One would have been motivated to do so with a reasonable expectation of success because WO996 teaches (p. 20 L1-6) the Cms1 enzyme (a.k.a. Cpf1/CasΩ) can cause collateral activity against RNA and/or DNA once upon binding its target and because US490 teaches RNA is yet another target of the Cpf1 nuclease (a.k.a. Cms1/CasΩ); therefore an artisan would have realized the WO996 system could be used to target and induce collateral damage upon binding an RNA target. Furthermore, US490 teaches the guide RNA used with Cpf1 can target any RNA sequence (including an RNA residing within a eukaryotic cell) and for treating HBV. An artisan would have readily recognized that although HBV is not an RNA virus, there are RNA viruses of great medical importance (see Wikipedia, §Negative-strand RNA virus-Disease and § Positive-strand RNA virus ¶3)—as well as other pathogens, all of which produce mRNA in one way or another—who could be targeted with the WO996 system.
When the complex comprising the Cms1/Cpf1/CasΩ nuclease and the non-naturally occurring guideRNA comprising a modified nt is used as disclosed by US490 (e.g., Col 37 L23-35) it binds to the target RNA (previously disclosed to be any RNA including an mRNA) and has cleavage activity or (WO996, p. 7 L25-32) induces collateral damage to nucleotides nearby. During that process, the complex would be bound to the target RNA. Therefore modifying the composition of WO996 with the teachings of US490 would have produced all the limitations of Claims 1-3, 20, and 22.
Claim(s) 1-3, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WO996 (published 27 May 2021; of record) and US Patent No. 9790490 (issued 17 October 2017, “US490”, of record) as applied to Claims 1-3, 20, and 22 above, and further in view of Chen (2018; of record). This rejection is maintained and has been updated in response to the 04 November 2025 claim amendments.
The teachings of WO996 and US490 as applicable to Claim(s) 1-3, 20, and 22 have been described in the 103 rejection above.
Claim 1 requires that the complex is bound to the single stranded target RNA via the guide RNA specifically hybridizing to the target RNA. The previous 103 rejection explains that when the complex comprising the CasΩ nuclease and the guideRNA is used in a cell, it will be bound to the target RNA that is flanked by at least one RNA PAM.
As discussed in the previous 103 rejection, WO996 describes target sequences at least 90% complementary to the guideRNA and US490 described CRISPR systems comprising a Cpf1 nuclease that comprises a guide RNA that binds a target RNA. As explained above and based on Applicant’s Spec. and sequence information in the prior art, Cms1, Cpf1, CasΩ are terms that all describe the same endonuclease. As discussed in the previous 103 rejection, WO996 teaches that when their Cms1 (a.k.a. Cpf1/CasΩ) binds its target sequence, it unleashes collateral damage against DNA and RNA in a nonsequence specific manner.
WO996 and US490 do not teach another reason why the CasΩ nuclease-guideRNA complex may be bound to a target RNA molecule.
However, Chen teaches using Cas12a nucleases that are already bound to their target to cause collateral damage to any ssDNA. Chen is drawn to a CRISPR-Cas12a nuclease that unleashes indiscriminate ssDNAse activity. Chen teaches that Cas12as cause “indiscriminate” damage which was tested by binding the guideRNA to its complementary target and observing DNA damage: (§Main text ¶2):
LbCas12a also catalyzed M13 degradation in the presence of a different guide RNA and its complementary ssDNA “activator” that have no sequence homology to the M13 phage genome (Fig. 1C). These findings reveal that binding of the LbCas12a-crRNA complex to a guide-complementary ssDNA unleashes robust, nonspecific ssDNA trans-cleavage activity.
Chen §Main text ¶4 teaches RNA-guided DNA binding activates LbCas12a for both site-specific dsDNA cutting and nonspecific ssDNA trans cleavage.
As discussed above, WO996 described target sequences at least 90% complementary to the guideRNA. Chen makes obvious the limitation of Claim 1 that the complex is bound to a target RNA molecule.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the complex comprising a CasΩ nuclease and a preselected non-naturally occurring guideRNA (designed for binding to a target ssRNA) of WO996 and US490, wherein the target sequence is RNA flanked by a PAM, with the teachings about using a target-bound Cas12a of Chen for the benefit of causing collateral dsDNA and RNA damage in a cell. One would have been motivated to do so with a reasonable expectation of success because Chen teaches (§Main text ¶2) binding the guide RNA’s target (i.e., “activator”) to the Cas12a protein-guideRNA complex leads to indiscriminate damage even in cells that have no sequence homology to the guideRNA target. WO996 teaches that (p. 7 L30-32) their complexes collaterally damage dsDNA and RNA. Additionally, an artisan would been motivated to modify the CasΩ nuclease-preselected non-naturally occurring guideRNA complex of WO996, wherein the target sequence is RNA preceded by a PAM because they would have wanted to use a guideRNA that targets a ssRNA target flanked by a PAM because that would have allowed the artisan to “detonate” the CasΩ enzyme in a cell only when a particular RNA was produced, which would have provided the benefit of selectively targeting cells that express a deleterious gene variant or are infected by a virus. Success would have been a reasonable expectation because Chen teaches the same concept as WO996 but uses a different enzyme; swapping one enzyme for another enzyme with different properties would have been obvious to an artisan because of the desirable effect of damaging both dsDNA and RNA with Cms1 (i.e., CasΩ/Cpf1). They would have known it is possible to damage by dsDNA and RNA because WO996 teaches (p. 7 L30-32) …the RuvC endonuclease domain [of the Cms1 enzyme] may also exhibit secondary, collateral activity directed against dsDNA and/or RNA in a non-sequence specific manner and because US490 teaches Cpf1 (i.e., CasΩ/Cms1) can target RNA sequences, including an mRNA, a disease-associated RNA, or an RNA that resides within a eukaryotic cell. Modifying the complex of WO996 and US490 with the teachings of Chen would have produced a CasΩ endonuclease complex the limitations of Claims 1-3, 20, and 22.
Claim(s) 1-3, 19-20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WO996 (published 27 May 2021; of record), US Patent No. 9790490 (issued 17 October 2017, “US490”), and Chen (of record) as applied to Claims 1-3, 20, and 22 above, and further in view of Davis (and O’Connell. 2020. Put on Your Para-spectacles: The Development of Optimized CRISPR-Cas13-Based Approaches to Image RNA Dynamics in Real Time. Molec. Cell. 77:207-209; “Davis”, of record), and Webb (2012. Lab Tools: Live and In Color-How to track RNA in living cells. The Scientist 26[4]:61-63; “Webb”, of record). This rejection is maintained and has been updated in response to the 04 November 2025 claim amendments.
The teachings of WO996, US490, and Chen as applicable to Claim(s) 1-3, 20, and 22 have been described in the 103 rejections above.
As discussed in the previous 103 rejections, WO996 describes target sequences at least 90% complementary to the guideRNA and US490 described CRISPR systems comprising a Cpf1 nuclease that comprises a guide RNA that binds a target RNA. As explained above and based on Applicant’s Spec. and sequence information in the prior art, Cms1, Cpf1, CasΩ are terms that all describe the same endonuclease. As discussed in the previous 103 rejections, WO996 teaches that when their Cms1 (a.k.a. Cpf1/CasΩ) binds its target sequence, it unleashes collateral damage against DNA and RNA in a nonsequence specific manner. As described in the previous 103 rejections, WO996, US490, and Chen teach using a Cas endonuclease/guide RNA complex that can target RNA, wherein the complex is bound to its target and used to cause collateral damage to nucleic acids.
US490 teaches (Col 40 L30-35) incorporating a detectable marker on the nucleic acid-targeting protein so its location within a cell may be visualized. US490 discusses (Col 42 L60-65) placing fluorescent markers in an RNA template, indicating that markers can be placed in RNA. US490 teaches (Col 159 L5-10 labeling a polynt with a labeling component. US490 teaches (Col 177 L50-65) detectable labels in nt probes and targets. All of those teachings indicate incorporating fluorescent labels into polynt, including RNA, for the purpose of visualizing them within a cell, was known and routine before the effective filing date of the claimed invention.
It would have been obvious to an artisan of ordinary skill before the effective filing date of the claimed invention to modify the complex of WO996, US490, and Chen with the teachings regarding fluorescent labels for visualization of US490. One would have been motivated to do so with a reasonable expectation of success because US490 indicates incorporating fluorescent labels into polynt for various purposes, including as probes, was routine and conventional. Modifying the complex of WO996, US490, and Chen with the fluorescently labeled polynt of US490 would have produced a complex with a fluorescently labeled target RNA.
WO996, US490, and Chen do not explicitly teach that the guideRNA comprises a label as defined in Applicant’s 22 July 2024 arguments, wherein “label” indicates a visual label such as a dye or fluorophore (i.e., an alternate limitation of Claim 1).
However, Davis teaches a guideRNA that comprises a fluorescent label. Davis is drawn to a Spotlight discussing recent developments of Cas-based techniques to image RNA dynamics in real time. Davis teaches (pp. 207-208 right column, starting at last ¶ and continuing on p. 208):
… Wang et al. (2019) successfully utilized RfxCas13d in tandem with dCas9 to simultaneously label RNA and DNA in live cells (Figure 1B).…the authors were able to visualize both the transcription of a MS2-repeat-tagged mRNA and also the genomic locus from which the tagged mRNA emanates in real time… Wang et al. (2019) directly labeled the gRNA with a fluorescent dye (ATTO-647)… it can be inferred that the dRfxCas13d:gRNA and/or dRfxCas13d:gRNA:RNA-target complexes are the predominate species being observed. These observations suggest that direct gRNA labeling may circumvent some of the specificity issues associated with Cas13-protein labeling and perhaps help to resurrect additional Cas13 orthologs for imaging applications…
A portion of Fig. 1B is shown here:
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That figure shows that the guideRNA is tagged with ATTO-647 dye and shows that the target RNA comprises MS2 repeats. The guideRNA comprising a label is an alternate limitation of Claim 1. The text and figure also discuss that the mRNA comprises 24 MS2-repeats which Davis teaches (¶1) is a fluorescent tool for visualizing RNA localization dynamics. Davis teaches (cited §) …the authors were able to visualize both the transcription of a MS2-repeat-tagged mRNA…. That indicates that the target RNA comprises an MS2 repeat tag.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the complex comprising CasΩ nuclease and a guide RNA designed for binding to at least one target RNA, wherein the complex binds to a single stranded target RNA flanked by at least one RNA protospacer-adjacent motif (rPAM), wherein said nuclease comprises an NLS, and wherein the guideRNA comprises a modified nucleotide of WO996, US490, and Chen with the teachings of Davis (including the fluorescent ATTO-647 dye directly labeled to a guideRNA and the MS2-repeat tagged RNA target) for the benefit of observing the complex in real time. One would have been motivated to do so with a reasonable expectation of success because Davis teaches that ATTO-647 can be directly labeled to a guideRNA and that (cited §) direct gRNA labeling may circumvent some of the specificity issues associated with Cas13-protein labeling and because an artisan would have wanted to identify the location of the complex in real time. Modifying the complex of WO996, US490, and Chen with the fluorescent ATTO-647 dye directly labeled to a guideRNA and the RNA target comprising 24 MS2 repeats of Davis would have produced a complex with all the limitations of Claims 1-3 and some limitations of Claim 19.
WO996, US490, Chen, and Davis do not explicitly teach that the target RNA is directly labeled with a visual label (i.e., Claim 19).
However, Webb, drawn to lab tools that are used to track RNA in living cells, teaches transfecting cells with a plasmid that expresses MS2-GFP. Webb teaches (§Tagging RNA with GFP-The back story) by fusing GFP to this MS2 protein, Robert Singer and his colleagues… first demonstrated that they could follow RNA as it migrated within cells (Molecular Cell, 2:437-45, 1998). Webb teaches (same §-The method) the first step is adding copies of MS2's RNA-binding sequence, which forms a characteristic stem loop structure, to the noncoding region of the gene of interest. In addition, the cells need to be transfected with a plasmid so that they can express the MS2-GFP fusion protein. Webb teaches (Figure caption for Fig. on p. 62) LIGHTING UP RNA: Bacteriophage MS2 coat protein fused with GFP binds to mRNAs containing copies of the MS2's RNA-binding sequence in the nucleus of cultured cells.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the complex comprising a dye-labeled guide RNA (including the target RNA modified to comprise MS2 repeats) of WO996, US490, Chen, and Davis with the MS2-GFP fusion protein of Webb for the benefit of visualizing the dynamics of the complex and the target in a cell in real time. One would have been motivated to do so with a reasonable expectation of success because Davis showed that a guideRNA and its DNA target could be tracked in a cell and an artisan would have seen that the MS2-GFP fusion protein of Webb would allow tracking of a guideRNA and its RNA target, and it would have been a routine matter for an artisan to insert MS2 repeats into a target RNA and to transfect cells with the MS2-GFP fusion protein plasmid because Webb teaches (§Equipment and cost) the materials are available for less than $150. Modifying the complex comprising a dye-labeled guideRNA and target RNA modified to comprise MS2 repeats of WO996, US490, Chen, and Davis with the MS2-GFP fusion protein of Webb would have produced the complex wherein the complex comprises a label in the target RNA, i.e., the limitations of Claim 19.
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 1-3, 19-20, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-17 of copending Application No. 18564684 (reference application, “App684”; of record). This rejection is maintained and has been updated in response to the 04 November 2025 claim amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to complexes comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, and wherein the nuclease comprises or can comprise an NLS. Both claim sets require CasΩ. The App684 claims recite methods for using the complex, including detecting a change in signal of a label in a reporter nucleic acid, which limitation can be interpreted to read on the limitations of instant Claim 19 (wherein the complex comprises a label in the target RNA). Those methods could not be used without the instantly claimed complex. The App684 claims recite a method for specifically inactivating an undesired cell or virus, comprising contacting the cell or virus with the complex of the App684 claims. That can be interpreted as encompassing using the App684 claimed complex as a pharmaceutical composition, so it reads on the limitations of instant Claim 22. The invention of App684 requires the claimed invention. It would not be possible to use the claimed invention without the methods of App684.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 19-20, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-11, and 18 of copending Application No. 18872146 (reference application, “App146”) as evidenced by Dmytrenko (et al. 2022. Cas12a2 elicits abortive infection via RNA-triggered destruction of double-stranded DNA. BioRxiv, “Dmytrenko”, of record), and in view of US Patent No. 9790490 (issued 17 October 2017, “US490”, of record). This rejection is maintained and has been updated in response to the 04 November 2025 claim amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to complexes comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, and wherein the nuclease comprises or can comprise an NLS. The App146 claims are directed to an isolated protein comprising Cas12a2 or a functional variant thereof, wherein said isolated protein is capable of indiscriminately cleaving a single stranded nucleic acid (which can be DNA or RNA) upon recognition of a specific complementary RNA target, and further wherein one or more residues are mutated such that double stranded nucleic acid cleavage is reduced or abrogated compared to native Cas12a2, including by 10% or more reduction; and to methods of using the Cas12a2.
An artisan would not necessarily know that CasΩ and Cas12a2 are the same thing, but Dmytrenko provides evidence that is the case. Dmytrenko’s Fig. 1a shows that CasΩ is a kind of Cas12a2 because they are in the same area of the phylogenetic tree:
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Therefore both claims are inherently drawn to the same enzyme and both claim sets require CasΩ, even if App146 calls it Cas12a2.
The App146 claims do not recite an NLS or an unnatural guideRNA designed for binding at least one target RNA, do not recite a virus or a modified nt, or a pharmaceutical composition, but those limitations would have been obvious in view of US490.
US490 teaches (Col 7 L4-15) their endonuclease can comprise heterologous functional domains such as one or more NLS domains. US490 teaches (Col 33 L24-44) the guide RNA can be selected to target any RNA sequence, including an mRNA and (Col 43 L24-54) the target RNA of an RNA-targeting complex can be any RNA endogenous or exogenous to a eukaryotic cell, including an RNA residing in the eukaryotic cell’s nucleus or any disease-associated RNA. US490 teaches (Col 57 L29-51; Col 58 L44-67) guide RNAs that comprise modifications that increase stability or activity. US490 teaches (Col 6 L24-31) compositions comprising their components for use in therapeutic treatments and (Col 65 L5-12) methods of using their engineered Cpf1 to treat viral infections including HBV. US490 teaches (Col 9 L4-6) in some embodiments of their invention, a PAM directs binding of the effector protein complex to the target locus of interest and (Col 180 L38-63) the target sequence should be associated with a PAM that is recognized by the CRISPR complex. Additionally, US490 teaches (Col 6 L35-45) mutating residues on Cpf1 to changes it nuclease activity.
It would have been obvious to an artisan to modify the endonuclease of the App146 claims with the teachings of US490 for the benefit of making the guide RNA resistant to nucleases, targeting the endonuclease to a nucleus where it could be used to treat viral infections, and to use a PAM for the benefits of improving the targeting of the nuclease of the App146 claims. When the endonuclease of the App146 claims is used, it would bind and therefore be bound to the target RNA.
Therefore the invention of the App146 claims requires the claimed invention and the claimed invention would have been obvious in view of the App146 claims and US490.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 08 January 2025 have been fully considered but they are not persuasive. Arguments that are no longer relevant are not addressed.
112(b) rejection
The 112(b) rejection is necessitated by Applicant’s claim amendments. Briefly, the single stranded target RNA molecule having a sequence that is at least 90% complementary to said guide RNA that specifically hybridizes with the single stranded target RNA molecule lacks antecedent basis because no single stranded target RNA molecule having a sequence that is at least 90% complementary to said guide RNA is recited in Claim 1. Amending the claim to recite the single stranded target RNA molecule has a sequence that is at least 90% complementary… will obviate this rejection.
103 rejection
Applicant's arguments filed 08 January 2025 have been fully considered but they are not persuasive.
Applicant argues (pp. 8-9) the Gray/WO996 reference teaches compositions and methods for targeting DNA.
That argument is not persuasive because the facts indicate that an artisan would have recognized that, as it is described in the Spec., CasΩ is the same as both WO996’s Cms1 and US490’s Cpf1, and US490 teaches Cpf1 possesses the property of targeting/binding RNA. For example, US490 discloses several passages disclosing that Cpf1 is RNA-targeting, including Col 37 L4-5 which explicitly says …the Type V/Type VI RNA-targeting effector protein, in particular Cpf1… and the passage excerpted below (underlining added):
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That indicates that the Cpf1 system of US490 targets RNA. The instant Spec. discloses that (p.3 L20-21) US979049082 describes Cas12a (Cpf1) enzymes, including Cas12a (type V), which corresponds to CasΩ according to the present invention. That is further discussed in the next several ¶.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The following discussion demonstrates how the synthesis of the various references makes obvious the claimed invention.
Applicant argues (p. 8 ¶4) that WO996 teaches (p. 2 L20-27) Cms1 is described as having a distinct secondary activity from Cpf1/Cas12a. It is unclear what Applicant means because in the cited passage, WO996 teaches Type V CRIPSR enzymes possess primary, sequence-specific activity and also a secondary, non–sequence-specific collateral activity. That passage teaches Cpf1/Cas12a possesses primary double-stranded break production activity against double-stranded DNA (dsDNA). After Cpf1 hybridizes with and cleaves its primary target, the protein is then capable of cleaving single-stranded DNA (ssDNA) in a nonsequence-specific manner. WO996 teaches (same §):
Other Type V CRISPR enzymes have been shown, for example, to harbor a primary activity against RNA, with secondary activities directed against RNA and ssDNA ... The present invention describes the primary and secondary activities of Cms1 enzymes, a group of Type V CRISPR enzymes whose secondary activities can result in bacterial cell death.
That passage indicates that Cpf1 possesses primary activity against its primary target (after hybridizing said primary target) and then can engage secondary activity against further targets. The above passage does not clearly teach what Applicant asserts it teaches—distinct activities. That passage in WO996 teaches other Type V CRISPR enzymes … harbor a primary activity against RNA; that primary activity is understood as hybridizing and cleaving the primary target, namely RNA. If Applicant is referring to collateral (“secondary”) activities, WO996 discusses that (PDF p. 7 L5-20) Cms1 possesses those: the Cms1 protein is then able to perform a secondary collateral activity directed against double-stranded DNA (dsDNA) or RNA without any sequence specificity…
The rejection describes that WO996 discloses sequences of Cms1 endonucleases and one such sequence (namely WO996 SEQ ID NO 153) is 100% identical to instant SEQ ID NO 1 which the instant Spec. discloses is a CasΩ. The rejection discusses that since the instant Spec. identifies SEQ ID NO 1 as a CasΩ and SEQ ID NO 1 is identical to WO996 SEQ ID NO 153, SEQ ID NO 153 has the same structure as a CasΩ nuclease, is a CasΩ nuclease and therefore inherently encompasses all the properties of a CasΩ nuclease. In turn, that means that CasΩ possesses, inherently due to its structure, all the functions of WO996 SEQ ID NO 1.
The rejection further describes that (see p. 6, underlining added here):
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That passage explains how Applicant’s own Spec. discloses that CasΩ is US490’s Cpf1, excerpt from the instant Spec. provided here:
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In that passage above, Applicant’s own Spec. has indicated that CasΩ = Cpf1. Then the sequence alignment provided in the rejection determined that CasΩ = Cms1 because they share 100% structural identity. Logic then dictates that WO996’s Cms1 = CasΩ (100% sequence match) = Cpf1 (as disclosed by Applicant: US979049082 describes Cas12a [Cpf1] enzymes, including Cas12a [type V], which corresponds to CasΩ according to the present invention).
Whether or not those three compounds are called by the same or different names—an artisan would readily recognize that the name of an enzyme can change over time or depending on who is naming it—they are all the same enzyme and possess the same structure and therefore same properties disclosed for each enzyme. WO996 clearly discusses that Cms1 produces collateral damage and the 100% sequence alignment of what Applicant themselves identified as CasΩ (i.e., SEQ ID NO 1) to WO996’s SEQ ID NO 153 would have indicated to an artisan that CasΩ possesses all the properties disclosed for WO996’s Cms1. Then Applicant themselves have indicated that CasΩ possesses the properties disclosed in US490 for Cpf1 because Applicant says Cpf1… corresponds to CasΩ according to the present invention.
The 103 rejection discusses that US490 teaches their invention includes RNA-targeting systems:
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Altogether, Applicant’s arguments about Cms1, Cpf1, and CasΩ are confusing because, as explained at length, those three names—at least as they are used in the instant Spec., WO996, and US490—describe the same enzyme.
Whether or not Gray/WO996 not explicitly discloses that their Cms1 targets RNA sequences, US490 teaches that Cpf1 targets RNA sequences, and the instant Spec. discloses that Cpf1—not just any Cpf1 but specifically the Cpf1 of US490—corresponds to CasΩ according to the present invention. Therefore an artisan would understand that WO996’s SEQ ID NO 153 and US490’s Cpf1 possess the same properties, including RNA-targeting.
Applicant then argues that Zhang/US490 does not teach a CasΩ nuclease-guideRNA complex bound to a target RNA molecule.
That is not persuasive because the rejections discuss that (1) once the Cas enzyme of WO996 and US490 is inside a cell comprising the target, it will become bound to its target, thereby producing a complex bound to a single-stranded target RNA target. That means when the invention that would have been obvious in view of WO996 and US490 is used as intended, it will produce the claimed invention. The rejections further explain (2) Chen teaches a system comprising different Cas12a nucleases already bound to their target and used to cause collateral damage to ssDNA, that it would have been obvious to modify the complex comprising a CasΩ nuclease (a.k.a. Cpf1 in US490 and Cms1 in WO996) and guideRNA with Chen’s teachings about a target-bound Cas12a, and one would have done so for the benefit of causing collateral damage to dsDNA and RNA in a cell since WO996 teaches (PDF p. 6 L15-30) Cms1 can degrade dsDNA and/or RNA. The rejection explains that swapping one enzyme for another enzyme with different properties would have been obvious to an artisan because of the desirable effect of damaging both dsDNA and RNA with Cms1 (i.e., CasΩ/Cpf1).
Regarding the papers presented by Applicant stating that Cpf1 targets DNA, the 103 rejection is maintained because US490 teaches that Cpf1 is an RNA-targeting enzyme (and the instant Spec. discloses that CasΩ is the same as US490’s Cpf1). The teachings of US490 (and sum teachings of WO996 and US490) cannot be discarded just because other references teach something else about Cpf1. As disclosed, the compound names may change, but what matters for patentability is compound structure. As discussed at length, a sequence alignment demonstrates that instant CasΩ sequence SEQ ID NO 1 is 100% identical to WO996 SEQ ID NO 153 and the instant Spec. itself discloses that what they call CasΩ is the same thing as US490’s Cpf1. Those facts indicate that the structures of CasΩ, WO996’s Cms1, and US490’s Cpf1 are the same, at least as they are defined and described in those references.
Applicant has not discussed or presented any evidence of how/why the Examiner’s logical determination is factually incorrect. The determination that WO996 SEQ ID NO 153 = the instant disclosure’s SEQ ID NO 1 = US490’s Cpf1 relies only upon sequence alignment and Applicant’s own words.
Although Applicant asserts (p. 9 ¶3) CasΩ has a fundamentally different property of targeting RNA, that cannot be persuasive because Applicant themselves say what is instantly called CasΩ is the same thing as US490’s Cpf1 and then US490 repeatedly refers to Cpf1 as an RNA-targeting effector protein (i.e., enzyme) [emphasis added]. To be clear, US490 teaches (Col 29 L1-5) in general, a RNA-targeting system is characterized by elements that promote the formation of a RNA-targeting complex at the site of a target RNA sequence. That clearly indicates that US490’s RNA-targeting effector protein binds to a target RNA sequence.
Altogether, Applicant’s arguments on Remarks pp. 8-9 are not persuasive because the facts indicate that the structures are the same and a physical structure inherently produces a compound’s properties.
Applicant then argues (p. 10 ¶1-5) Chen teaches DNA-binding Cas complexes. Chen’s teaching about DNA-binding Cas complexes was acknowledged in the rejection: Chen teaches that Cas12as cause “indiscriminate” damage which was tested by binding the guideRNA to its complementary target and observing DNA damage: (§Main text ¶2) LbCas12a also catalyzed M13 degradation in the presence of a different guide RNA and its complementary ssDNA “activator”. [emphasis added.] The passage also discusses that Chen teaches RNA-guided DNA binding activates Chen’s enzyme to unleash collateral damage. That makes it clear that Chen’s complex’s target is DNA, not RNA; the rejection understands that point and posits using a different enzyme whose target is RNA would have been obvious.
The gist of the rejection is that an artisan understanding Chen would have readily recognized that they could use Chen’s idea of a target-bound Cas enzyme that unleashes collateral damage by simply swapping a different known enzyme that binds a different target (i.e., the known RNA-binding Cpf1 of US490 which is also WO996’s SEQ ID NO 153 which is the same as the instantly claimed CasΩ). That would have motivated the artisan to produce a target-bound Cpf1 complex. A target-bound Cpf1 complex clearly would have required the target to be RNA because US490 teaches Cpf1 binds RNA. The rejection explains the artisan would have made that swap because WO996 teaches that (p. 7 L30-32) Cms1 produces indiscriminate damage to dsDNA and RNA. The discussion above already demonstrates that WO996’s Cms1 is the same as US490’s Cpf1.
Therefore Applicant’s arguments are not persuasive.
Then Applicant argues that (pp. 10-11 ¶6-10) Davids and Webb don’t teach a CasΩ system or provide any suggestion to specifically combine them with the other references.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it was known that it is desirable to track both Cas systems and RNA in living cells.
Although Applicant argues that the skilled artisan wouldn’t have had any motivation or a reasonable expectation of success, that is not persuasive because the cited references demonstrate there was a desire in the art to observe complexes and RNA in real time as well as techniques and tools that could be used to do so. Applicant hasn’t presented any evidence of why success wouldn’t have been a reasonable expectation.
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCE
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
See MPEP § 2145 generally for case law pertinent to the consideration of applicant’s rebuttal arguments.
MPEP §716.01(c)
Altogether, all of the claims would have been obvious in view of the prior art and how a person of ordinary skill—not an automaton—would have understood it.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
In addition to the factors above, Office personnel may rely on their own technical expertise to describe the knowledge and skills of a person of ordinary skill in the art. The Federal Circuit has stated that examiners and administrative patent judges on the Board are "persons of scientific competence in the fields in which they work" and that their findings are "informed by their scientific knowledge, as to the meaning of prior art references to persons of ordinary skill in the art." In re Berg, 320 F.3d 1310, 1315, 65 USPQ2d 2003, 2007 (Fed. Cir. 2003). In addition, examiners "are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art ." PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 86 USPQ2d 1385 (Fed. Cir. 2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1360, 220 USPQ 763, 770 (Fed. Cir. 1984). See MPEP § 2141.03 for a discussion of the level of ordinary skill.
MPEP §2141(II)(c)
It is not possible to issue a valid patent simply because the enzymes in the different references are called by different names. Applicant has acknowledged that their CasΩ is the same as Cpf1. The 103 rejection above shows that the CasΩ/Cpf1 protein sequence is 100% identical to the Cms1 protein sequence of WO996. US490 describes that, prior to the effective filing date of the claimed invention, Cpf1 was known to possess RNA-binding ability. Therefore it would have been obvious to an artisan to use Cpf1/Cms1/CasΩ in applications that utilize the enzyme’s RNA-binding abilities. Therefore Applicant’s arguments against the 103 rejection are not persuasive.
Regarding Applicant’s arguments that the references don’t teach a CasΩ system, the 103 rejection explains that Cms1, Cpf1, and CasΩ are simply different terms used to describe the same enzyme. Furthermore, US490 teaches using their system to target exogenous RNA within an eukaryotic nuclease and teaches using their system to treat viral infections. As artisan knows that viral infections require production of viral mRNA (i.e., in order to produce virus proteins) so an artisan would have realized they could use the system of WO996 and US490 to target viral RNA in virus-infected eukaryotic cells.
Overall, the rejections of the instant claims on the basis of obviousness are maintained.
NSDP rejection
Applicant has stated that these rejections will be addressed upon indication of allowable subject matter, so the rejections are maintained.
Conclusion
Claims 1-3, 19-20, and 22 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636