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
This action is written in response to applicant’s correspondence received on 6/24/2026. Claims 1,6, and 8-32 are pending. Claims 1, 9-10, and 29-31 have been amended. Claims 2-5 and 7 have been cancelled. Claims 16-28 are withdrawn from consideration because they are directed to a non-elected invention. Claims 1, 6, 8-15, and 29-32 are currently under examination.
Any rejection 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. This Office Action is Final.
Election/Restrictions
Applicant’s election without traverse of invention Group I, which reads on claims 1, 6, 8-15, and 29-32, in the reply filed on 2-6-2026 is acknowledged. Accordingly, claims 16-28 are not presently under examination as they are drawn to a non-elected invention. Furthermore, the Applicant has elected the following species: RNAse with SEQ ID NO: 49, RNAse dimer of SEQ ID NO: 57, NLS species SEQ ID NO: 110, and fusion protein species with SEQ ID NO: 732 and SEQ ID NO: 49. It is noted that the present claims do not read on the Applicant’s elected species because the present claims have been amended to exclude an RNase with a sequence of SEQ ID NO: 49 (i.e., independent claim 1 recites that the RNase must be one of SEQ ID NOs 63-66 or 68, which do not comprise SEQ ID NO: 49). Thus, presently none of the Applicant’s claims read on their elected species. Nonetheless, the present claim set will be examined, albeit without consideration of the Applicant’s elected species of SEQ ID NO: 49 because this sequence is excluded from the present claims.
Claim Rejections - 35 USC § 112 – New Rejection Necessitated by Amendment
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 30 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.
Regarding claim 30, claim 30 has been amended to now depend from claim 29. Claim 29 recites a method of decreasing RNA transcripts in a subject. Claim 30 recites that the method can be “in vitro.” It is unclear how a method which is occurring “in a subject” can also be an “in vitro” method because “in a subject” and “in vitro” are mutually exclusive. The metes and bounds of the claim are therefore not properly identifiable.
Response to Arguments
The Applicant’s arguments filed 6/24/2026 have been considered but are not persuasive. The Applicant’s amendments have addressed the previous claim dependency issue of claim 30. However, the corrected claim dependence of claim 30 raises the present 112(b) issue.
101 – Withdrawn
The Applicant has amended independent claim 1 to be drawn to chimeric fusion proteins not found in nature. The previous 101 rejection is therefore withdrawn.
102 – Withdrawn
The Applicant has amended independent claim 1 to recite specific sequences of the Cas and RNase domains, where such domains as a fusion product are not anticipated within one single prior art reference.
112(a) – Withdrawn
The Applicant has amended independent claim 1, where the amendments have substantially narrowed the scope of the claims by recitation of specific sequences for the Cas proteins and RNase domain. The 112(a) rejection is therefore withdrawn, as the unpredictable genera previously recited are no longer recited in the claims.
Claim Rejections - 35 USC § 103 – New Rejection Necessitated by Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 6, 8, 11-15, and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu (US 2019/0062724 A1, published 2/28/2019) in view of Yeo (WO 2019/204828 A1, published 10/24/2019, of record) and Greiner (DE 102005047717 A1, published, 2011, provided as English machine translation with original copy at the end). The rejection is further evidenced by Anderson (US 2019/0365781 A1, published 12/5/2019, of record).
Regarding claim 1, Hsu teaches fusion proteins comprising a Cas protein and an RNAse:
“the Cas13d protein has a native HEPN domain(s) or is fused to
an appropriate effector domain bearing RNase activity, the
RNA can be cut,” (paragraph 437).
Thus, Hsu teaches Cas13 proteins fused to RNAse proteins (paragraph 437). Hsu further teaches that the Cas13 protein can be a catalytically dead Cas13 (dCas13, paragraphs 520-522). In addition, Hsu specifically teaches the Cas13b protein PspCas13b (paragraph 32, 498, 532, and Figure 10A). Thus, Hsu teaches that PspCas13b is a known, functional Cas13b enzyme which can be used with their methods.
Hsu does not teach that the PspCas13 protein has the sequence of SEQ ID NO: 47 or that the RNase T1 has a sequence of SEQ ID NO: 64.
Yeo is a patent document which teaches methods and systems involving Cas effector proteins and RNA targeting (Title, Abstract, and throughout). Yeo and Hsu therefore directly overlap in subject matter and field of endeavor. Furthermore, Yeo teaches the sequence of PspCas13b (SEQ ID NO: 79, see page 161). An alignment of Yeo’s SEQ ID NO: 79 and instant SEQ ID NO: 47 are a 100% match (see page 1 of Yeo). Thus, SEQ ID NO: 47 is the known sequence of PspCas13b, a Cas13 enzyme also taught by Hsu (Hsu paragraphs 32, 498, 532, Figure 10A, and page 161 of Yeo).
In addition, Greiner is a patent document which teaches specific embodiments of RNase T1 enzymes which can be applied to RNA applications (Title, Abstract, Description, Claims, and throughout). Greiner furthermore teaches RNase T1 ribonuclease, and teaches that such RNase T1 enzymes are preferable because they are active at a wide range of pH and do not require active cofactors (page 2, paragraph 5). Furthermore, Greiner teaches that their preferred embodiment of RNase T1 is that of A. oryzae, which they teach as SEQ ID NO: 1 (page 4, 2nd paragraph). SEQ ID NO: 1 of Greiner is shown below in alignment with instant SEQ ID NO: 64, where it is a 100% match to instant SEQ ID NO: 64:
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415
1413
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Thus, Greiner teaches a strong motivation to use RNase T1, as this is a known RNase T1 with desirable qualities such as functionality in a wide range of pH conditions which does not require cofactor activity (above).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to apply the sequence information taught by Yeo and Greiner with the systems taught by Hsu, and furthermore to use PspCas13b and RNase T1 in the systems and methods of Hsu, because such a combination is the simple substitution of one known prior art element for another with predicable results. In the present case, a practitioner would simply exchange the Cas13b enzymes taught by Hsu with Yeo’s PspCas13b sequence. This substitution is especially obvious in light of the fact that Hsu already teaches PspCas13b, where Yeo is simply supplying the sequence. Likewise, Greiner has already taught and reduced to practice the RNase T1 of instant SEQ ID NO: 64 and taught a beneficial motivation of including it because it is known that such an enzyme has wide functionality in different pH reaction conditions and does not require cofactors. Furthermore, the results are obvious because Hsu not only teaches PspCas13b but also reduces it to practice and shows that it is a functional Cas enzyme (e.g., Figure 10A). Additionally, given that Greiner teaches and reduces to practice the characterized RNase T1 of A. oryzae, the results are predictable.
Regarding claim 6, Hsu teaches that the Cas13 protein can comprise multiple RNAse domains (paragraph 383). Furthermore, Hsu teaches that Cas13 comprises HEPN “domains,” plural, which reasonably includes at least two (paragraph 437 and paragraph 383). As evidenced by Anderson, HEPN domains are RNAse domains (Anderson, paragraph 320). Thus, the Cas13 proteins taught by Hsu comprise RNAse dimers, as they comprise multiple HEPN domains, and furthermore can comprise multiple additional RNAses which, being fused to the Cas13 protein, are reasonably interpreted to be dimers (paragraph 383).
Regarding claim 8, Hsu teaches that the Cas13 protein can comprise an NLS (e.g., paragraph 382).
Regarding claims 11-12, Hsu teaches the fusion proteins can be encoded in a nucleic acid (e.g., paragraph 340).
Regarding claims 13-14, Hsu teaches that the kits and compositions of their invention can comprise targeting nucleic acids such as crRNA (e.g., paragraph 410).
Regarding claim 15, Hsu teaches that targeting nucleic acids can be DNA oligos (e.g., paragraph 496).
Regarding claim 29, Hsu/Yeo/Greiner render obvious the elements of claim 1 (above). Hsu further teaches that such a system can be used to target an RNA:
“If the Cas13d protein has a native HEPN domain(s) or is fused to
an appropriate effector domain bearing RNase activity, the
RNA can be cut,” (paragraph 437).
Hsu further teaches that their methods can be used to degrade target transcript RNA using targeting nucleic acids like gRNA (paragraph 482 and also 488).
Regarding claim 30, Hsu teaches that their targeting methods can be used either in vitro or in vivo (paragraph 436).
Regarding claims 31-32, Hsu teaches that their methods can be used to target viral RNAs to treat disease, where the Cas13 protein and its effector domains of their invention is paired with a targeting nucleic acid/gRNA to target RNA viruses (e.g., paragraph 489). Furthermore, Hsu also teaches that the method can be used to treat Myotonic dystrophy (paragraph 449).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Hsu (US 2019/0062724 A1, published 2/28/2019) in view of Yeo (WO 2019/204828 A1, published 10/24/2019, of record) and Greiner (DE 102005047717 A1, published, 2011, provided as English machine translation with original copy at the end), as applied to claims 1, 6, 8, 11-15, and 29-32, above, and further in view of Voytas (US 6,228,647 B1, issued 5/1/2001).
Regarding claim 9, the teachings of Hsu/Yeo/Greiner are discussed above in the rejection of 1 and are incorporated here. Hsu/Yeo/Greiner render obvious the elements of claim 1, and furthermore teaches that such fusion proteins can comprise nuclear localization signals (NLS, paragraph 382 of Hsu).
Hsu does not teach the NLS is SEQ ID NO: 110 (Applicant’s elected species).
Voytas is a patent document which focuses on methods of genetic manipulation at targeted sites, and therefore overlaps in subject matter with Hsu (Title, Abstract, and throughout). Furthermore, Voytas teaches the Ty1 NLS sequence, and specifically identifies the region of Ty1 which is critical for its functionality as an NLS (see Figure 2B, partially reproduced below):
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74
1189
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Voytas teaches that, with regards to Figure 2B reproduced above:
“Lines above Ty1 amino acid residues indicate sequences important for nuclear localization [Kenna et al. (1997); Moore et al. (1997),” (column 4, 5th paragraph).
An alignment of the section of Ty1 underneath the “lines” in Figure 2B with instant SEQ ID NO: 110 is shown below:
NSKKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRIH – Figure 2B, Voytas
NSKKRSLEDNETEIKVSRDTWNTKNMRSLEPPRSKKRIH – SEQ ID NO: 110
As shown above, the NLS signal taught by the region of Voytas to be critical as an NLS is 100% identical to instant SEQ ID NO: 110. Furthermore, Voytas references Kenna and Moore when describing the NLS sequence; thus, instant SEQ ID NO: 110 was an established NLS well-known in the art at the time of filing.
It would have been obvious to a person of ordinary skill in the art to exchange the NLS sequence taught by Hsu with the Ty1 NLS sequence taught by Voytas because such a combination is the simple substitution of one known prior art element for another with predictable results. In the present case, the practitioner would simply exchange the NLS of Hsu for the art-recognized NLS taught by Voytas. Furthermore, the result is predictable because, as taught by Voytas, the Ty1 NLS (i.e., SEQ ID NO: 110) was an art-established NLS which would therefore produce expected results.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Hsu (US 2019/0062724 A1, published 2/28/2019) in view of Yeo (WO 2019/204828 A1, published 10/24/2019, of record) and Greiner (DE 102005047717 A1, published, 2011, provided as English machine translation with original copy at the end), as applied to claims 1, 6, 8, 11-15, and 29-32, above, and further in view of Voytas (US 6,228,647 B1, issued 5/1/2001), and Reddy Chichili (Reddy Chichili VP et al. Protein Sci. 2013 Feb;22(2):153-67, of record).
Regarding claim 10, as an initial matter, Applicant has elected SEQ ID NO: 732. As noted above in the section “Election/Restriction,” the Applicant as deleted their original RNase election of SEQ ID NO: 49. Thus, the present rejection takes into consideration the newly recited claim limitations which do not include the Applicant’s elected species.
Regarding SEQ ID NO: 732, per the Applicant’s specification, SEQ ID NO: 732 is a sequence which comprises a 3x FLAG tag, Ty1 NLS, and dPspCas13b, followed by a linker and RNAse. As addressed above in the rejections of claims 1, 6, and 8-9, the prior art teaches each of these elements with the exception of a linker. For instance, Voytas teaches NLS Ty1 (see rejection of claim 9), Hsu/Yeo teach dPspCas13b (see rejection of claim 1), and Greiner teaches the known RNAse T1 sequence of SEQ ID NO: 64 (see rejection of claim 1, above). In addition, Hsu also teaches FLAG tagging as a method of purification/tagging (e.g., paragraph 387). Thus, each of the components in SEQ ID NO: 732 are taught in the prior art. Thus, SEQ ID NO: 732 in combination with SEQ ID NO: 64 is characterized as a known Cas13b (dCas13b, Hsu/Yeo), which has a routine tag (i.e., FLAG, as taught by Hsu), a known, routine addition of a known NLS (Ty1, Voytas) fused with a known RNAse (Greiner), where furthermore the fusion of Cas13b to an RNAse is already a strategy taught by Hsu.
Hsu, Yeo, Voytas, and Greiner do not explicitly teach glycine rich linkers such as those in SEQ ID NO: 732.
Reddy Chichili is a review article which teaches linkers used in structural biology to join protein domains (Title, Abstract, and throughout). Reddy Chichili teaches that it is known that glycine and/or serine rich linkers, such as those used in SEQ ID NO: 732, were already known in the art as routine linkers of protein domains (Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to arrive at fusion protein comprising SEQ ID NOs 732 and 64, as such a fusion protein is the simple combination of known prior art elements to arrive at a predictable result. In the present case, FLAG tagging and the addition of an NLS are routine laboratory practices as taught by Hsu and Voytas. Furthermore, Hsu has already taught the dPspCas13b in SEQ ID NO: 732, and furthermore teaches that such FLAG-tagged, NLS-bearing Cas13b proteins should be fused with RNAses to target RNAs (paragraph 437). SEQ ID NO: 64 is simply a known, functional RNAse with beneficial properties (Greiner, rejection of claim 1, above). Additionally, linkers such as glycine and serine linkers are also routine in the art, as taught by Reddy Chichili’s teachings (e.g., Abstract). Thus, the combination is predictable, where each component is known and is being used for its known use.
Response to Arguments
The Applicant’s arguments filed 6/24/2026 have been considered but are not persuasive. The Applicant argues that there is no motivation in the art to combine the references (as applied to the combination of Hsu and Yeo), and that no expectation of success exists. This argument is not persuasive. As an initial matter, Hsu teaches the same PspCas13 protein as Yeo, and simply does not teach the sequence of SEQ ID NO: 47. The practitioner is therefore obviously motivated to combine Yeo with Hsu, because they are teaching the exact same Cas protein, where a practitioner applying the teachings of Hsu would inherently be using SEQ ID NO: 79 of Yeo, because Hsu teaches PspCas13, which is the same sequence as SEQ ID NO: 79 of Yeo (see page 161 o Yeo for description of SEQ ID NO: 79, “PspCas13,” as taught by Hsu). The results of the combination of the two references are therefore predictable because both references are talking about the same enzyme (PspCas13). Furthermore, the instant claims now require SEQ ID NO: 64, which is 100% identical to the RNase T1 enzyme taught and reduced to practice by Greiner. Contrary to the Applicant’s assertion, Greiner teaches a strong motivation to incorporate their Rnase T1 SEQ ID NO: 1 (i.e., the exact sequence of instant SEQ ID NO: 64) because they teach that such enzymes are widely applicable and functional across a large pH range and furthermore have the added benefit of not requiring cofactor activation (see 103 rejection above, of claim 1). Furthermore, Greiner teaches instant SEQ ID NO: 64 (SEQ ID NO 1, per Greiner) as their preferred embodiment in their application and has reduced the recited RNase T1 to practice. Therefore, contrary to the Applicant’s assertions, strong motivation exists in the art to combine each of the recited prior art references, where given that each protein functional domain has been reduced to practice the results are predictable.
The Applicant argues that there is variability in their data, which is evidence of unpredictability. In response, the Office points out that Greiner teaches that their RNase T1 is a preferred Rnase which is highly functional across a wide range of reaction conditions and has minimal functionality requirements such as cofactors (see rejection of claim 1). In light of these teachings in the prior art, it is not in fact unpredictable or unexpected that such an RNAase T1 as instant SEQ ID NO: 64 (i.e., SEQ ID NO 1 of Greiner) would be functional as an RNase. MPEP 2143.02 teaches that obviousness does not require absolute predictability, but only a reasonable expectation of success is required. As all of the components recited in the fusion protein of claim 1 were known and have been reduced to practice, including the fact that such Cas proteins can be fused to RNase proteins, the practitioner has a reasonable expectation of success when combining the elements.
The Applicant argues that the Office has acknowledged unpredictability, and cites the previously filed 112(a) written description over the previously recited genera recited in claim 1 (i.e., the broad genus of RNase and Cas protein). This argument is not persuasive because it mischaracterizes the 112(a) written description rejection as well as its implications. The 112(a) written description rejection in the response mailed 3/24/2026 addressed the Applicant’s claim to the entire general of Cas and RNase proteins, where it is known in the art that not all Cas proteins are structurally and functionally characterized, and furthermore that RNase proteins are still being discovered. However, as presently recited, the claims are drawn to Cas proteins and RNase proteins which have been characterized and reduced to practice in the art. Thus, the present subject matter is not unpredictable. The mere fact that the entire genera of Cas and RNase proteins have not been shown to be in possession by the Applicant does not impart an unpredictable status to the species within the genera which in fact have been identified and characterized (i.e., PspCas13 and RNase T1 of A. oryzae, SEQ ID NOs 47 and 64, respectively, as presently recited). Thus, it is not a contradiction to argue that the Applicant was not in possession of the genera “Cas” and “RNase” but also that some species of these genera, namely those which are already taught and have been reduced to practice, could be predictably combined. The argument is therefore not persuasive that the 112(a) rejection applies to the unpredictability of the presently recited subject matter.
The Applicant argues that the remaining prior art references sited do not cure the deficiencies of Hsu/Yeo. This argument is not persuasive because the 103 rejection given above, which includes Greiner, is sufficient to render obvious the presently recited subject matter. Thus, the combination of Hsu, Yeo, and Greiner does not have a deficiency in rendering obvious subject matter for the reasons given in the 103 rejection above.
Conclusion
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 DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.C.R./ Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635
