S just also 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/05/2026 has been entered.
Claim Status
Claims 1, 15, 17, 25, 33, 38, and 55 are pending.
Claims 17 and 25 are amended.
Claims 2-14, 16, 18-24, 26-32, 34-37, 39-54, and 56-85 are canceled.
Priority
This application is a CON of PCT/CN2021/121926 filed 09/29/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/05/206 was filed after the mailing date of the final office action on 11/05/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Allowable Subject Matter
The indicated allowability of claim 1 and 55 is withdrawn in view of the newly discovered reference(s) to Zhang et al. (US Patent Application Publication No: US 2023/0025039 A1; published Jan. 26, 2023; Provisional Application No. 62/903,604 filed September 20, 2019). Rejections based on the newly cited reference(s) follow.
Claim Objections
Claims 15, 17, and 25 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
(previous rejection, withdrawn) Claim 25 is rejected under 25 U.S.C.112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and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. Claim recites "The engineered Cas13 of claim 1, wherein the engineered Cas13 is cfCas13e (Y672A, Y676A). First, it is unclear what elements and limitations are imparted on the claim by the recitation of "cfCas13e". This term is not defined in the specifications and does not appear to be known in the art. As such, one of ordinary skill would not be able to reasonably ascertain the scope of this element, and therefore not be able to reasonably ascertain the scope of the claim for the purposes of avoiding infringement. For example, it is unclear if cfCas13e consists of or comprises full-length SEQ ID NO: 4. Additionally, it is unclear if the mutations enclosed in parentheses are intended to be limitations of the claim. For the reasons shown above, one of ordinary skill cannot reasonably ascertain the scope of the claims for the purpose of avoiding infringement. Accordingly, claim 25 is rejected.
Response to Arguments
Applicant’s arguments, see pg. 5-6, filed 02/05/2026, with respect to claim 25 have been fully considered and are persuasive. Applicant has amended claim 25 to recite that the engineered Cas13 “is a polypeptide of SEQ ID NO:4 further consisting of a Y672A substitution and a Y676A substitution”. The rejection of 11/06/2025 has been withdrawn.
Claims 25 and 33 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.
With regards to claim 25, it is unclear how the engineered Cas13 is a polypeptide of SEQ ID NO:4 (has the amino acid sequence of SEQ ID NO: 4) and also consists of amino acid substitutions. A polypeptide either has the amino acid sequence of a given sequence identifier or it does not. Therefore, the claim is rendered indefinite.
Claim 33 recites “the wild-type Cas13” and “the target RNA” and “the non-target RNA”. There is lack of antecedent basis for “the wild-type Cas13”, “the target RNA”, and “the non-target”, thus the claim is rendered indefinite.
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.
(previous rejection, withdrawn) Claim 67 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. An "analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention." MPEP 2164.01. "A conclusion of lack of enablement means that the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention [i.e. commensurate scope] without undue experimentation." In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); MPEP 2164.01.
In In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988), several factors implicated in determination of whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is "undue" are identified. These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). No single factor is independently determinative of enablement; rather "[i]t is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above
factors while ignoring one or more of the others." MPEP 2164.01. Likewise, all factors may not be relevant to the enablement analysis of any individual claim. "According to In re Bowen, 492 F.2d 859, 862-63, 181 USPQ 48, 51 (CCPA 1974), the minimal requirement is for the examiner to give reasons explaining the uncertainty of the enablement. This standard is applicable even when there is no evidence in the record of operability without undue experimentation beyond the disclosed embodiments." See also In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995); MPEP 2164.04.
A) Claim 67 is drawn to a method of treating a condition or disease in a subject in need thereof, using the Cas13 of claim 1 or a polynucleotide encoding the same. The breadth of the claims are not limited to any particular disease or condition or subject. According to the current claim language, it appears that any disease, condition, or subject would meet these recited elements of claim 67.
B) The nature of the invention is predicated on the Cas13 being capable of treating any condition or disease by binding to a target RNA associated with the condition or disease, and cleaving the target RNA, thereby treating the subject.
C) The state of the prior art does not demonstrate that any disease or condition is treatable using a Cas13 to bind and cleave target RNA associated with the condition or disease. For example, Rajendran (see for PTO-892) teaches that mRNA is associated in bone healing (Rajendran, abstract). However, the examiner has not found any examples in the prior art of a Cas13 being used to treat a condition such as a bone fracture.
F) The amount of direction provided by the inventors does not support the enablement for the claimed invention. As shown above, the breadth of claim 67 is not limited to any particular disease, condition, or subject. Applicants have not provided any direction on how the components of the method of treating may differ depending on the variation in the above factors. For example, applicants provide no direction on how dosage, route of administration, and administration schedule would vary between different diseases, conditions, and subjects which are not necessarily limited to humans. Furthermore, applicants do not provide guide sequence RNAs that can be used to treat any disease or condition in any subject as claimed by applicants.
G) Applicants have provided working examples of the invention being used on mammalian cell cultures (specifications filed 06/09/2022, pg.103). However, this does not support applicants claim for a method of treating any condition or disease in any subject using the Cas13 of claim 1. Additionally, this working example does not demonstrate any treatment of a particular disease, but merely demonstrates the Cas13s RNA cleavage efficacy in vivo. In fact, applicants do not show any examples of the Cas13 of claim 1 being used to treat any disease in any subject. In view of the above factors, the present disclosure is not sufficient to enable one of ordinary skill in the art to use the invention of claim 67. Accordingly, claim 67 is rejected.
Response to Arguments
Claim 67 is canceled by the applicant, thereby rendering the previous rejection moot, which is accordingly withdrawn.
Claims 1, 15, 17, 25, 33, 38, and 55 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 15, 17, 25, 33, 38, and 55 are directed to an engineered Cas13 effector enzyme of any Cas13 effector enzyme having the amino acid sequence of SEQ ID NO: 4, wherein the engineered Cas13 effector enzyme has the recited amino acid substitutions and any other amino acid modifications compared to SEQ ID NO: 4. Therefore, the claims are directed to engineered Cas13 effector enzymes having unknown structure except not having Tyr residues at the positions corresponding to 643, 647, 672, 676, and/or 715 of SEQ ID NO: 4. For claims 33 and 55, said engineered Cas13 effector enzymes having unknown structure also has the properties recited in claims 33 or 55. The sequence search of SEQ ID NO: 4 shows (1) that a polypeptide having 100% sequence identity to SEQ ID NO: 4 is an uncharacterized protein and (2) very little structural similarity or no structural similarity to other known Cas13. Neither the prior art nor the specification disclose which amino acids with SEQ ID NO: 4 or other known Cas13 can be modified and result in a polypeptide having Cas13 effector enzyme activity or the properties recited in claims 33 and 55.
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Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 38, and 55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Zhang et al. (US Patent Application Publication No: US 2023/0025039 A1; published Jan. 26, 2023; Provisional Application No. 62/903,604 filed September 20, 2019), hereinafter referred to as Zhang.
With regards to claim 1, Zhang discloses a non-natural Cas13 (SEQ ID NO: 4722) (see claim 4, pg. 390, Table 3, pg. 120, and Paragraph 0319, pg. 30) that comprises a Y to F substitution a position relative to Y643 of SEQ ID NO: 4 of the current instant application (see sequence alignment below).
RESULT 27
US-17-761-292-4722
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
Sequence 4722, US/17761292
Publication No. US20230025039A1
GENERAL INFORMATION
APPLICANT: The Broad Institute, Inc.
APPLICANT: Massachusetts Institute of Technology
APPLICANT: Zhang, Feng
APPLICANT: Altae-Tran, Han
APPLICANT: Kannan, Soumya
TITLE OF INVENTION: Novel Type VI CRISPR Enzymes and Systems
FILE REFERENCE: BROD-4860WP
CURRENT APPLICATION NUMBER: US/17/761,292
CURRENT FILING DATE: 2022-03-17
PRIOR APPLICATION NUMBER: US 62/903,604
PRIOR FILING DATE: 2019-09-20
PRIOR APPLICATION NUMBER: US 62/905,645
PRIOR FILING DATE: 2019-09-25
PRIOR APPLICATION NUMBER: US 62/967,408
PRIOR FILING DATE: 2020-01-29
PRIOR APPLICATION NUMBER: US 63/044,190
PRIOR FILING DATE: 2020-06-25
NUMBER OF SEQ ID NOS: 6066
SEQ ID NO 4722
LENGTH: 838
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: Synthetic
Query Match 34.1%; Score 1390.5; Length 838;
Best Local Similarity 40.0%;
Matches 334; Conservative 129; Mismatches 288; Indels 83; Gaps 22;
Qy 6 KQTSKKRELSIDEYQGARKWCFTIAFNKALVNRDKNDGLFVESLLRHEKYSKHDWYDEDT 65
| | :| |||:|:||:|||| | |:| | : | || ||||| |: :: ||:|:|
Db 7 KDTGQKPIYSIDQYEGAKKWCFAIVLNRACDNYEDNPQLFSESLLRFEEVNRRDWFDKDI 66
Qy 66 RALIKCS------------TQAANAKAEALRNYFSHYRHSPGCLTFTAEDELRTIMERAY 113
| ||| : | : :|||||| || || | :| :| ||| ||
Db 67 RDLIKKADTEDQIEPKRKPNTPVNRRLHDIRNYFSHSRHQDDCLYFKNDDPMRCIMEAAY 126
Qy 114 ERAIFECRRRETEVI-IEFPSLFE-GDRITTAGVVFFVSFFVERRVLDRLYGAVSGLKKN 171
|:| : |:|| | | ||: ::||:|||:| |||||| :| || | : | | |
Db 127 EKAKIHIKGRQTEQSDIPLPELFDANNKITSAGVLFLASFFVERGILHRLMGNIGGFKDN 186
Qy 172 EGQYKLTRKALSMYCLKDSRFTKAWDKRVLLFRDILAQLGRIPAEAYEYYHGE-----QG 226
|:| || : |||||| | | :|:||||| | : | | | : |
Db 187 RGKYGLTHDIFTTYCLKDSYSIHASDPKVVLFRDIAGYLSLVACEYYPTYLSKIPKENAG 246
Qy 227 DKKRANDNEGTNPKRHKDKFIEFALHYLE-------AQHSEICFGRRHIVREEAGAGDE- 278
| : :| :| |||| ||| ||| : || |:|||: :|
Db 247 GK---SSDEEKYAERKTDKFILFALKYLEEFVLPSLKDDYLVDIGRIDIIREESKETEEK 303
Qy 279 ---HKKHRTKGKVVVDFSKKDEDQSYYISKNNVIVRIDKNAGPRSY--RMGLNELKYLVL 333
:| | :||| | | ::: |||: | ||:|| || | :| ::|:|:||||:|
Db 304 DEQYKPHPNQGKVKVVFDSINKELPYYINHNTVILRIQKN-GVMAYSCKIGVNDLKYLLL 362
Qy 334 LSLQGKGDDAIA KLYRYRQHVENILDVVKV--TDKDNHVF--LPRFVLEQHGIGRKAFKQ 389
| |||| | |: :| | ::: :|||: ||| :| || |:|:| || : :
Db 363 LCLQGKTDKALDAIYNYLHSMQDPPEVVKIGATDK---LFQGLPEFILKQSGIKVQDKNK 419
Qy 390 RIDGRVKHVRGVWEKKKAATNEMTLHEKARDILQYVNENCTRSFNPGEYNRLLVCLVGKD 449
|:|::| |||||: : :: || | ||||:||| :| :|::||| || |:
Db 420 EKAARIKYIRDKWEKKKSESADIELHRKGRDILRYVNWHCETPLGTEKYDQLLVLLVNKN 479
Qy 450 VENFQAGLKRLQLAERIDGRVYSIFAQTSTINEMHQVVCDQILNRLC---RIGDQKLYDY 506
| | :|: | | :: : ||| :|| ||: :| | : :|| :|
Db 480 FAGFGDELNQLKRTEIISKDIFEKLSGFKTINTLHQKVCNLVLEELSFFEKSNPEKLEEY 539
Qy 507 VGLGKK------DEIDYKQKVAWFKEHISIRRGFLRKKFWYD---------SKKGFAKLV 551
:|| :| :||:|| | | | :|||| :|: : :| |||||
Db 540 IGLIRKPAPENNPPPEYKEKVRRFVEQPMIYKGFLRDQFFVNKDQDGKKLKEQKTFAKLV 599
Qy 552 EEHLESGGGQRDVGLDKKYYHIDAI------GRFEGANPALYETLARDRLCLMMAQYFLG 605
|| | | || | | :|:: | || | |||||| |||| |||: |
Db 600 EETL---GQNADVPLGKDFYYVPNIEKDEKKNRFHKDNAVLYETLALDRLCAMMARKCLT 656
Qy 606 SVRKELGNK---IVWSN----DSIELPVEGSVGNEKS--IVFSVSDYGKLYVLDDAEFLG 656
: | | | | | | | | | : | ::: | | |:|: ||||:|| :|||
Db 657 QINKNLAEKSEEIDWRNEDGKDFIYLKLVKSDRPQETFKIRFKVNDFAKLYVMDDPDFLG 716
Qy 657 RICEYFMPHEKGKIRYHTVYEKGFRAYNDLQKKCVEAVLAFEEKVVKAKKMSEKEGAHYI 716
: ::| | | | || :| | | | || :||:| |: |:: | | | :||
Db 717 GLMKHFFPQEH-SIEYHKLYRNGIERYTDRQKDGIEAILRLEDSVIRQKGMKPKPAKNYI 775
Qy 717 DFREILAQTMCKEAEKTAVNKVRRAFFHHHLKFVIDEFGLFSDVMKKYGIEKEW 770
| ||:||| | :: :|||||| |:|||| :: | |:||| :| |
Db 776 SFSEIMAQTDYPEHDQKVLNKVRRALLHYHLKFEPADYNRFVDIMKK---DKFW 826
With regards to claim 38, Zhang discloses that the non-natural Cas13 comprises one or more nuclear export signals (see claim 10, pg. 390). Zhang discloses that in preferred embodiments, at least one or more C-terminal or N-terminal nuclear localization signals are attached (see Paragraph 0429, pg. 212). Zhang further discloses that the Cas protein comprises one or more nuclear export signals (see claim 11, pg. 390).
With regards to claim 55, Zhang discloses that in some embodiments, a spacer sequence (guide sequence) is about 15 nucleotides in length for CRISPR-Cas effectors (see paragraph 0095, pg. 9) and is designed to have complementary where hybridization between a target sequence and a guide sequence promotes formation of a CRISPR complex (see pg. 0094). Zhang defines a target sequence as RNA (see paragraph 0023, pg. 3). Note that the specification of the current instant application states a spacer/guide sequence is complimentary to at least a portion of the target RNA (see instant current instant application specification, pg. 45). Zhang discloses that the ability of a guide sequence to direct sequence-specific binding of a CRISPR complex to a target sequence may be assessed by a suitable assay. Zhang discloses that the components of a CRISPR system sufficient to form a CRISPR complex, including the guide sequence (spacer sequence), may be provided to a host cell having the corresponding target sequence followed by assessment of preferential cleavage within the target sequence (see paragraph 0095, pg.9).
Conclusion
No claims are allowed.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
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