DETAILED ACTION
Status of the Application
Claims 13, 19, 22-23 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment of claim 13 a submitted in a communication filed on 5/14/2026 is acknowledged.
Claims 13, 19, 22-23 are at issue and are being examined herein.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 13, 19, 22-23 were 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 pre-AIA the applicant regards as the invention. In view of Applicant’s amendment, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claims 13, 19, 22-23 remain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is necessitated by the introduction new matter.
As set forth in MPEP 2163 (I)(B), new or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads). Claim 13 and dependent claims 19, 22-23 as amended are directed to a method that consists of three steps, wherein said steps are (a) contacting a sample with a composition that consists of five components, a Cas polypeptide, a nucleic acid component that forms a complex with the Cas polypeptide, Mg2+, a pH buffer, and a salt, (b) incubating the sample at a temperature and for a time sufficient to allow cleavage of the target RNA, and (c) quenching the sample with a protease, a cation chelator, or both.
While the Examiner has found support for an in vitro or ex-vivo method as claimed that comprises the step of contacting a sample with a composition that comprises a Cas polypeptide having nuclease activity, and a guide RNA, the Examiner is unable to find support for an in vitro or ex-vivo method as claimed that consists of three steps, wherein said three steps are (a) contacting a sample with a composition that consists of five components, a Cas polypeptide, a nucleic acid component that forms a complex with the Cas polypeptide, Mg2+, a pH buffer, and a salt, (b) incubating the sample at a temperature and for a time sufficient to allow cleavage of the target RNA, and (c) quenching the sample with a protease, a cation chelator, or both. Thus, there is no indication that a method that consists of three steps, wherein said three steps are (a) contacting a sample with a composition that consists of five components, a Cas polypeptide, a nucleic acid component that forms a complex with the Cas polypeptide, Mg2+, a pH buffer, and a salt, (b) incubating the sample at a temperature and for a time sufficient to allow cleavage of the target RNA, and (c) quenching the sample with a protease, a cation chelator, or both, was within the scope of the invention as conceived by Applicant at the time of the invention. Accordingly, Applicant is required to cancel the new matter in the response to this Office Action.
With regard to the prior written description rejection, Applicant argues that the claims have been amended to recite contacting, incubating and quenching. Applicant refers to paragraph [001016] as providing written description support for all three method steps now recited. Applicant states that this paragraph discloses a nuclease assay having the recited steps. Applicant states that this paragraph also provides written description support for the amended composition. Applicant states that the buffer described contains 40 mM Tris-HCl (a pH buffer), 60 mM NaCl (a salt) and 6 mM MgCl2, which is a source of Mg2+. Applicant states that the claims have been amended so that they Cas polypeptides have two catalytically active HEPN domains. Therefore, the Cas polypeptides have RNase activity.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendment of claim 13, including the requirement of catalytically active HEPN domains in the Cas polypeptide. However, the Examiner disagrees with Applicant’s contention that the entire scope of the claims is adequately described.
With regard to paragraph [001016], while it is agreed that this paragraph discloses nuclease assays performed with labeled target single stranded RNA, a C2c2 protein from Leptotrichia shahii (Cas polypeptide) and crRNA (nucleic acid component), wherein these assays require a nuclease assay buffer that comprises Tris-HCl, NaCl and MgCl2, the composition of the claims require a genus of Cas polypeptides, a genus of nucleic acid components, a genus of pH buffers and a genus of salts. Moreover, the nuclease assays disclosed in paragraph [001016] comprise incubating for a specific period of time at a specific temperature, quenching with proteinase K and EDTA for a specific period of time at a specific temperature, denaturing the reaction mixture with urea using a denaturing buffer at a specific temperature for a specific period of time, and analysis using gel electrophoresis under specific conditions. The steps of the claims require a genus of temperatures, periods of times to perform the recited steps, proteases, and cation chelators. Therefore, one cannot reasonably conclude that paragraph [001016] provides support for a composition that consists solely of 5 components and a method that consists solely of three steps as recited.
With regard to the requirement of two catalytically active HEPN domains, it is noted that this limitation does not necessarily imply that the Cas polypeptides have RNase activity. Please note that the Cas polypeptides are over 1000 amino acids long. As known in the art, HEPN domains are about 100 amino acids long. Since a single amino acid substitution can result in enzymatic inactivation, and proper folding provides the 3D structure required for an enzyme to have enzymatic activity, the presence of two catalytically active HEPN that represent no more than 20% of the entire structure is not necessarily all that is required to have RNase activity as other modifications in different domains can alter 3D structure and have an effect on activity. Therefore, contrary to Applicant’s assertions, the claimed invention is not adequately described by the teachings of the specification.
Claims 13, 19, 22-23 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an in vitro or ex vivo method for targeting and cleaving a target RNA in a eukaryotic or prokaryotic cell, wherein the method comprises contacting a sample with a composition that comprises a Cas polypeptide that comprises any one of SEQ ID NO: 571-591 and a nucleic acid component, wherein the Cas polypeptide forms a complex with the nucleic acid component, and wherein the Cas polypeptide cleaves the target RNA, does not reasonably provide enablement for an in vitro or ex vivo method that consists of three steps, wherein said steps are (a) contacting a sample with a composition that consists of five components, a Cas polypeptide, a nucleic acid component that forms a complex with the Cas polypeptide, Mg2+, a pH buffer, and a salt, (b) incubating the sample at a temperature and for a time sufficient to allow cleavage of the target RNA, and (c) quenching the sample with a protease, a cation chelator, or both. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that the claims have been amended to now require three steps. Applicant states that these steps address the Examiner’s concerns. Applicant also states that the claims now require two catalytically active HEPN domains, thus ensuring that every Cas polypeptide in the claims has RNase activity. Applicant states that the claims further include a statement indicating the formation of a complex with the target RNA and cleavage, which allegedly confirms that RNA cleavage is an inherent outcome of the contacting step and not an independent step separate from the “consisting of” recitation. Applicant cites paragraph [001016] as describing nuclease assays with a Cas polypeptide, a nucleic acid component, and a buffer containing the claimed components, followed by incubation, and quenching, thus corresponding precisely to teach of the three method steps. Applicant states that the specification further demonstrates that the Cas polypeptides used in these methods achieved RNA cleavage through conserved basic residues within its two HEPN domains. Applicant states that the working examples enable one of skill in the art to make and use the claimed method without undue experimentation.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendment of claim 13, including the requirement of catalytically active HEPN domains in the Cas polypeptide. However, the Examiner disagrees with Applicant’s contention that the entire scope of the claims is fully enabled by the specification. With regard to the requirement of two catalytically active HEPN domains, it is reiterated herein that this limitation does not necessarily impart RNase activity to the recited Cas polypeptides. As known in the art, HEPN domains are about 100 amino acids long and Cas polypeptides are over 1000 amino acids long. SEQ ID NO: 573 has 1285 amino acids. The presence of two catalytically active HEPN represent no more than 20% of the entire structure and is not necessarily all that is required to have RNase activity as other modifications in different domains can alter activity. Therefore, the Cas polypeptides required by the claims may or many not cleave a target RNA. The specification fails to disclose how to use a method that consists of three steps, wherein one of the steps is the contacting of a sample with a composition that consists of a variant of any one of the polypeptides of SEQ ID NO: 573-591 that has at least 95% sequence identity to any one of the polypeptides of SEQ ID NO: 573-591, wherein said variant does not cleave a target RNA.
With regard to the teachings of paragraph [001016] as describing nuclease assays with a Cas polypeptide, a nucleic acid component, and a buffer containing the claimed components, followed by incubation, and quenching, it is noted that while it is agreed that this paragraph discloses nuclease assays performed with labeled target single stranded RNA, a C2c2 protein from Leptotrichia shahii (Cas polypeptide) and crRNA (nucleic acid component), wherein these assays require a nuclease assay buffer that comprises Tris-HCl, NaCl and MgCl2, the composition of the claims require a genus of Cas polypeptides, a genus of nucleic acid components, a genus of pH buffers having any pH and a genus of salts. While the claims require any pH buffer, and any salt, it is unclear if any composition that consists of any Cas9 polypeptide having the recited structural features, any nucleic acid component, Mg2+, any pH buffer having any pH and any salt would be enzymatically active and cleave a target RNA as required by the claims. Moreover, while the claim requires cleavage of a target RNA, there is no indication that the sample must have the target RNA, thus contacting the sample with the recited composition may not result in cleavage of an RNA.
The claims require a method that consists of three steps, namely (a) contacting a sample with a composition that consists of five components, a Cas polypeptide, a nucleic acid component that forms a complex with the Cas polypeptide, Mg2+, a pH buffer, and a salt, (b) incubating the sample at a temperature and for a time sufficient to allow cleavage of the target RNA, and (c) quenching the sample with a protease, a cation chelator, or both. The specification is silent with regard to how to use a method that consists solely of the three steps recited. The nuclease assays disclosed in the specification are carried out to determine whether or not cleavage of a particular RNA has taken place. A method that consists only of the recited three steps does not provide such information. One of skill in the art would have to analyze the results of contacting the sample, incubating the sample and quenching the sample for such method to have any use. As indicated above, the sample may or may not have a target RNA and the composition recited may or may not be able to have RNase activity to cleave a target RNA. Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the claimed invention is fully enabled by the teachings of the specification.
Conclusion
No claim is in condition for allowance.
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 extension fee 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 date of this final action.
Applicant is advised that any Internet email communication by the Examiner has to be authorized by Applicant in written form. See MPEP § 502.03 (II). Without a written authorization by Applicant in place, the USPTO will not respond via Internet email to any Internet correspondence which contains information subject to the confidentiality requirement as set forth in 35 U.S.C. 122. Sample written authorization language can be found in MPEP § 502.03 (II). An Authorization for Internet Communications in a Patent Application or Request to Withdraw Authorization for Internet Communications form (SB/439) can be found at https://www.uspto.gov/patent/forms/ forms-patent-applications-filed-or-after-september-16-2012, which can be electronically filed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
August 9, 2026
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