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 claims 13 and 19 as submitted in a communication filed on 12/4/2025 is acknowledged.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/4/2025 has been entered.
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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/4/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 13, 19, 22-23 remain 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. New grounds of rejection are necessitated by amendment.
Claim 13 (claims 19, 22-23 dependent thereon) is indefinite in the recitation of …composition consisting of a Cas polypeptide…. a nucleic acid component…and a nuclease assay buffer comprising Mg2+” for the following reasons. If the nuclease assay buffer comprises Mg2+, such buffer can also comprise other undefined components because “comprising” is open language. Since the composition is now required to have the buffer, and the buffer can comprise other components beyond Mg2+, the composition is no longer a composition consists of a defined number of components, but rather a composition that comprises the Cas polypeptide, the nucleic acid and a buffer that comprises Mg2+. Correction is required.
Claim 13 (claims 19, 22-23 dependent thereon) is indefinite in the recitation of “…Cas polypeptide …with at least 95% amino acid sequence identity to any one of the polypeptides of SEQ ID NO: …591….” for the following reasons. As written, it is unclear if the “at least 95% sequence identity to any one of the polypeptides of SEQ ID NO: 573-591” refers to the Cas polypeptide or the HEPN domains. If the intended limitation is “wherein the Cas polypeptide has…domains and has at least 95%..”, the claim should be amended accordingly. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
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.
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 a single step, wherein said step is contacting a sample with a composition that consists of (i) a Cas polypeptide that has any function and comprises at least 95% sequence identity to any one of SEQ ID NO: 571-591, (ii) a nucleic acid component, wherein the Cas polypeptide forms a complex with the nucleic acid component, and (iii) a nuclease assay buffer that comprises Mg2+. 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 specification provides clear and direct enablement for methods using compositions comprising a Cas polypeptide, a nucleic acid component and a nuclease assay buffer containing Mg2+. Applicant states that multiple paragraphs of the specification provide extensive examples using nuclease assay buffers containing Mg2+ and the necessary cofactors for enzymatic activity. Applicant states that the claims have been amended to explicitly recite a composition consisting of three components. Applicant states that the nuclease assay buffer comprises the cofactors needed for the reaction to proceed. Applicant states that the Office incorrectly mischaracterizes the claimed method as requiring additional steps beyond delivery. According to Applicant, the specification provides multiple working examples that demonstrate that once the composition is provided, RNA targeting and cleavage occur during the reaction period. According to Applicant, proteinase K treatment, denaturation, gel electrophoresis and imaging in paragraph [01016] are clearly post reaction steps. Applicant submits that the specification enables a method consisting of the single step of contacting a sample with a composition comprising a Cas polypeptide, a nucleic acid component, and a nuclease assay buffer that comprises Mg2+ after which the natural molecular processes of complex formation, target binding and RNA cleavage proceed without human intervention. Applicant states that the Office’s reliance on the teachings of Zhen et al. are misplaced and that the specification demonstrates the successful RNA targeting and cleavage using the claimed system without requiring additional transfection enhancers. Applicant states that the specification need not use identical language to provide enablement and that the term “consisting of” in the context of a method claim refers to the procedural steps actively performed and not a prohibition on the natural molecular interactions that inherently follow, such as binding and cleavage that naturally occur as a result of the step.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendments made to the claims, and the teachings of the specification. However, the Examiner disagrees with Applicant’s contention that the entire scope of the claims is fully enabled by the teachings of the specification.
The claims as amended still require a genus of “Cas polypeptides” which are variants of any one of the polypeptides of SEQ ID NO: 573-591, wherein said Cas polypeptides can have any function. As such, the Cas polypeptides may or may not cleave a target RNA. The specification fails to disclose how to use a method that consists of a single step, wherein said step 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 argument that the specification discloses examples of using nuclease assay buffers that contain Mg2+ and cofactors for enzymatic activity, the issue is not whether the specification discloses buffers that can be used to cleave a target RNA in combination with a Cas polypeptide and a nucleic acid construct such as a guide RNA. As correctly pointed out by Applicant, all the compositions disclosed in the specification that are used to cleave a target RNA are compositions that comprise the Cas polypeptide, a nucleic acid construct that can form a complex with the Cas polypeptide and can target the desired RNA, and additional components that allow the Cas polypeptide to reach its target and effectively cleave the target RNA. The additional elements beyond the Cas polypeptide and the nucleic acid construct vary depending on the objective of the method that uses the Cas polypeptide and the nucleic acid construct.
The claims have been deemed indefinite because there is a contradiction between the term “consisting of” as it relates to the composition and the new component, which is a buffer that comprises Mg2+ and other undefined components. These undefined components would be part of the composition by virtue of the fact that the buffer contains them. Therefore, the composition can no longer be a composition that is limited (consists of) to defined elements. See also Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for additional discussion of this issue. Please note that the term “nuclease assay buffer” does not define the components of the buffer because, as correctly pointed out by Applicant, the specification discloses several recipes of buffers with different components. Moreover, the art does not recognize a single recipe for a nuclease assay buffer. Even if the argument is made that the claims require a composition that consists of a Cas polypeptide, a nucleic acid construct that forms a complex, water and Mg2+, it is noted that a composition that solely comprises those components is not going to allow binding of the nucleic acid construct to the Cas polypeptide, binding of the complex to the target RNA, or cleavage of the target RNA. Therefore, even if the Cas polypeptides were to have nuclease activity, it is unclear as to how one could use a method where the only step is contacting a sample with a composition that would not necessarily allow cleavage of a target RNA in the sample.
With regard to the argument that the specification provides multiple working examples that demonstrate that once the composition is provided, RNA targeting and cleavage occur during the reaction period, and that proteinase K treatment, denaturation, gel electrophoresis and imaging in paragraph [01016] are clearly post reaction steps, it is reiterated herein that the methods described in the specification require at least one step (see recitation of “comprises”), namely contacting the sample comprising the target RNA composition, and also require a composition that comprises at least two components, namely a Cas polypeptide and a guide RNA. While it is agreed that gel electrophoresis and imaging are detection steps that follow the reaction step, just the mere contact of a sample with a composition that has the recited Cas polypeptide, nucleic acid construct and buffer is not enough to observe cleaving of a target RNA. It is reiterated herein that the specification (e.g., Example 4, paragraphs [1016]-[1017]) and the art teach that one would also require additional steps such as an incubation step. Also, steps such as quenching with proteinase K and EDTA would be required to stop the reaction, presumably because after a certain amount of time, the Cas protein could also degrade non-specific targets. Even if the argument is made that a single step of contacting a sample with the recited composition results in cleavage of RNA, it is noted that unless the target RNA is cleaved and non-specific nucleic acid degradation is minimized, it is unclear as to how one could use a method that is intended to cleave specific RNA targets and instead produces non-specific nucleic acid degradation.
With regard to the argument that the teachings of Zhen et al. are misplaced and that the specification demonstrates the successful RNA targeting and cleavage using the claimed system without requiring additional transfection enhancers, it is noted that the teachings of Zhen et al. were introduced to show that contacting a cell with a composition that comprises solely a Cas polypeptide and a guide RNA is not sufficient to obtain targeting and cleavage. Applicant is reminded that the claims as previously presented required a single step of delivering to a cell a composition that consists of two components. The teachings of Zhen et al. are clear evidence that one cannot deliver to a cell a composition that consists solely of a Cas polypeptide and a nucleic acid construct without additional reagents.
With regard to the argument that the specification need not use identical language to provide enablement and that the term “consisting of” in the context of a method claim refers to the procedural steps actively performed and not a prohibition on the natural molecular interactions that inherently follow, such as binding and cleavage that naturally occur as a result of the step, it is noted that the instant rejection is not raised simply because the claims do not use identical language as that provided in the specification. Applicant is reminded that the terms “consisting of” and “comprising” have different meanings. As set forth in MPEP § 2111.03, the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps, while the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. In the instant case, the Examiner is not arguing that one would not observe binding and cleavage of a nucleic acid as a consequence of contacting a sample with the recited composition. Instead, the Examiner has indicated that a method that consists of a single step as recited is not enabled for the reasons extensively discussed above.
Thus, for the reasons of record and those set forth above, one cannot reasonably conclude that, the claimed invention is fully supported by the originally filed disclosure and the enablement requirements have been met.
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. New grounds of rejection are necessitated by the introduction of 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). Claims 13, 19, 22-23 as amended are directed to a method that consists of one step, wherein said step is contacting a sample with a composition that consists of three components, a Cas polypeptide, a nucleic acid component, and a buffer that comprises Mg2+.
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, a guide RNA, and a buffer that comprises Mg2+, the Examiner is unable to find support for an in vitro or ex-vivo method as claimed that consists of a single step, wherein said single step is contacting a sample with a composition that consists of a Cas polypeptide having nuclease activity, a guide RNA, and a buffer comprising Mg2+. Thus, there is no indication that a method that consists of one step, wherein said step is contacting a sample with a composition that consists of three components, a Cas polypeptide, a nucleic acid component, and a buffer 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.
This rejection has been discussed at length in the prior Office action. It is maintained for the reason of record and those set forth below.
Applicant argues that this rejection does not apply to the present claims. Applicant states that the specification describes nuclease assays performed using compositions consisting of a Cas polypeptide, a nucleic acid component and nuclease assay buffers comprising Mg2+ and specific cofactors. Applicant refers to paragraphs [0016], [0160] and [0183] in support of the argument that Applicant has possession of the claimed subject matter at the time of filing. Applicant states that the specification need not use identical language to provide adequate written description support, citing that the subject matter of the claim need not be described literally. Applicant states that the working examples provided clearly demonstrate possession of the claimed methods.
Applicant’s arguments have been fully considered but not deemed persuasive to withdraw the rejection of claims 13, 19, 22-23. The Examiner acknowledges the amendments made to the claims. However, the Examiner disagrees with Applicant’s contention that the claimed invention is supported by the specification as originally filed. With regard to the sections of the specification cited by Applicant, it is noted that none of the paragraphs cited disclose a method consisting of one single step, wherein said step is contacting a sample with a composition that consists of a Cas polypeptide, a nucleic acid component, and a buffer that contains Mg2+. Paragraph [016], which is reproduced below, describes a complex between the Cas polypeptide and the nucleic acid component, and provide preferred embodiments for the nucleic acid component.
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Paragraph [0160] which is reproduced below refer to the results of in vitro cleavage experiments where an RNA target was combined with a C2c2 protein and crRNA, the mixture that comprises the RNA target, C2C2 protein and crRNA was incubated in buffers that comprise several components including Mg2+, and the mixture was later quenched with proteinase K. See also paragraphs [0947]-[0948] of the specification that describe Figure 71, which are reproduced below.
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Paragraph [0183], which is reproduced below, refers to the finding that C2c2 processes its own array and provide different buffers that comprise several compounds and Mg2+ that were used in an assay where a C2c2 endonuclease cleaves two arrays.
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Therefore, from the paragraphs cited by Applicant, the only full description of a method where there is contact between a sample, and a composition is a method that comprises more than one step, namely contacting, incubating, and quenching with a proteinase, and the composition used contains several components including a Cas polypeptide, a nucleic acid construct, and a buffer comprising several salts and other components. Thus, contrary to Applicant’s assertions, neither the working examples nor the specification as a whole disclose a method that consists of one step and uses a composition consisting of a Cas polypeptide, a nucleic acid construct, and a buffer that comprises Mn2+ recited in the claims.
With regard to the argument that the specification need not use identical language to provide adequate written description support, citing that the subject matter of the claim need not be described literally, it is noted that the instant rejection is not raised simply because the claims do not use identical language as that provided in the specification. Applicant is reminded that the terms “consisting of” and “comprising” have different meanings. As set forth in MPEP § 2111.03, the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps, while the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. This was also indicated by Applicant in the response of 10/31/2024 (pages 6-7) with regard to arguments traversing the previous obviousness rejections over claims of U.S. Patent No. 10,266,887, 11,174,515, and 11,788,083, where Applicant stated on the record that a method that consists of a step does not require additional steps, and a composition that consist of a Cas polypeptide and a nucleic acid component is limited to the components recited. Therefore, contrary to Applicant’s assertions, the issue in the instant case is not that the specification still provides support even if the language used in the claims is not identical to that of the specification.
There is no indication that a method that consists of a single step, wherein said step is the contacting of a sample with a composition that consists of a Cas polypeptide that may or may not have RNase activity , a nucleic acid construct, and a buffer 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.
Conclusion
No claim is in condition for allowance.
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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
January 9, 2025