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 .
Response to Amendment
The amendment filed June 4th, 2026 is acknowledged. Regarding the Office Action mailed March 4th, 2026:
Maintained or modified rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1-2, 11-12, 14, 17, 26-27, 32, 35-36, and 45 have been amended. Claims 3-4, 9-10, 13, 21-22, 24-25, 28-30, 33-34, 37, and 40-44 have been canceled. Claims 1-2, 5-8, 11-12, 14-20, 23, 26-27, 31-32, 35-36, 38-39, and 45 are pending. Claims 8, 20, 31, 38-39, and 45 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-2, 5-7, 11-12, 14-19, 23, 26-27, 32, and 35-36 are under examination and discussed in this Office action.
Claim Rejections - 35 USC § 112(b) - New - 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 15 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.
Claim 15 recites the limitation “wherein the Type VI Cas nuclease comprises an amino acid sequence having at least 80% sequence identity to any one of SEQ ID NO: 18 -SEQ ID NO: 35”. It is unclear from this recitation, given the newly amended limitation of claim 1 requiring the Type VI Cas nuclease to be a Cas13a nuclease, how the Type VI Cas nuclease can comprise at least 80% sequence identity to SEQ ID NOs: 26-35. As noted in Table 1 of the specification, SEQ ID NOs: 26-30 are for Cas13b nucleases and SEQ ID NOs: 31-35 are for Cas13c nucleases. Therefore, the claim is found indefinite. While claim 16 depends from claim 15, claim 16 specifically claims a SEQ ID that is noted as a Cas13a nuclease in Table 1 of the specification and therefore does not suffer from the issue identified for claim 15.
Claim Rejections - 35 USC § 112(a) – Modified – Necessitated by Amendment
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.
Claims 1-2, 5-7, 11-12, 14-19, 23, 26-27, 32, and 35-36 are 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 a Cas13a polypeptide of LbuCas13a or LwaCas13a, does not reasonably provide enablement for any Cas13a nuclease as embraced by the claims. The Declaration filed June 4th, 2026 provides enablement for a further Cas13a nuclease, HheCas13a, which is included as a Cas13a nuclease option in the specification. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 1 as currently drafted encompasses a composition comprising a Type VI Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated (Cas) nuclease, wherein the Type VI Cas nuclease is a Cas13a nuclease. “Cas13a nuclease” does not limit the nuclease in question to the LbuCas13a or LwaCas13a nucleases as described in the specification, or the HheCas13a as described in the Declaration. Consequently, the breadth of the claim is expansive. Claims 2, 5-7, 11-12, 14-19, 23, 26-27, 32, and 35-36 encompass the same breadth as claim 1 since they do not limit the Cas13a nuclease to a LbuCas13a, LwaCas13a, or HheCas13a nuclease.
(B) The nature of the invention: The invention is in the field of CRISPR-Cas nuclease compositions directed to target single-stranded deoxyribonucleic acid (ssDNA).
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Freije (Detect and destroy: CRISPR-based technologies for the response against viruses, Cell Host Microbe, April 2021, 29, 689-703) teaches on Cas13 proteins specifically cleaving single-stranded RNA (Page 691, column 1, paragraph 2; previously cited). Freije further teaches that Cas13 (e.g. Type VI CRISPR-Cas nuclease) collaterally cleaves ssRNA (Page 691, column 1, paragraph 4), which has been used for detection techniques like SHERLOCK to generate a signal from a synthetic, fluorescent ssRNA when a target RNA is present (Page 692, column 1 paragraph 5 to column 2, paragraph 1). Cas13a nucleases specifically have been used in SHERLOCK based on their specific action of cleaving target ssRNA and collaterally cleaving non-target ssRNA (Page 692, column 1, paragraph 5 to column 2, paragraph 1).
Zhou (CRISPR/Cas-based nucleic acid detection strategies: Trends and challenges, February 2024, 10, 1-20; previously cited) also supports the same teachings, where Cas13 proteins specifically cleave single-stranded RNA (Page 5, paragraph 2; Page 13, paragraph 3) and Cas13 collaterally cleaves ssRNA (Page 5, paragraph 2; Page 13, paragraph 4), which can be used for detection techniques like SHERLOCK to generate a signal when a target RNA is present (Figure 5). Cas13a nucleases have been used extensively in SHERLOCK and other methods based on their specific action of cleaving target ssRNA and collaterally cleaving non-target ssRNA (Page 13, paragraph 3 to Page 15, paragraph 1; Figure 5A).
Taken together, the art supports the use of RNA targets with Cas13a nucleases. A composition comprising a DNA target interacting with a Cas13a nuclease beyond those nucleases described in the specification, and further the Cas13a nuclease presented in the Declaration, remains highly unpredictable.
The invention is drawn to biological molecules, and is therefore in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The level of skill in the art is therefore deemed to be high.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: While the Applicant has provided description of many Cas13a nucleases (see paragraphs [0101]-[0104], Table 1, and Table 2), the provided working examples are only directed to the Cas13a polypeptides LbuCas13a or LwaCas13a. As seen in Figure 2C, Figure 4B, paragraph [0175], and paragraph [0178], these two Cas13a polypeptides are capable of use without an RNA polymerase through direct detection of ssDNA.
The Applicant has further provided evidence via a Declaration of a third Cas13a polypeptide, HheCas13a, that is capable of use without an RNA polymerase through direct detection of ssDNA.
The Applicants have not provided working examples comprising any other Cas13a nucleases. Given the state of the art, as cited above, Cas13a nucleases are known to interact with target RNA as opposed to target ssDNA, and more evidence would be required to enable any other Cas13a nucleases in the composition.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high predictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that any Cas13a nuclease is distinct from the Cas13a polypeptides LbuCas13a, LwaCas13a, or HheCas13a, and thus applicability of the claimed method to any Cas13a nuclease as embraced by the claim remains unpredictable, requiring undue experimentation. For example, multiple compositions each comprising different Cas13a nucleases would have to be prepared and tested for their ability to form a complex directly with a target ssDNA. Thus, the quantity of experimentation in this area would be extremely large since there are a significant number of parameters that would have to be studied. Furthermore, the ultimate outcome of such experimentation is completely unpredictable.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, 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 without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1-2, 5-7, 11-12, 14-19, 23, 26-27, 32, and 35-36, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the full scope of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 1-2, 5-7, 11-12, 14-19, 23, 26-27, 32, and 35-36 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed invention to it the full scope embraced by the claims.
Declaration under 37 C.F.R. 1.132
The Declaration under 37 CFR 1.132 filed June 4th, 2026 and written by Inventor Janice Chen is insufficient to overcome the rejection of claims 1-2, 5-7, 11-12, 14-19, 23, 26-27, 32, and 35-36 based upon 35 U.S.C. §112(a) as set forth in the last Office action because: the facts presented fail to overcome the scope of enablement issue as presented.
The Inventor first provides details related to their expert status in the subject area of the invention (Page 1, paragraph 1 of the Declaration filed June 4th, 2026). The Inventor then provides a summary of details of the invention (Page 1, paragraph 2 of the Declaration filed June 4th, 2026). The Inventor then provides further illustrative experiments exemplifying the claimed composition (Page 1, paragraph 3 of the Declaration filed June 4th, 2026). The first illustrative experiment was performed with HheCas13a nuclease and corresponding guide RNAs, which were tested with ssDNA in 4 different concentrations and an RNA reporter (Page 2, paragraph 3 of the Declaration filed June 4th, 2026). A graph of the produced fluorescence is provided, demonstrating HheCas13a’s ability to detect ssDNA without transcription into RNA (Page 2, paragraph 3 of the Declaration filed June 4th, 2026). The Inventor further provides an experiment showing the specificity of the HheCas13a’s ability to target ssDNA produced by LAMP amplification when provided the appropriate guide RNAs by testing with no template, target genomic DNA, non-target RNA, and a combo of target DNA and non-target RNA (Pages 2-3, paragraph 4 of the Declaration filed June 4th, 2026). The provided results graph shows options with target DNA produced fluorescent signal, confirming HheCas13a’s ability to specifically target ssDNA (Page 3, paragraph 4 of the Declaration filed June 4th, 2026).
It is acknowledged that HheCas13a, based on the presented experimentation, possesses the same ssDNA targeting capabilities as presented for LbuCas13a and LwaCas13a in the instant specification. The use of HheCas13a in compositions as described is found to be commensurate in scope with the claims.
The Inventor states the provided results for HheCas13a are consistent with the results provided in the working examples for LbuCas13a and LwaCas13a, even though they differ considerably in amino acid sequence (Page 4, paragraph 5 of the Declaration filed June 4th, 2026). The Inventor states that the trans-collateral cleavage of an RNA reporter by a guided Cas13a complex response to a target ssDNA is an activity of Cas13a nuclease regardless of their particular amino acid sequence (Page 4, paragraph 5 of the Declaration filed June 4th, 2026). The Inventor concludes that further Cas13a nuclease would reasonably be expected to exhibit this same activity (Page 4, paragraph 5 of the Declaration filed June 4th, 2026).
In response these arguments, it is first noted that there are many known Cas13a nucleases presented in the art. As evidenced by Adler (Broad-spectrum CRISPR-Cas13a enables efficient phage genome editing, Nature Microbiology, October 2022, 7, 1967-1979), there are over 40 recognized Cas13a sequences across a variety of bacterial phyla (Figure 1; Supplementary Figure 1). While the DNA targeting ability of HheCas13a as above presented, as well as LbuCas13a and LwaCas13a as presented in the specification, is acknowledged, three working examples are not representative of Cas13a nucleases as a whole. Finding a new function within just three Cas13a nucleases is not representative of a group of nucleases with over 40 recognized sequences, particularly when the sequence identity between Cas13a nucleases from different origins is quite low, as has been noted by the Inventor. With further regard to the sequence identity argument, it is known that there are specific domains related to the recognition and cleavage of Cas protein targets. In the case of Cas13 proteins, as taught by both Freije (Page 691, column 1, paragraph 2) and Zhou (Page 5, paragraph 2), HEPN domains are responsible for the enzymatic action required for target RNA cleavage. As evidenced by Pillon (HEPN RNases – An Emerging Class of Functionally Distinct RNA Processing and Degradation Enzymes, Critical Reviews in Biochemistry and Molecular Biology, December 2020, 56, 88-108), HEPN domains are known for RNA recognition and cleavage activities (Introduction). As also taught by Freije (Page 690, column 2, paragraph 4 to Page 691, column 1, paragraph 1) and Zhou (Page 3, paragraph 3), the RuvC domain is responsible for dsDNA and ssDNA recognition and cleavage in the DNA targeting Cas12 nucleases. There is no recorded RuvC domain or any other domain related to target DNA cleavage in any Cas13 proteins, including Cas13a. Regardless of the low sequence identity between the exemplary Cas13a proteins, the art indicates that there are recognized domains that are maintained across Cas proteins that provide the ability to recognize and further cleave their intended targets.
While the Inventor concludes that trans-collateral cleavage of an RNA reporter by a Cas13a nuclease is an activity of this class of nucleases and further Cas13a nuclease would reasonably be expected to exhibit this activity, the lack of evidence showing a common domain across Cas13a nucleases responsible for DNA recognition means that every Cas13a would need to be tested for DNA recognition ability before use in actual experimentation. Given the above identified diversity of bacteria and Cas13a nucleases, as well as the lack of known DNA recognition domain, it would require undue experimentation from one of ordinary skill in the art to work through the known Cas13a nucleases to confirm that other Cas13a nucleases exhibit DNA recognition activity. Therefore, the Declaration is found insufficient to overcome the rejection under 35 U.S.C. §112(a).
Response to Arguments
Applicant's arguments filed June 4th, 2026 have been fully considered but they are not persuasive.
The Applicant first summarizes the Examiner’s previous rejection (Pages 7-8 of the Remarks filed June 4th, 2026). The Applicant also provides a summary of the claim amendments (Page 8 of the Remarks filed June 4th, 2026). The Applicant provides citations from the MPEP regarding the test of enablement, arguing that based on MPEP guidance regarding undue experimentation, the Examiner has not met the burden of identifying the information that is missing and why supplying such information would require undue experimentation (Page 8 of the Remarks filed June 4th, 2026). The Applicant argues that the Examiner’s art citations do not change this conclusion, and the fact that neither tested Cas13a nuclease with a DNA target and RNA reporter is not evidence to doubt that such combination would work as taught (Page 8 of the Remarks filed June 4th, 2026).
In response to this argument, it is noted that the Examiner has identified the information that is missing and why supplying such information would require undue experimentation in the above rejection, which is quoted again here: “A skilled artisan recognizes that any Cas13a nuclease is distinct from the Cas13a polypeptides LbuCas13a or LwaCas13a, and thus applicability of the claimed method to any Cas13a nuclease as embraced by the claim remains unpredictable, requiring undue experimentation. For example, multiple compositions each comprising different Cas13a nucleases would have to be prepared and tested for their ability to form a complex directly with a target ssDNA. Thus, the quantity of experimentation in this area would be extremely large since there are a significant number of parameters that would have to be studied. Furthermore, the ultimate outcome of such experimentation is completely unpredictable.” The art citations are provided to show that ssDNA is not a recognized target molecule for Cas13a nucleases and are not used to indicate what information is missing and why supplying such information would require undue experimentation.
The Applicant further argues that the specification provides guidance that one skilled in the art could make and use the claimed compositions across their full scope without undue experimentation, followed by a cited passage from the specification (Page 9 of the Remarks filed June 4th, 2026). The Applicant further argues that the specification teaches on Cas13a enzymes from 30 example bacteria, with 18 exemplary Cas13a enzymes including those appearing in working examples, and the specification also provides exemplary enzyme sequences for those 18 Cas13a enzymes (Page 9 of the Remarks filed June 4th, 2026). The Applicant argues that a skilled person is expressly taught that a known class of enzymes may be used in the presently claimed invention (Page 9 of the Remarks filed June 4th, 2026). The Applicant argues that the Examiner does not explain why other nucleases would not be expected to operate in the presently claimed assay aside from no one having tried, or why testing additional Cas nucleases would require more than routine experimentation (Page 9 of the Remarks filed June 4th, 2026). The Applicant argues that the nucleases which have been noted to be enabled are both Cas13a nucleases that share only 26.9% sequence identity, that it would be reasonable for a person of ordinary skill to expect other Cas13a nucleases to possess similar activities, and that it would not require undue experimentation (Page 9 of the Remarks filed June 4th, 2026).
The Applicant then summarizes the aspects detailed in the Declaration provided by Inventor Janice Chen (Page 10 of the Remarks filed June 4th, 2026). The specific aspects of the Declaration are addressed above. The Applicant places emphasis on the Inventor’s presented argument that trans-collateral cleavage of an RNA reporter by a Cas13a complex responsive to target ssDNA is an activity of this class of nucleases, regardless of the particular amino acid sequence (Page 10 of the Remarks filed June 4th, 2026). The Applicant argues, based on the exemplary assays provided in both the instant specification and in the Declaration, that Cas13a nucleases share ssDNA targeting ability despite wide sequence diversity (Page 10 of the Remarks filed June 4th, 2026). The Applicant argues that it would be clear to a person of ordinary skill in the art that the application enables the preparation of compositions according to the presented claimed invention and uses thereof according to the presently claimed methods (Page 10 of the Remarks filed June 4th, 2026).
In response to these arguments, it is noted that while the Applicant argues that there are 18 exemplary Cas13a enzymes provided in the specification, the Examiner can only identify 8 (see paragraph [0103] of the specification), as well as 8 sequences on Table 1 that correspond to Cas13a nucleases (SEQ ID NOs. 18-25). The other sequences correspond to other Cas13 subgroups. Aside from this discrepancy, the Applicant presents substantially similar arguments regarding sequence identity and widely applicable target DNA activity as have been presented in the Declaration. A response to these arguments with citations from the art appears above in response to the Declaration, addressing the breadth of known Cas13a nucleases and the aspects of RNA and DNA domains known to lend RNA and DNA recognition and cleavage capabilities to Cas nucleases. It is reiterated here that the lack of evidence showing a common domain across Cas13a nucleases responsible for DNA recognition means that every Cas13a would need to be tested for DNA recognition ability before use in actual experimentation. Given the identified diversity of bacteria and Cas13a nucleases, as well as the lack of known DNA recognition domain, it would require undue experimentation from one of ordinary skill in the art to work through the large number of additional known Cas13a nucleases to find one that works in the composition as claimed beyond what has been exemplified for LbuCas13a, LwaCas13a, and HheCas13a. Lastly, with regard to the mention of the use in claimed methods, the methods have been withdrawn from consideration and do not factor in to the considerations for either the enablement rejection or these responses to arguments.
Conclusion
All claims stand rejected.
THIS ACTION IS MADE FINAL. 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 Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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