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 .
DETAILED ACTION
Status of Claims
Claims 1, 3, 5-6, 8-10 and 13-31 are pending and the subject of this FINAL Office Action.
Claim Rejection - 35 USC § 112 – Written Description - Maintained
The following is a quotation 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.
Claims 1, 3, 5-6, 9-10, 14-15, 18-22, 24, 26-28 and 31 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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, at the time the application was filed, had possession of the full scope of the claimed invention.
The specification does not demonstrate possession of all CRISPR systems “capable of forming a single-stranded DNA region” used with all base editing systems in all organisms or cells to detect base editing. Instead, the specification demonstrates possession of base editing system that uses a fusion protein composed of cytosine deaminase and nSpCas9, along with CRISPR system that uses nSaCas9 in rice. In fact, in Example 1, pdSaCas9 and pdLbCpf1 CRISPR systems failed to detect base editing.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.”’ Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353–54 (Fed. Cir. 2010) (en banc). Whether the disclosure of a patent satisfies the written description requirement is a question of fact. See id. at 1351. The test for sufficiency of the written description support is “whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date sought.” Id. This “possession” test “requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art.” Id. Possession shown by evidence “outside of the specification is not enough,” and “a description that merely renders the invention obvious does not satisfy the requirement.” Id. at 1352. Instead, it is the specification itself that must demonstrate possession. Id.
Where, as here, a genus is claimed using functional language to define a desired result, “the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” Id. at 1349; AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014). A “sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad Pharms., 598 F.3d at 1350. Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1301. And any claimed functions of the various generic terms and phrases that “merely draw[s] a fence around the outer limits of a purported genus [and] is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.” See Ariad, 598 F.3d at 1350.
Here, the claims encompass identifying any base editing using any CRISPR system in any cell or organism, and “the CRISPR detection system being capable of forming a single-stranded DNA region.” However, the 9-page specification only discloses a single example that worked in a proof-of-principle experiment of a nascent technology. See Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351 (Fed. Cir. 2011) (“For generic claims,” the Federal Circuit has “set forth a number of factors for evaluating the adequacy of the disclosure, including ‘the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.’”) (quoting Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005)). Given the scope of the claimed genus of base editing system, CRISPR system, and cells and organisms, the Examiner finds that the Specification provides at most a wish or research plan, “leaving it to others to explore the unknown contours of the claimed genus.” See AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014); see also Centocor, 636 F.3d at 1351. Thus, like in Centocor, the Specification here “at best describes a plan for making [a CRISPR detection system for base editing systems] and then identifying those that satisfy the claim limitations,” but such a “‘mere wish or plan’ for obtaining the claimed invention is not sufficient.”
Response to Arguments
The rejection is maintained because Applicants fail to address the specific arguments based on specific data. Again, the 9-page specification only discloses a single example that worked in a proof-of-principle experiment of a nascent technology. Specifically, the 9-page specification with one example demonstrates possession of base editing system that uses a fusion protein composed of cytosine deaminase and nSpCas9, along with CRISPR system that uses nSaCas9 in rice. In fact, in Example 1, pdSaCas9 and pdLbCpf1 CRISPR systems failed to detect base editing. Example 2 implements this single successful nSpCas9 detection system. Example 3 merely confirms that results of Example 2 using sequencing data. More specifically, Example 1 describes “Verification of TA-AS System in Rice Protoplast Transformation” as follows:
The A3A-BE3 vector was combined with pnSaCas9/pSa-sgRNA-OsCDC48-SaT1, pnSaCas9/pSa-sgRNA-OsNRT1.1B-SaT1, pdSaCas9/pSa-sgRNA-OsCDC48-SaT1, pdSaCas9/pSa-sgRNA-OsNRT1.1B-SaT1, pdLbCpf1/pLb-crRNA-OsEPSPS-Cpf1T1 and pdLbCpf1/pLb-crRNA-OsPDS-Cfp and co-transferred into rice protoplasts.
Through amplicon high-throughput sequencing of the target sites, it was found that A3A-BE3 without editing targets had a high-level C-to-T base editing phenomenon on nSaCas9 targeted OsCDC48-SaT1 and OsNRT1.1B-SaT1 target sites, there was no obvious base editing phenomenon detected in other two groups [pdSaCas9 and pdLbCpf1] during treatment, and no base editing phenomenon was detected in an untreated group (FIG. 2). It indicated that nSaCas9 could generate a continuous and stable ssDNA region in plants for detecting the random off target effect of the cytosine base editing system in a high-throughput mode.
Figure 2 clearly shows that both detection systems pdSaCas9 and pdLbCpf1 failed to detect C to T conversions; whereas nSaCas9 succeeded:
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This is why in Examples 2-3, only the “TA-AS [nSpCas9] system was used for analyzing random off-target effect of reported cytosine base editing systems BE3, YEE-BE3, RK-BE3, A3A-BE3 and eA3A-BE3.” In sum, the 9-page specification shows that only one of three tested CRISPR detection systems worked in the claimed invention.
To this end, Applicants’ assertion that “[t]he ‘single example’ noted by the Patent Office is therefore representative of the full scope of the claims, and thus applicant respectfully submits that it is unnecessary to limit claim 1 to the specific system verified in the Examples” is absurd on its face. Whether an example is “representative” is not the issue; rather, whether a single example in a nascent technology provide written description support for the full scope of the claim. Applicants completely miss this point, which must be addressed. The claims are directed to any Cas9-based detection system used with any base editing system of CRISPR-deaminase. In this nascent field, Applicants have provided a meager 9-page specification with one example. In that one example, two of the three Cas9-based detection systems failed to detect the same base edits as the one that worked. Thus, in this context, as supported by the cited case law above, a single example does not suffice for written description of the entire scope of the claimed invention.
Prior Art
The prior art fails to teach or suggest to detect base editing system off-target edits by sequencing using CRISPR systems, which require vector transfection of cell with a cytosine deaminase fused to a nSpCas9 in addition to vector transfection of an nSaCas9. This yields orthogonal guide RNAs from the different Cas9 of the editing versus CRISPR systems. The closest prior art teaches to detect edits from cytosine deaminases already in cells (i.e. not Cas9 fusion systems) using a CRISPR detection system (Lei et al, APOBEC3 induces mutations during repair of CRISPR-Cas9-generated DNA breaks, Nat Struct Mol Biol. 2018 Jan;25(1):45-52. doi: 10.1038/s41594-017-0004-6. Epub 2017 Dec 11).
Allowable Subject Matter
Claims 8, 13, 16-17, 23, 25 and 29-30 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.
Conclusion
No claims are allowed.
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.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681