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 .
Drawings
The drawings filed on 1/13/23 and 11/26/25 are objected to because they are not fully legible. Many of the drawings (Figures 1, 2A, 2B, 4A, 4D, 6A, 6B, 7A, 7B, 8A, 9A, and 11 are not acceptable) are fuzzy and cannot be clearly interpreted.
Claim Rejections - 35 USC § 112
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, 4-7, 12-22, 25, 27, 28, and 31 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.
The claims are directed to any gRNA that specifically binds a 5’ LTR HIV-1 sequence comprising SEQ ID NO: 1, 2, or 3; and a nucleic acid sequence that binds a Cas protein. The specification does not adequately describe the structure required for the function of these compounds. The specification does not adequately describe the structure required for a gRNA to specifically bind to a 5’ LTR HIV-1 sequence comprising SEQ ID NO: 1, 2, or 3 and achieve the recited functions; and does not adequately describe the structure required for a nucleic acid sequence to bind at any level to any Cas protein and function. The species of gRNAs and Cas proteins of the specification are not representative of the entire claimed genus.
The claims require for the gRNA to hybridize with a target sequence in HIV-1 selected from SEQ ID NOs: 1-3, but the specification does not adequately describe what level of hybridization is required between the gRNA and the target sequence. Without further description of the structure or sequence required for the gRNA, one would not be able to readily recognize which gRNAs are necessarily included or excluded from the recited genus and would not be able to recognize that applicant was in possession of the entire genus at the time of filing.
The claims require for the gRNA to “uniquely” hybridize with the target HIV-1 sequence, but the specification does not adequately describe what structure is required for the gRNA to meet the limitation of uniquely hybridizing to the target HIV-1 sequence.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being gRNAs of any length that bind to SEQ ID NOs: 1, 2, or 3 at any level; or comprise any sequence of any length that is complementary to SEQ ID NOs: 1, 2, or 3 and function as claimed; and nucleic acid sequences that bind to any Cas protein.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To achieve the desired function, it appears that the structure is required to be of a shorter length and to be complementary to the target sequence. For example, Wilson et al. (Frontiers in Pharmacology, 2018, 9, 749, 1-6) teaches The CRISPR-Cas9 system allows for targeted editing of DNA in vitro. The system is targeted to the DNA via association with a guide RNA (gRNA) molecule, which binds to the targeted DNA through base complementarity and enables precise DNA cleavage (page 1).
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for agents within the instant enormous genus that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that one of skill in the art, at the time of filing, would understand that CRISPR guide RNAs, as currently claimed, are defined structurally by Watson-Crick complementarity to the target sequence and by the universally conserved region required for Cas binding. Thus, identifying the target sequence (e.g., SEQ ID NO:1, 2, or 3) provides more than enough information for the skilled artisan to determine what would specifically bind to the target sequence. Furthermore, a definition for "specifically binds" is provided in the specification (see para [0034]).
Although one of skill in the art would understand that CRISPR guide RNAs, as currently claimed, are defined structurally by Watson-Crick complementarity to the target sequence, the instant claim breadth encompasses gRNAs that bind at any level to instant SEQ ID NOs: 1-3, which would not likely function as claimed. The definition of the specification for "specifically binds" is as follows: [0034] As used herein, "selectively binds" is meant that a guide RNA or composition recognizes and physically interacts with its target (for example, LTR of HIV-1) and does not significantly recognize and interact with other targets. In some aspects, "specifically binds" as used throughout, can be used interchangeable with "selectively binds" or "specifically targets."
This definition does not set forth any specific structure required for the function and does not set forth what level of complementarity is required between the gRNA and the target for the function. The claims encompass gRNAs that specifically bind at two nucleotides of the recited sequences, for example.
Applicant argues that para [0144] describes how to identify gRNA target sequences by using specific gRNAs. Therefore, the specification provides examples of gRNAs. However, the claim language is not limited to the examples of the specification, but rather is much broader and encompasses gRNAs that would not have the structure required for the function.
Applicant argues that it is well known in the art and one of skill in the art would have understood that gRNA sequences have a general structure of about 17-24 nucleotides that binds to a target sequence. However, the claim language is not limited to the examples of the specification, but rather is much broader and encompasses gRNAs that would not have the structure required for the function. Although applicant asserts that therefore, any random (for example, a 5 nucleotide sequence) sequence that happens to bind to SEQ ID NO:1, 2, or 3 would not be considered a gRNA, gRNAs that are 17-24 nucleotides in length and bind at 2 nucleotides to SEQ ID NO: 1, 2, or 3 would meet the instant limitation of being a gRNA and specifically binding to SEQ ID NO: 1, 2, or 3. The structure of gRNAs is not in question, but rather the gRNAs encompassed by the instantly recited claim language are.
For example, Khahimzhan et al. (Phys Biol, 18, 2021, 056003, 1-16) teach that is established that for CRISPR-Cas9 applications guide RNAs with 17–20 bp long spacer sequences are optimal for accurate target binding and cleavage (abstract). Instant claim 1 does not require this combination which appears to be the structure required for the function.
Khahimzhan et al. teach that they performed cell-free CRISPRa (CRISPR activation) and CRISPRi (CRISPR inhibition) experiments to demonstrate the existence of a complex dependence of CRISPR-Cas9 binding as a function of the spacer length and complementarity (abstract). It is known that spacer length and complementarity parameters are crucial for CRISPR function. Instant claim 1 encompass gRNAs that specifically bind at any number of nucleotides to one of the instantly recited sequences, a genus of compounds that has not been adequately described by the specification.
Matson et al. (PLoS ONE 14(12): e0226107, 1-16) teach that extension of sgRNA length, responsible for recognition of the target DNA sequence for Cas9 cleavage, resulted in improved specificity for the GGTA1 gene and less off-target DNA cleavage (abstract). Matson et al. teach sgRNAs that are up to 53 nucleotides in length (Figure 1). The instant claims are not limited to sgRNAs of any specific length range or any specific level of complementarity to the instantly recited target sequences, a genus that has not been adequately described by the specification.
Conclusion
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 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 Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636