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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-7, 9, 11, 13, 17-19, 21, 22, 25-27, 47-49 and 56 in the reply filed on 12/23/2025 is acknowledged.
Claim 53 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/23/2025.
Claims 1-7, 9, 11, 13, 17-19, 21, 22, 25-27, 47-49 and 56 are examined in the instant application.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 9, 11, 13, 17-19, 21, 22, 25-27, 47-49 and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,939,607 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly gene editing system comprises the same Cas12i2 polypeptide and RNA guide and comprises the same positions and amino acid substitutions in SEQ ID NO: 1166 as claimed in claims 2-19 of ‘607.
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 1-7, 9, 11, 13, 17-19, 21, 22, 25-26 and 47-49 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.
When the claims are analyzed in light of the specification, the instant invention encompasses a gene editing system for genetic editing that utilizes a genus of Cas12i2 variant peptides that function to edit a target sequence in a LDHA gene.
Regarding function, the claims recite that the claimed system one or more mutations relative to SEQ ID NO: 1166 and will genetically edit the LDAH gene. However, the specification provides no description of any positions and mutations at said positions, other than D581R, I926R and V1030G, that would indicate possession at the time of filing for a gene editing system for genetic editing of the LDHA gene.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their structure. In the instant case, only the mutations D581R, I926R and V1030G are sufficiently described to indicate possession of a gene editing system for genetic editing of the LDHA gene. The specification does not provide any disclosure as to what the complete structure would be of any nucleic acid sequence comprising other mutations in SEQ ID NO: 1166, other than D581R, I926R and V1030G.
As of the filing date, there was no known or disclosed correlation between a structure other than SEQ ID NO: 1166 and comprising mutations D581R, I926R and/or V1030G and a gene editing of the LDHA gene. There is no general knowledge in the art about regarding the activity of one or more mutations in Cas12i2 to suggest that general similarity of structure confers the activity.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the specification teaches two Cas12i2 variants, encoded by SEQ ID NOs 1168 and 1171, and shows that the variants are capable of functioning in vitro by cleaving within an LDHA gene (see starting on pg. 147 with Examples 4, 5, 7).
Alignment of SEQ ID NOs 1168 and 1171 show both comprise D581R, I926R and V1030G substitutions relative to wild-type (i.e., SEQ ID NO: 922). SEQ ID NO: 1171 further comprises a G624R, P868T, E1035R and an S1046R mutation. There is no disclosure as to how these additional substitutions affect Cas12i2 function, or whether a Cas12i2 variant without these substitutions, having only the D581R, I926R and V1030G mutations, would function.
Thus, the specification discloses two Cas12i2 variants within the working examples that are encompassed by the instant claims. Both variants comprise the same D581R, I926R and V1030G substitutions.
This is significant because the prior art teaches that mutations in Cas proteins do not always provide the intended function of editing a target gene. For example, Slaymaker et al. (2016, Science, Vol. 351(6268), pgs. 84-88) teaches methods of mutating Cas9 using a rational mutagenesis to reduce off-target cleavage. Slaymaker, using knowledge of the crystal structure of the Cas9 in contact with target DNA, suspected that non-specific cleavage was a result of positively charged amino acids within the binding pocket, and then mutated 31 positively charged amino acids within the binding pocket to alanine, in order to determine if off-target cleavage was reduced while maintaining target cleavage (See page 84). Each mutant was tested for cleavage of target DNA, as well as known off-target sites. While some of the 31 were capable of maintaining target DNA cleavage, some mutations increased cleavage at off-site locations compared to WT (K862A, K1296A, H1296A and K1300A). Further, a K974A mutation appeared to abolish all cleavage, including cleavage of target DNA (see Fig. S3, reproduced below).
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Thus, Slaymaker shows rational mutagenesis can be used to target specific residues for mutagenesis, but the functional result requires testing and validation.
Further the teachings of Strecker et al., (2019, Nature Communications, Vol. 10 (212), pg. 1-8) demonstrate that Cas12b variants that are more specific for target DNA cleavage with reduced off-target cleavage using rational engineering. Strecker, using the crystalized structure of Cas12b interacting with target DNA, identified 12 amino acid residues within the DNA interacting pocket, and generated 176 single amino acid substitutions (pg. 2, Figs. 2B, 2C, 2D, 2E). In testing cleavage of VEGFA and DNMT1, of the 176 variants, Strecker shows many of the variants have reduced cleavage VEGF compared to wildtype Fig. 2C, and determines that mutations at different residues identified by rational engineering can have different functional effects when tested.
Thus, the prior art teaches that Cas variants using rational engineering demonstrate inconsistency in the effect of the mutations on Cas function. Further, the prior art shows that variants need to be tested in order to validate any function associated with an amino acid substitution. The art shows a single substitution designed to generate a functional effect within a Cas protein may not produce any functional effect.
The specification does not teach any other identifying characteristics such as domains relating to function/activity or any other related sequences that would guide the artisan to contemplate other nucleic acid sequences that would be function to genetically edit the LDHA gene as encompassed by the claims. While the specification does teach success with three specific substitution mutations, this does not demonstrate possession for the breadth of mutations encompassed by the claims.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a Cas12i2 polypeptide comprising one ore mutations in SEQ ID NO: 1166, other than D581R, I926R and V1030G at the time of filing.
Applicants' attention is directed to the decision in Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, which clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
With the exception of the sequences referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides, and therefore conception is not achieve regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only the D581R, I926R and V1030G mutations in SEQ ID NO: 1166, meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the genus of mutations in SEQ ID NO: 1166 thereof as embraced by the claims.
Closest Prior Art
The closest prior art with respect to the claimed invention is set forth in WO2021/202800, which claims priority to US provisional 63/002,999, filed 3/31/2020. WO2021/202800 was published October 7, 2021, which is later than the earliest priority date of the instant application (June 4, 2021). WO2021/202800 is co-owned with the present application, by Arbor Biotechnologies. Thus, a 102(b)(2)(c) exception applies under AIA , barring the WO2021/202800 document from being used in a rejection. Therefore, the prior art fails to teach or suggest a Cas12i2 polypeptide variant with an amino acid structure of the claimed SEQ ID NO: 1166 that further comprises the recited mutations.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6.
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/DAVID A MONTANARI/Examiner, Art Unit 1632
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