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 .
Track One Status
A Track One Request has been submitted on 29 September 2025 for the instant application. The Track One Request was granted 24 November 2025.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for Figure 6 that appear on several sheets are followed by "Cont." instead of a capital letter such as FIG. 1A, FIG. 1B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1 and 11 are objected to because of the following informalities:
Regarding claims 1 and 11, the claims recites the phrase “SEQ ID No. 535” in line 2 (see Claim 1) and line 3 (see Claim 11) of the claims. MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.” Accordingly, the phrases should read “SEQ ID NO:”.
Regarding claim 11, the claim recites the phrase “wherein the engineered nucleases comprises an amino acid sequence the engineered nuclease comprises an amino acid sequence” in lines 1-2 of the claim. The repeated phrase should be deleted from the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 8-10 and 15-16 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Regarding claims 8-10 and 15-16, the claims recite a cell comprising the claimed composition. The instant specification teaches that the claimed cell may be a human cell and in some cases the cell is in vivo (Instant specification; [0296]). Accordingly, since the in vivo application of a cell would necessarily mean that the cell residues or will residue in a subject, the claimed cell encompasses a human cell in a human subject.
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 1-16 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.
Regarding claim 1, the claim is broadly drawn towards a composition comprising a nuclease that comprises an amino acid sequence with at least 90% identity to the claimed SEQ ID NO: 535, wherein the nuclease comprises an arginine at position 156 and an arginine at position 547 relative to the numbered positions of the claimed SEQ ID NO: 535.
Accordingly, the claims are interpreted as claiming a nuclease that comprises an amino acid sequence with at least 90% identity to the claimed SEQ ID NO: 535, wherein the nuclease comprises an arginine at position 156 and an arginine at position 547 relative to the numbered positions of the claimed SEQ ID NO: 535.
The instant specification does not provide support for the broadly claimed nuclease and the prior art provides evidence that the sequence of the claimed SEQ ID NO: 535 was not well known.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would leave one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP 2163. A claimed genus may be satisfied through sufficient descriptions of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with known or disclosed correlation between function and structure. MPEP 2163(3)a(II). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
As the claims currently recite, as described above, the claim is directed towards a nuclease that comprises an amino acid sequence with at least 90% identity to the claimed SEQ ID NO: 535, wherein the nuclease comprises an arginine at position 156 and an arginine at position 547 relative to the numbered positions of the claimed SEQ ID NO: 535. While claiming a genus of structures is not prohibited, there must be a sufficient number of species described in the specification such that the claimed genus was represented by a representative number of species or the teachings of the specification, or, the prior art can be used to support a well-known structure-function relationship.
In the instant case, the instant specification does not provide support for the broadly claimed nuclease. Further, the prior art demonstrates that structural analysis of Cpf1 proteins is required in order to understand their functional domains, Cpf1 is a diverse family of proteins which does not always share homology within the family, and that further efforts are needed to fully understand the structure and mechanism of these proteins.
Working Examples
With regard to working examples, the specification provides little evidence on the possession of a sufficient number of species which are encompassed by the entirety of the claimed genus.
MPEP 2163 teaches that “for some arts, there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement. Information which is well known in the art need not be described in detail in the specification. See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed [emphasis added].”
In the instant case, the specification does not teach the use of the claimed SEQ ID NO: 535. The instant specification does teach the measurement of editing efficiency of 26 different nucleases, identified by their respective SEQ ID NOs, that were tested in HEK293T cells ([0373]; see FIG. 7). However, the instant specification does not teach that the claimed SEQ ID NO: 535’s editing efficiency was measured. Further, the instant specification does not teach if the claimed arginines at positions 156 and 547 in the claimed SEQ ID NO: 535 are directed towards amino acids that have been mutated or if the arginines are the wild-type amino acids at the claimed positions. Further, the Applicant has offered seven examples in the specification (Examples 1-7, pages 102-107). Examples 1-6 concern nucleases encoded by SEQ ID NOs 1-7, where these nucleases are characterized (editing efficiency, PAM site analysis, etc.), and thus do not concern SEQ ID NO 535. In the final example, the Applicant tested 26 nucleases, one of which was SEQ ID NO 341, which matches 1233/1235 residues of SEQ ID NO 535 (i.e., 99.8% sequence identity, Figure 7 and 8C; see attached sequence alignment). SEQ ID NO: 341 does not comprise an arginine at positions 156 and 547 relative to the claimed positions of the claimed SEQ ID NO: 535. The Applicant has therefore not tested a nuclease encoded by SEQ ID NO 535 that comprises an arginine at positions 156 and 547, but has tested a nuclease of very similar sequence and structure (i.e., SEQ ID NO 341, Figures 7 and 8C). The Applicant provided no functional data on any other mutations of SEQ ID NO 535 with the exception of SEQ ID NO 341, which comprises two mutations to SEQ ID NO 535 (i.e., SEQ ID NO 341 does not comprise an arginine at positions 156 and 547). Thus, the Applicant has not tested or identified functional regions of SEQ ID NO 535, or which regions are critical for its capacity to act as a nuclease, wherein the claimed SEQ ID NO 535 comprises an arginine at positions 156 and 547.
Thus, when taken as a whole, the nucleases described in the specification is not representative of the claimed genus as a whole because the claimed genus is directed towards a nuclease that comprises an amino acid sequence with at least 90% identity to the claimed SEQ ID NO: 535, wherein the nuclease comprises an arginine at position 156 and an arginine at position 547 relative to the numbered positions of the claimed SEQ ID NO: 535 while the nucleases in the specification do not fall within the claimed genus.
Therefore, the instantly claimed nuclease present in claim 1 is not adequately described in the specification.
Thus, the instant specification does not provide written description for the entirety of the claimed nuclease that comprises an amino acid sequence with at least 90% identity to the claimed SEQ ID NO: 535, wherein the nuclease comprises an arginine at position 156 and an arginine at position 547 relative to the numbered positions of the claimed SEQ ID NO: 535 (see Claims 1 and 11).
Prior Art
Regarding the state of the prior art, the prior art teaches that although a nuclease comprising at least 90% identity to the claimed SEQ ID NO: 535 was known, structural analysis of Cpf1 proteins is required in order to understand their functional domains, Cpf1 is a diverse family of proteins which does not always share homology within the family, and that further efforts are needed to fully understand the structure and mechanism of these proteins
With regard to the closest prior art, GenBank MBR6223972 (GenBank accession number MBR6223972, published 22 April 2021) discloses a nuclease that has a 99% match (at least 90% and/or 95%, per claims 21-22, respectively), to the claimed SEQ ID NO: 535 (see pg. 1 of attached sequence alignment). GenBank MBR6223972 teaches that the claimed nuclease is a naturally occurring Cpf1 protein of Lachnospiracae bacterium (see pg. 3-4 of attached sequence alignment).
However, GenBank MBR6223972 does not teach or suggest that the nuclease sequence comprises an arginine at positions 156 and 547.
With regards to the state-of-the-art, Safari (Cell Biosci. 2019 May 9;9:36) is a review article which discusses Cpf1 (Cas12a) proteins (Abstract). Note that, as evidenced by GenBank MBR6223972, a protein with over 90% homology to SEQ ID NO 535 is identified as a Cpf1 protein (pages 1-2). Safari teaches that Cpf1 proteins are a diverse family of proteins (page 2, right column, second paragraph). Furthermore, Safari teaches that of these non-redundant family proteins, 16 were studied for functional analysis, where only eight were found to induce efficient cleavage on target DNA (page 2, right column, second paragraph). Thus, Safari teaches that Cpf1 proteins are a diverse protein family which requires functional analysis to determine nuclease efficacy. Furthermore, Safari teaches that uncharacterized Cpf1 proteins have varying homology/structural similarity with well-studied orthologs (page 3, left column, second paragraph). Safari further teaches that structural analysis is required to determine active functional domains of Cpf1 proteins (page 2, right column, third paragraph). Safari teaches that efforts are ongoing in order to understand the structure and mechanism of action of Cpf1 proteins (page 17, right column, fourth paragraph).
Thus, overall, Safari teaches that structural analysis of Cpf1 proteins is required in order to understand their functional domains, that Cpf1 is a diverse family of proteins which does not always share homology within the family, and that further efforts are needed to fully understand the structure and mechanism of these proteins.
Conclusion
The specification does not identify a representative number of species of the broadly claimed nuclease that comprises an amino acid sequence with at least 90% identity to the claimed SEQ ID NO: 535, wherein the nuclease comprises an arginine at position 156 and an arginine at position 547 relative to the numbered positions of the claimed SEQ ID NO: 535. Further, the prior art shows that prior to the effective filing date of the claimed invention that the structure of the claimed nuclease was not well known and that rigorous structural analysis of Cpf1 proteins is required in order to understand their functional domains. Therefore, a person of ordinary skill in the art would not have concluded that Applicant was in possession of the invention as claimed. Thus, claims 1 and 11 are rejected under 35 U.S.C. 112(a).
Regarding claims 2-10 and 12-16, as the claims are ultimately dependent on claims 1 and 11 and do not rectify the 35 USC 112(a) rejection above, the claims are also rejected under 35 USC 112(a).
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 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21, 24-25, 27-28, and 32034 of copending Application No. 19/056,045 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1-3 and 11, copending claim 21 claims the use of an engineered nuclease that comprises the amino acid sequence of SEQ ID NO: 535. The copending SEQ ID NO 535 has 100% identity to the claimed SEQ ID NO: 535 and comprises an arginine at position 156 and an arginine at position 547 relative to the numbered positions of the claimed SEQ ID NO: 535 (see attached sequence alignment).
Regarding claims 4-5, copending claims 24-25 claim identical limitations.
Regarding claims 6-7, copending claims 27-28 claim identical limitations.
Regarding claims 8-10, copending claims 32-34 claim identical limitations.
Claims 12-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21, 24-25, 27-28, and 32-34 of copending Application No. 19/056,045 as described above, further in view of Safari (Cell Biosci. 2019 May 9;9:36).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 12-16, copending claims 21, 24-25, 27-28, and 32-34 of copending Application No. 19/056,045 anticipate claims 1-11 as described above.
The copending claims do not teach or suggest the use of a nucleic acid encoding the engineered nuclease of claim 11 (Claim 12) or a vector comprising the nucleic acid (Claim 13). The copending claims do not teach or suggest the use of the claimed nucleases in a method of modifying a target nucleic acid (Claim 14), wherein the target nucleic acid is present within a mammalian cell (Claims 15-16).
However, one of ordinary skill in the art would have considered the teachings of Safari as both references are common fields of endeavor pertaining to the study of Cpf1 proteins.
As discussed above, Safari is directed towards a review study concerned with Cpf1 proteins (Abstract). Safari further teaches that Cpf1 can be utilized to edit target nucleic acids of interest within human hepatocytes (i.e., mammalian cells) via the delivery of an Ad-vector comprising a nucleic acid encoding a Cpf1 protein to the cell (pg. 7). Safari teaches that the Ad vector provide lower immunogenicity than AAV vectors and are safer for therapeutic applications of the Cpf1 protein (pg. 7).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the copending claims nuclease such that a vector comprising a nucleic acid encoding the nuclease was utilized to modify a target nucleic acid in a mammalian cell, as described by Safari. A person of ordinary skill in the art would have been motivated to do so in order to edit a target nucleic acid of interest within a mammalian cell via the use of a safe therapeutic means of delivery of the Cpf1 protein. A person of ordinary skill in the art would have had a reasonable expectation of success because both the copending claims and Safari teach the use of a Cpf1 nuclease.
Subject Matter Eligibility
Regarding the claimed SEQ ID NO: 535, the claimed nuclease is eligible subject matter under 35 USC 101 because its naturally occurring counterpart, described in GenBank MBR6223972 (GenBank accession number MBR6223972, published 22 April 2021), discloses a nuclease that has a 99% match to the claimed SEQ ID NO: 535 (see pg. 1 of attached sequence alignment) but does not comprise an arginine at positions 156 and 547, as claimed. Accordingly, the claimed SEQ ID NO: 535 is not directed towards a product of nature and possesses markedly different characteristics when compared to its naturally occurring counterpart.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636