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 .
Application Status
This action is written in response to applicant’s correspondence received 07/28/2023. Claims 1-9 are currently pending and are examined herein.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claim 6 is objected to for the following informalities: the claim recites “any one of” claim 1. This appears to be a typographical error introduced by the amendment to remove multiple dependency. Appropriate correction is required.
Claim 4 is objected to for the following informalities: the claim recites “recognizing by homing endonuclease”. This is grammatically incorrect and should be, “recognized by the homing endonuclease”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 4 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 4 is unclear over recitation of “the endonuclease target sequence”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 4 ultimately depends, recites a pair of endonuclease target sequences. It is unclear to which one of the pair claim 4 refers.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 4 recites wherein the endonuclease target sequence is specifically recognized by [the] homing endonuclease. However, claims 2 and 3 recite that the endonuclease is target-specific and specifically cleaves the target sequence. Therefore, the endonuclease target sequence must be, by definition, specifically recognized by the target-specific endonuclease. Therefore, claim 4 fails to further limit the subject matter of the claim(s) upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 6-9 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by U.S. PGPUB 2017/0121691 A1 to Wacker (hereinafter ‘Wacker’).
Regarding claim 1, Wacker teaches a plasmid for recombination, the plasmid comprising a pair of homologous recombination sequences sandwich a gene insertion site, a pair of endonuclease target sequences sandwiching the homologous recombination sequences, and a counter selection marker:
[0006] In one aspect, provided herein are methods for inserting contiguous sequences of DNA, including large, contiguous sequences of DNA, into host cell genomes.
[0015] …wherein the donor plasmid comprises: (i) from 5′ to 3′: (1) the recognition sequence of the restriction endonuclease; (2) a first homology region of at least 0.5 kilobases (kb), (3) a heterologous insert DNA of at least 8 kb; and (4) a second homology region of at least 0.5 kb; and (ii) a counterselection marker.
Please see also FIG. 1, which is a “schematic map of the donor plasmid pDOC-C and relevant elements” (para [0037]) and clearly shows two SceI recognition sites flanking, or sandwiching, the homology regions.
Regarding claim 6, Wacker teaches that the plasmid comprises the gene of interest (see above).
Regarding claims 7-9, Wacker teaches the method for introducing a gene of interest into a host cell (i.e., producing a transformant per Applicant’s definition in para [0002] of the instant specification), as described above, comprising introducing the plasmid of claim 1into a host cell, where the gene of interest is incorporated into the host genome via homologous recombination, the gene of interest is expressed, and the counter selection market functions to induce the death of a host comprising the plasmid (i.e., the unintegrated plasmid):
[0091] In an exemplary embodiment, a method of inserting a large sequence of DNA (i.e., heterologous insert DNA) into the genome of a host cell comprises the use of (i) a donor plasmid comprising (a) heterologous insert DNA flanked by homology regions (HR), e.g., long homology regions (e.g., HR of any appropriate size, e.g., from 0.4-2.0 kb), which direct the site of recombination in the host cell genome (use of such HR increases efficiency of insertion), and (b) a counter selection marker that represses growth of host cells that comprise the donor plasmid, i.e., the non-integrated donor plasmid following introduction of the donor plasmid into the host cell (use of the counter selection marker eliminates false positive clones)
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. PGPUB 2020/0399659 A1 to Onishi (hereinafter ‘Onishi’, published 12/24/2020, effectively filed date 06/24/2019), in view of Wacker (cited above), as evidenced by CD Genomics (CD Genomics Blog. Plasmid Fact Sheet: Definition, Structure and Application. Published 09/25/2019. Accessed online 01/12/2026 at https://www.cd-genomics.com/blog/plasmid-fact-sheet-definition-structure-and-application/).
NOTE: the instant claims enjoy priority to a foreign application JAPAN-20200213177 filed on 12/23/20, however:
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
If applicant files a certified English translation, then a 102(a)(2) based on Onishi would be applicable to the claimed invention.
Regarding claim 1, Onishi teaches a plasmid for transformation comprising a site into which a gene of interest is to be incorporated, a pair of homologous recombination sequences sandwiching the site, a pair of endonuclease target sequences sandwiching the pair of homologous recombination sequences (underlining added for emphasis):
[0016] …the linear genome-introduced nucleic acid fragment comprises the pair of homologous recombination sequences to be incorporated into the predetermined position of the genome at positions sandwiching the gene of interest, the pair of endonuclease target sequences outside of the pair of homologous recombination sequences
The instant specification does not provide an explicit definition for the word “plasmid”. As evidenced by CD Genomics, plasmids are defined as “small circular or linear double-stranded DNA molecules”. The broadest reasonable interpretation of the word “plasmid” in instant claim 1 therefore encompasses linear and circular DNA molecules. Under that interpretation, Onishi teaches a linear plasmid.
Onishi does not teach that the plasmid comprises a counter selection marker.
Wacker teaches a plasmid for recombination, the plasmid comprising the same elements and a counter selection marker:
[0006] In one aspect, provided herein are methods for inserting contiguous sequences of DNA, including large, contiguous sequences of DNA, into host cell genomes.
[0015] …wherein the donor plasmid comprises: (i) from 5′ to 3′: (1) the recognition sequence of the restriction endonuclease; (2) a first homology region of at least 0.5 kilobases (kb), (3) a heterologous insert DNA of at least 8 kb; and (4) a second homology region of at least 0.5 kb; and (ii) a counterselection marker.
Wacker teaches that the counter selection marker is used to repress growth of host cells that comprise the non-integrated plasmid (para [0091]).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the plasmid for recombination as taught by Onishi with the counter selection marker as taught by Wacker, to achieve the predictable result of a plasmid for recombination which can be used to eliminate cells which have not successfully undergone recombination, as an additional verification and quality control mechanism.
Regarding claim 2, Onishi teaches the plasmid comprising an expressible, target-specific endonuclease gene that cleaves the double strands of the target sequence:
[0017] (12) The transformation method according to the above (9), wherein the helper plasmid for transformation comprises a target-specific endonuclease gene that specifically cleaves the double strands of the endonuclease target sequences in an expressible state.
Regarding claim 3, Onishi teaches that the target-specific endonuclease is a homing endonuclease:
[0017] (19) The helper plasmid for transformation according to the above (18), wherein the target-specific endonuclease gene is a homing endonuclease gene.
Regarding claim 4, Onishi teaches wherein the endonuclease target sequence is specifically recognized by the homing endonuclease (see above).
Regarding claim 5, Onishi teaches that the plasmid comprises an inducible promoter which regulates the expression of the endonuclease:
[0048] Moreover, as shown in FIG. 4, the helper plasmid for transformation according to the present disclosure may comprise an inducible promoter and an endonuclease gene. For the expression of an endonuclease gene, not only an inducible promoter, but also a constant expression promoter may be used.
Regarding claim 6, Onishi teaches that the plasmid comprises the gene of interest (para [0015]).
Regarding claims 7-9, Onishi in view of Wacker render obvious the method of producing a transformant, comprising introducing the plasmid into a host cell, incorporation of the gene of interest into the host genome via homologous recombination, and counter selection of host cells comprising the unintegrated plasmid (see above).
Claims 2-5 are rejected under 35 U.S.C. 103 as being unpatentable over Wacker (cited above), as applied to claims 1 and 6-9 in the rejection of the claims under 35 U.S.C. §102 above, in view of David (Florian David et al. Advances in yeast genome engineering. FEMS Yeast Research, Volume 15, Issue 1, February 2015, Pages 1-14.; of record, applicant’s submission), as evidenced by Moure (Moure et al. Crystal structures of I-SceI complexed to nicked DNA substrates: snapshots of intermediates along the DNA cleavage reaction pathway. Nucleic Acids Res. 2008 Apr 19;36(10):3287–3296.).
Wacker anticipates the limitations of claims 1 and 6-9, as already described.
Regarding claims 2-5, Wacker further teaches that the endonuclease recognition sites are specifically recognized by a SceI homing endonuclease:
[0037] …SceI: homing endonuclease restriction site for mobilizing the DNA from the donor plasmid
[0118] In a specific embodiment, the endonuclease encoded by the helper plasmids described herein is SceI. SceI is a member of the LAGLIDADG (SEQ ID NO: 1) DNA endonuclease family. This is a family of site-specific DNA endonucleases encoded by DNA mobile elements. Functionally, SceI is a homing restriction endonuclease that cuts an 18-base pair recognition sequence TAGGGATAACAGGGTAAT (SEQ ID NO: 3), that never occurs in the E. coli genome. The specific, rare and long recognition sequence is crucial for its application in for the invention. In certain embodiments, the SceI is under the control of an inducible promoter, e.g., the arabinose promoter.
Moure evidences that SceI specifically cleaves double-stranded DNA (Abstract).
Wacker does not teach that the gene encoding the endonuclease is on the same (termed ‘donor’) plasmid. Instead, Wacker teaches that the gene is present on a helper plasmid, under the control of an inducible promoter (see above).
David teaches a variety of plasmid configurations for recombination which all comprise some combination of homologous recombination sequences, endonuclease recognition sites, selection markers, and, in multiple cases, an expression cassette for a SceI endonuclease (see Figure 1, especially (b) and (d). These include systems such as the TREC system (Figure 1(b)), which places the SceI coding sequence on the same plasmid as the other elements. David also states that methods that “require as few transformation steps as possible” are preferred (p. 2 1st para). Therefore, David provides a teaching, suggestion or motivation to limit the number of plasmids which must be constructed and introduced to the host cell, because this would have reduced the number of transformation steps.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the donor and helper plasmids for recombination, collectively comprising all of the recited elements, as taught by Walker, with the single plasmid approach as taught by David. One having ordinary skill would have been motivated to do so based on David’s teachings that these elements could be combined on a single plasmid, and on David’s teachings that methods of recombination preferably should require as few transformation steps as possible.
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 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-7 of U.S. Patent No. 12,338,454 B2 in view of Wacker (cited above).
Regarding claims 1 and 6, patented claims 1 and 5 recite a methods of producing a transformed yeast host comprising a plasmid which comprises the gene of interest, a pair of homologous recombination sequences, and a pair of endonuclease target sequences, wherein the circular plasmid is cleaved at the target sites to produce a fragment comprising the gene and the recombination sequences. This indicates that the structure of the plasmid has the endonuclease target sequences sandwiching the homologous sequences and gene of interest, because otherwise the fragment would not include those elements.
Patented claims 1 and 5 do not recite that the plasmid has a counter selection marker. However, Wacker teaches plasmids for transformation which comprise counter selection markers to induce the death of host cells which have the unintegrated plasmid, as already described above. It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the construct used in the method of patented claim 1 by adding a counter select marker to eliminate non-transformed cells, as taught by Wacker. The ordinary artisan would have been motivated to do so and would have a reasonable expectation that such an element could be successfully included based on Wacker’s teachings that the inclusion of such a marker yields a functional plasmid able to eliminate un-transformed cells.
Regarding claims 2 and 4, patented claims 1 and 5 recites that the plasmid comprises a gene encoding the endonuclease that specifically cleaves double strands of the endonuclease target sequences.
Regarding claim 3, patented claims 2 and 6recite that the endonuclease gene is a homing endonuclease.
Regarding claim 5, patented claims 3 and 7 recite that the plasmid comprises an inducible promoter that regulates expression of the endonuclease gene.
Regarding claims 6-9, these merely recite methods using the plasmid and describe outcomes in which the gene of interest undergoes homologous recombination and is incorporated into the host genome, as recited in patented claims 1 and 5, and further recite that a counter selection marker is used to eliminate non-transformed hosts, which is rendered obvious by Wacker.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636