DETAILED ACTION
The Amendment filed January 26 2026 has been entered.
Claims 1-20 are cancelled.
Claims 21 and 31 are currently amended.
Claims 21-35 are pending.
Claims 22-30 and 32-35 are withdrawn.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
All previous objections and rejections not set forth below have been withdrawn.
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 .
Withdrawn Claim Objection
The objection to claim 31 is withdrawn in light of the amendment of claim 31.
Claim Objections
Claims 22-30 and 32-35 are objected to because of the following informalities: claims 22-30 and 32-35 have incorrect status identifiers – the correct status identifier for claims 22-30 and 32-35 is “withdrawn”. See page 2 of the Office Action mailed November 10, 2025.
Claim Rejections - 35 USC § 112
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.
Claims 21, and claim 31 DEPENDENT THEREON, are 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. This rejection is modified in light of the amendment of claim 21.
Claim 21 is indefinite because there is insufficient antecedent basis for “the cleaved site specific nuclease binding sites that flank the donor polynucleotide” in part e., as only a single site specific nuclease binding site is said to flank the donor polynucleotide in part b.
Response to Arguments
Applicant’s assertion that the amendment of claim 21 overcomes the previous rejection of claim 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is acknowledged. The rejection is maintained however in light of the issue of antecedent basis raised by the amendment of claim 21, as set forth above.
Claim Rejections - 35 USC § 103
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
Claims 21 and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ainley et al. (U.S. Patent Application Publication No. 2011/0191899, published Aug. 4, 2011) in view of Church et al. (U.S. Patent Application No. 2018/0171361, published Jun. 21, 2018).
Claim 21 as currently amended is drawn to a method for targeted excision of a donor polynucleotide from a plant genome, the method comprising the following steps:
a. Stably inserting the donor polynucleotide sequence within the plant genome;
b. Introducing a site specific nuclease to bind a first site specific nuclease binding site, wherein the first site specific nuclease binding site flanks the donor polynucleotide;
c. Cleaving the first site specific nuclease binding site;
d. Removing the donor polynucleotide sequence from the plant genome;
e. Recombining the cleaved site specific nuclease binding sites that flank the donor polynucleotide, wherein the recombined site specific nuclease binding site is identical to the first site specific nuclease binding site;
f. producing a genome comprising the site specific nuclease binding site stably integrated within the genome.
Claim 31 as currently amended is drawn to the method of claim 21, the method further comprising the steps of:
g. Targeting the recombined site specific nuclease binding site with the site specific nuclease;
h. Cleaving the recombined site specific nuclease binding site with the site specific nuclease;
i. Introducing a second donor polynucleotide sequence;
j. Integrating the second donor polynucleotide sequence within the cleaved site specific nuclease binding site; and
k. Producing a genome comprising the second donor polynucleotide sequence stably integrated within the plant genome.
Ainley et al. teach the introduction of an engineered landing pad (ELP) into a genome of a host organism in order to facilitate the integration and excision of further nucleic acid molecules of interest into the host organism, including a host organism that is a plant (paragraphs [0037];[0038]). The integration of further nucleic acid molecules of interest into the host organism can be accomplished by a methods that comprise stably inserting a donor polynucleotide sequence (e.g. a transgene) within a plant genome, introducing a site specific nuclease (e.g., an engineered zinc finger nuclease, or eZFN) to bind a site specific nuclease binding site, wherein the site specific nuclease (i.e., a targeting endonuclease) binding site flanks the donor polynucleotide, cleaving at least one site specific nuclease binding site, removing the donor polynucleotide sequence from the plant genome, and recombining (repairing by non-homologous end-joining or by homologous single-strand repair) the site specific nuclease binding sites that flank the donor polynucleotide. The methods may further comprise targeting the recombined site specific nuclease binding site with the site specific nuclease, cleaving the recombined site specific nuclease binding site with the site specific nuclease, introducing a second donor polynucleotide sequence, integrating the second donor polynucleotide sequence within the cleaved site specific nuclease binding site, and producing a genome comprising the second donor polynucleotide sequence stably integrated within the plant genome (paragraphs [0008]; [0069]; [0144]; [0146]; [0152]; [0158]; claim 16).
Ainley et al. do not explicitly teach that the recombined site specific nuclease binding site is identical to the site specific nuclease binding site prior to recombination.
Church et al. teach in paragraph [0087]:
“It is generally understood that dsDNA cuts may be repaired either by non-homologous end joining (NHEJ) or Homologous Repair (HR), and that while HR can create precise copies of a DNA template sequence at the cut site given the presence of a template with suitable homology arms, NHEJ can generate mutations (especially indels) and is often considered “error prone.” However, there is also evidence that NHEJ can also repair dsDNA cuts highly accurately (11, 12), and the relative rates of mutated vs. perfect repair by NHEJ have never been precisely measured. Especially when efficient targeted nucleases such as Cas9 are expressed for protracted time periods, perfect repair of a cut site by either NHEJ or HR would regenerate a target site that could be cut again.”
References 11 and 12 cited by Church et al. being Byrne et al. (Multi-kilobase homozygous targeted gene replacement in human induced pluripotent stem cells. Nucleic Acids Res. 2015 Feb 18;43(3):e21. Epub 2014 Nov 20) and Betermier et al. (Is non-homologous end-joining really an inherently error-prone process? PloS Genet. 2014 Jan;10(1):e1004086. Epub 2014 Jan 16).
Given the teachings of Ainley et al. that an intervening polynucleotide sequence in a stably integrated engineered landing pad site can be flanked by one or more eZFN binding sites, and that following cleavage and excision by a site-specific nuclease, a site specific nuclease binding site in an engineered landing pad site in a plant genome can be repaired by non-homologous end joining or by homologous single-strand repair, and subsequently retargeted, and given the teachings of Church et al. that the repair of dsDNA cuts by non-homologous end joining (NHEJ) or Homologous Repair (HR) can be error-free as well as error prone, 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 that the methods taught by Ainley et al. could result in the production of a stably integrated recombined site specific nuclease binding site that is identical is identical to the site specific nuclease binding site prior to recombination. One skilled in the art would have recognized the production of a stably integrated recombined site specific nuclease binding site that is identical is identical to the site specific nuclease binding site prior to recombination as one of several alternative predictable outcomes of practicing the method of Ainley et al., because the inherent cellular processes of DNA repair and their effects were known in the art before the effective filing date of the claimed invention, as evidenced by Church et al. Thus, the claimed invention would have been prima facie obvious as a whole to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicant's arguments filed January 26 2026 have been fully considered but they are not persuasive.
Applicant traverses the rejection and maintains that Church fails to cure Ainley. In this regard Applicant cites the following sentence of Church Par [0087] "[a] plausible hypothesis is that the process of perfect repair and re-cutting would occur repeatedly until a mutation arose that destroyed the nuclease's ability to recognize the target site". Applicant also points out that this sentence follows the cited passage of Church Par [0087] provided at page 6 of the instant office action. Applicant maintains, accordingly, that Par [0087] of Church concludes that while there may be 'perfect repair of a cut site', that 'perfect repair and re-cutting would occur repeatedly until a mutation arose that destroyed the nuclease's ability to recognize the target site', and the he proposed combination of applying Church to cure Ainley would therefore arrive at a result inconsistent with the pending claims of the instant application.
Applicant also maintains that the Office fails to provide an articulated rationale explaining why a person of ordinary skill in the art would have been motivated to modify Ainley with the teachings of Church. Applicant notes, for instance, that Church describes a different application of site specific nuclease technology that is for elimination of PERV elements in mammalian cells, whereas comparatively the instant application and Ainley are related to plant cells. Applicant maintains that one with skill in the art would not rely upon a disclosure for inactivating an endogenous gene from the pig genome to removing a donor integrated polynucleotide from the plant genome. Applicant further points to Par [0061] of Church that the pig genome contains a few to several dozen copies of these PERV elements, and in summary Par [0067] of Church states that the "methods thus open the possibility of editing repetitive regions of biological significance." Applicant maintains that those with skill in the art would appreciate that a disclosure for targeting repetitive gene sequences is considerably distinct from targeting two site specific nuclease binding sites which flank a donor polynucleotide to release that donor polynucleotide, and that as such, a person of ordinary skill in the art would not have reasonably considered Church when attempting to solve the problem addressed by the claimed invention.
Applicant's arguments are not persuasive.
With respect to Applicant’s reliance on paragraph [0087] of Church, this is not persuasive because the conclusion that perfect repair and re-cutting can occur repeatedly until a mutation arises that destroys the nuclease's ability to recognize the target site was made in reference to the expression of efficient targeted nucleases such as Cas9 for protracted time periods; further, the conclusion does not negate the fact that it was known in the art that the repair of dsDNA cuts by non-homologous end joining (NHEJ) or Homologous Repair (HR) can be error-free as well as error prone. Accordingly one skilled in the art would have recognized the production of a stably integrated recombined site specific nuclease binding site that is identical is identical to the site specific nuclease binding site prior to recombination as one of several alternative predictable outcomes of practicing the method of Ainley et al.
With respect to Applicant’s assertion that the Office fails to provide an articulated rationale explaining why a person of ordinary skill in the art would have been motivated to modify Ainley with the teachings of Church, this is not persuasive because the outstanding rejection is not predicated on modifying Ainley with the teachings of Church. The outstanding rejection is predicated on what was known in the art with respect to the repair of dsDNA cuts by non-homologous end joining (NHEJ) or Homologous Repair (HR). Church teaches that that it was known in the art that the repair of dsDNA cuts by non-homologous end joining (NHEJ) or Homologous Repair (HR) can be error-free as well as error prone, with reference to the prior art of Byrne et al. (Multi-kilobase homozygous targeted gene replacement in human induced pluripotent stem cells. Nucleic Acids Res. 2015 Feb 18;43(3):e21. Epub 2014 Nov 20) and Betermier et al. (Is non-homologous end-joining really an inherently error-prone process? PloS Genet. 2014 Jan;10(1):e1004086. Epub 2014 Jan 16). Accordingly one skilled in the art would have recognized the production of a stably integrated recombined site specific nuclease binding site that is identical is identical to the site specific nuclease binding site prior to recombination as one of several alternative predictable outcomes of practicing the method of Ainley et al., even though Ainley et al. is silent with respect to whether any recombined site specific nuclease binding site produced by practicing their method is identical to the site specific nuclease binding site prior to recombination.
In response to Applicants' allusion that Church is nonanalogous art because Church is a reference focused on mammalian (pig) cells and genes, it has been held that a prior art reference must either be in the field of applicant's endeavor or, if not, then be reasonably pertinent to the particular problem with which the applicant was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Church is analogous art, because it is well understood in that cellular mechanisms for DNA repair are conserved across kingdoms. See, for example, Dudas et al. (DNA double-strand break repair by homologous recombination Mutat. Res. 2004 Mar;566(2):131-67, page 132 paragraph spanning columns 1 and 2).
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 21 and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of U.S. Patent No. 11634721. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 21 and 31 of the instant application are drawn to methods for targeted excision of a donor polynucleotide from a plant genome wherein recombination of site specific nuclease binding site(s) that flank the donor polynucleotide produces a recombined site specific nuclease binding site that is identical to the site specific nuclease binding site(s) that flanked the donor polynucleotide.
Claims 1 and 11 of U.S. Patent No. 11,634,721 are drawn to methods for producing a repaired site specific nuclease binding site in a plant genome wherein recombination of site specific nuclease binding sites that flank the donor polynucleotide produces a recombined site specific nuclease binding site that is identical to one of the site specific nuclease binding sites that flanked the donor polynucleotide.
The claims at issue are not identical because the methods of claims 1 and 11 of U.S. Patent No. 11,634,721 utilize two identical site specific nuclease binding sites that are located within 3,000 bp to 4,000 bp of each other, whereas the methods of claims 21 and 31 of the instant application are nonspecific with respect to the number, identity and location of the site specific nuclease binding sites used. Accordingly, the methods of claims 1 and 11 of U.S. Patent No. 11,634,721 are species within the genus of the methods of claims 21 and 31 of the instant application.
Response to Arguments
Applicant's assertion that they respectfully defer responding to the provisional non-statutory double patenting rejection until allowable subject matter has been found in the instant application, and that upon allowance of the instant application the Applicants will timely file a terminal disclaimer, is acknowledged. As there is currently no allowable subject matter indicated, the rejection is maintained.
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.
Remarks
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CYNTHIA E COLLINS whose telephone number is (571)272-0794. The examiner can normally be reached M-F 8:30 am - 5:00 pm.
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/CYNTHIA E COLLINS/Primary Examiner, Art Unit 1662
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