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
1. Applicant’s election of Group II (claims 39-51) and species WUS polypeptide and Cas endonuclease in the reply filed on July 13, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 27-51 are pending. Claims 27-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Accordingly claims 39-51 in conjunction with species WUS polypeptide and Cas endonuclease are examined on merits in the present Office action. This restriction is made Final.
Applicant is reminded that upon the cancellation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Information Disclosure Statement
2. Initialed and dated copies of Applicant’s IDS form 1449 filed in the papers March 26, 2025 and November 1, 2024 are attached to the instant Office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
3. Claims 44, 46, 49 are objected to because of the following informalities:
Claim 44 is objected for having non-elected subject matter. The non-elected subject matter: WOX polypeptide, BBM polypeptide and ODP2 polypeptide.
Claim 46 is objected for reciting “the maternal haploid embryo” which lacks antecedent basis. It appears to be typing error. Claim 46 should be dependent on claim 45 for proper antecedent basis.
Claim 49 is objected for having non-elected subject matter. The non-elected subject matter: zinc finger nuclease, a meganuclease, a TALEN.
Appropriate correction and/or clarifications is required.
Claim Rejections - 35 USC § 103
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
4. Claims 39-46 and 48-50 are rejected under 35 U.S.C. § 103 as being unpatentable over Lowe et al. (The Plant Cell, 28:1998-2015, 2016) in view of Svitashev et al. (Plant Physiology,169:931–945, 2015) and further in view of Kelliher et al. (Nature, 542:105–109, 2017).
Lowe et al. teach methods for transforming monocot plant cells and regenerating plants through use of the morphogenic regulators Baby boom (“Bbm”) and Wuschel2 (“Wus2”). Lowe et al. further teach that expression of Bbm and Wus2 substantially increases transformation frequency, stimulates somatic embryogenesis, broadens the range of transformable maize genotypes, and permits transformation and regeneration from additional explant types. Lowe et al. further teach providing plant cells with polynucleotides encoding the Bbm and Wus2 morphogenic polypeptides through in vitro transformation methods. The morphogenic-regulator expression constructs are introduced into maize explants through Agrobacterium-mediated transformation, and Lowe et al. also discuss biolistic transformation as a method for introducing genetic constructs into plant material. Lowe et al. further teach that Wus2 exhibits non-cell-autonomous activity. Lowe et al. clearly teach morphogenic stimulation resulting from non-cell-autonomous Wus2 activity and shows tissue containing transgenic and nontransgenic sectors. Lowe et al. further explain that Wus2 expressed by one cell or group of cells can stimulate embryogenic growth in neighboring cells that do not themselves contain the Wus2 transgene. Lowe et al. further teach that cells containing a Wus2 expression construct stimulate embryogenic growth in neighboring cells receiving a different T-DNA. Thus, Lowe teaches a first cell expressing a morphogenic polypeptide and a second neighboring cell that does not contain the morphogenic-polypeptide construct but nevertheless receives the benefit of non-cell-autonomous morphogenic activity. Lowe et al. further teach a separate-strain transformation arrangement. One Agrobacterium strain carries a Wus2-containing T-DNA, while another Agrobacterium strain carries a different T-DNA. Cells receiving the second T-DNA can receive the morphogenic benefit of Wus2 expressed by neighboring cells without themselves necessarily incorporating the Wus2 T-DNA. Lowe et al. further teach constructs containing multiple functional expression cassettes. The disclosed transformation constructs combine morphogenic-regulator expression cassettes with selectable-marker and other functional cassettes for delivery during plant transformation. Lowe et al. further teach recovery of embryogenic plant material and regenerated plants that receive the developmental benefit of morphogenic-regulator activity while avoiding persistent expression of the morphogenic regulator. Lowe et al. teach both non-cell-autonomous Wus2 activity and excision strategies for removing Bbm and Wus2 expression cassettes before plant regeneration. Thus, Lowe et al. expressly identifies Bbm and Wus2 as morphogenic regulators useful for inducing embryogenic growth and improving plant regeneration. Wus2 is a WUS/WOX-family morphogenic polypeptide, and Bbm is a Baby boom morphogenic polypeptide. See in particular, Abstract; Table 1, Figures 1-5, accompanying discussion pages 1999-2009; materials and methods, pages 2009-2012, supplemental data attached at the end of reference.
Lowe et al. do not expressly teach that the starting population of plant cells is a population of haploid plant cells. Lowe’s principal experiments concern immature maize embryos and other monocot explants that are not identified as haploid plant-cell populations. Lowe et al. do not expressly teach modifying a selected genomic DNA target site using a site-specific gene-editing component such as a Cas endonuclease operating with a guide RNA. Lowe et al. also do not expressly teach obtaining a doubled haploid embryo from an edited somatic embryo and regenerating a modified plant from that doubled haploid embryo. Lowe et al. further do not expressly teach a maternal haploid embryo produced by pollination of a female parent plant with pollen from a male haploid-inducer parent.
Svitashev et al. teach targeted mutagenesis, precise gene editing, and site-specific gene insertion in maize using Cas9 and guide RNA. Svitashev et al. teach introduced DNA vectors expressing maize codon-optimized Streptococcus pyogenes Cas9 endonuclease and single guide RNAs into maize immature embryos by biolistic transformation. Targeted mutations were obtained at selected endogenous genomic sites, and regenerated plants containing the resulting genomic modifications were recovered. Svitashev et al. thus teach a gene-editing component encoded by a polynucleotide sequence and introduced by an in vitro particle-gun or biolistic delivery method. The Cas9 and guide-RNA expression vectors were cointroduced into maize immature embryos and modified selected endogenous DNA target sites. Svitashev et al. further expressly teach a site-specific nuclease in the form of Cas9 endonuclease. The reference further teaches providing single guide RNAs that function with Cas9 to recognize, cleave, and modify selected genomic targets. Svitashev et al. additionally teach direct biolistic delivery of guide RNA molecules into maize immature embryo cells containing preintegrated Cas9. The delivered guide RNAs operated with Cas9 to produce targeted mutations at selected genomic sites.
Svitashev et al. thus supplies the gene-editing teachings not expressly disclosed by Lowe, including a polynucleotide-encoded gene-editing component, in vitro particle-gun delivery, modification of a selected genomic DNA target site, use of a site-specific nuclease in the form of Cas9, provision of a guide RNA, and operation of Cas9 with guide RNA to perform targeted genomic modification. See in particular, abstract, Figures 1-4, Tables I-V, results, discussion and materials and methods, pages 932-left column of page 942, attached supplemental data.
Kelliher et al. teach maternal haploid induction in maize using male haploid-inducer plants. Kelliher et al. further teach identification of MATRILINEAL (“MTL”), a sperm-specific phospholipase, as a genetic factor responsible for maize haploid induction and reports production of maternal haploid progeny following pollination involving pollen carrying the haploid-induction genotype. Kelliher et al. further teach that doubled haploid individuals are derived from chromosome-doubled haploid cells and that doubled haploid production permits recombinant haploid genomes to be rapidly fixed as homozygous inbred lines. The reference further teaches the reproductive mechanism associated with maize haploid induction, including abnormal fertilization events and failure or loss of the paternal genetic contribution during embryo formation. The resulting haploid progeny possess the maternal genome and arise following pollination with pollen from the haploid-inducer male. Kelliher et al. thus supplies the haploid biological context absent from Lowe et al. and provide an express breeding motivation for using haploid and doubled-haploid technology to rapidly obtain genetically fixed plant lines. See in particular, abstract at page 105, Figures 1-3, Tables 1-2; pages 106-108, methods, pages 110-111; extended data for Figures 1-2 at pages113-114.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Lowe et al., Svitashev et al., and Kelliher et al. to produce a gene-edited plant through morphogenic-regulator-assisted embryogenesis and regeneration of haploid plant material, followed by production of a doubled haploid containing the desired genomic modification.
The teachings of Lowe et al., Svitashev et al., and Kelliher et al. address complementary aspects of a common plant-biotechnology objective. Lowe et al. teach improving somatic embryogenesis and plant regeneration through expression of the morphogenic regulators Bbm and Wus2, including non-cell-autonomous activity of Wus2 whereby cells that do not themselves contain the Wus2 transgene receive the morphogenic benefit of Wus2 expressed by neighboring cells. Svitashev et al. teach targeted modification of selected genomic DNA sites in maize embryo cells using Cas9 and guide RNA and recovery of regenerated plants containing the resulting targeted genomic modifications. Kelliher et al. teach production of maternal haploid maize progeny using male haploid-inducer plants and explains the recognized breeding advantage of doubled-haploid technology for rapidly fixing a haploid genome as a homozygous inbred line.
In light of these combined teachings, a person of ordinary skill seeking to efficiently produce a genetically fixed maize plant containing a desired targeted genomic modification would have recognized that the respective teachings of Lowe et al., Svitashev et al., and Kelliher et al. provide complementary solutions to three interrelated technical requirements of that objective: obtaining haploid plant material capable of rapid genetic fixation, introducing a desired targeted genomic modification into plant cells, and efficiently inducing embryogenesis and regeneration of the modified plant material.
Specifically, Kelliher et al. would have provided the skilled artisan with maternal haploid maize material and a recognized reason for employing such material, namely, the ability to rapidly fix a haploid genome into a homozygous doubled-haploid line. Svitashev et al. would have provided an established means for introducing a targeted genomic modification into plant (maize) embryo cells using a Cas9-guide RNA editing system. Lowe et al. would have provided an established means for improving embryogenic growth and plant regeneration through Bbm or Wus2 morphogenic regulators, including the particular advantage of non-cell-autonomous Wus2 activity, which permits neighboring cells to receive morphogenic stimulation without necessarily themselves containing or persistently expressing the Wus2 transgene.
Thus, one of ordinary skill would have been motivated to apply Svitashev et al’s targeted Cas9-guide RNA editing system and Lowe et al’s morphogenic-regulator-assisted embryogenesis and regeneration system to the haploid plant material taught by Kelliher et al.. The resulting combined method would permit a selected genomic target to be modified in haploid plant material, permit embryogenic growth and regeneration to be enhanced by a known morphogenic regulator, and permit the resulting edited haploid genome to be chromosome-doubled and fixed in a homozygous modified plant.
The motivation to combine all three references arises from the known and complementary advantages expressly associated with their respective technologies. Targeted genome editing permits introduction of a desired genomic modification at a selected locus; morphogenic regulators improve embryogenic competence and regeneration of transformed plant material; and doubled-haploid technology permits rapid fixation of a haploid genome as a completely homozygous line. A skilled artisan seeking an efficient route to a genetically fixed, gene-edited maize plant therefore would have had reason to employ these technologies together because each addresses a distinct but complementary step toward that objective.
The combined teachings would have been particularly advantageous because genome editing of haploid material permits a desired modification to be introduced into a single-copy genome, while subsequent chromosome doubling permits that modified genome to be fixed directly in homozygous form. Lowe et al’s morphogenic-regulator system would facilitate embryogenic development and regeneration of the treated plant material, while its non-cell-autonomous Wus2 activity would further provide a known means for stimulating cells that do not themselves contain the Wus2 transgene. Svitashev et al’s Cas9-guide RNA system would provide the targeted genomic modification, and Kelliher’s haploid and doubled-haploid methodology would provide the biological route for rapid fixation of the resulting edited genome.
The proposed combination would not require a change in the basic operating principle of any reference. Lowe et al’s Bbm or Wus2 morphogenic regulators would continue to perform their known function of stimulating embryogenesis and regeneration. Svitashev et al’s Cas9-guide RNA system would continue to perform its known function of modifying a selected genomic DNA target. Kelliher et al’s haploid-induction and doubled-haploid methodology would continue to perform its known function of providing maternal haploid material and enabling rapid production of a homozygous line. The references therefore would have been combined according to their established functions to achieve the predictable objective of producing a gene-edited, regenerated, doubled-haploid plant.
The specific delivery arrangements recited in the claims likewise would have followed from the combined teachings. Lowe et al. expressly teach a separate-strain arrangement in which one Agrobacterium strain carries a Wus2-containing T-DNA and another strain carries a different T-DNA. In the combined method, a skilled artisan would have had reason to employ Svitashev et al’s known Cas9-guide RNA expression construct as the separately delivered genetic construct, thereby allowing edited cells to receive the morphogenic benefit of Wus2 expressed by neighboring cells without necessarily incorporating the Wus2 transgene. Similarly, where simultaneous delivery of the morphogenic-regulator and gene-editing components was desired, a skilled artisan would have had reason to provide the known expression cassettes through a common bacterial transformation system. Lowe et al. teach T-DNA constructs containing multiple functional expression cassettes, while Svitashev et al. teach polynucleotide constructs encoding the Cas9-guide RNA editing system. Combining the known expression cassettes in a common bacterial delivery system would have been a predictable configuration for providing both functions during the same transformation treatment.
A person of ordinary skill would have had a reasonable expectation of success in combining all three references. Lowe et al. demonstrate successful morphogenic-regulator-assisted embryogenesis and regeneration of maize embryo tissue, including non-cell-autonomous Wus2 activity. Svitashev et al. demonstrate successful Cas9-guide RNA modification of selected genomic sites in maize immature embryo cells and recovery of regenerated plants containing those modifications. Kelliher et al. demonstrate production of maternal haploid maize progeny and establishes the recognized utility of doubled-haploid technology for rapidly fixing haploid genomes as homozygous inbred lines.
The fact that no single reference performs the complete claimed method does not preclude a conclusion of obviousness. The relevant inquiry is whether the teachings of the prior art as a whole would have suggested the claimed subject matter to a person of ordinary skill and whether that person would have had an apparent reason to combine the known elements in the manner claimed. In the instant case, Lowe et al., Svitashev et al., and Kelliher et al. collectively provide a technically coherent pathway from haploid starting material, through targeted genomic modification and morphogenic-regulator-assisted embryogenesis, to production of a genetically fixed doubled-haploid plant.
The combination is consistent with the principles articulated in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417–18 (2007). The Supreme Court explained that a combination of familiar elements according to known methods is likely obvious when it does no more than yield predictable results and that, where a known technique has been used to improve one method, its application to a similar method may be obvious where a person of ordinary skill would recognize that it would provide the same predictable benefit. In the instant case, the combination of Lowe et al., Svitashev et al., and Kelliher et al. would have amounted to applying known and complementary plant-biotechnology techniques according to their established functions: using Kelliher et al.’s haploid technology to provide material suitable for rapid genetic fixation, using Svitashev et al’s Cas9-guide RNA system to introduce a selected genomic modification, and using Lowe et al’s Bbm/Wus2 system to enhance embryogenic development and regeneration, including non-cell-autonomous stimulation of cells not expressing the morphogenic regulator. The expected result—a regenerated, gene-edited, doubled-haploid plant containing the desired modified DNA target site—would have been a predictable result of the combined teachings.
Accordingly, claims 39-46 and 48-50 are rejected under 35 U.S.C. § 103 as being unpatentable over the combined teachings of the cited art.
5. Claims 39, 40, 42 and 47 are rejected under 35 U.S.C. § 103 as being unpatentable over Lowe et al. (The Plant Cell, 28:1998-2015, 2016) in view of Svitashev et al. (Plant Physiology,169:931–945, 2015) and Kelliher et al. (Nature, 542:105–109, 2017), as applied above to claims 39, 40, and 42, and further in view of Petolino et al. (US Patent Publication NO. 2015/0307889 A1, Published October 29, 2015).
Lowe et al. teachings are discussed supra.
Svitashev et al. teachings are discussed supra.
Kelliher et al. teachings are discussed supra.
Lowe et al., Svitashev et al. or Kelliher et al. do not teach that haploid cells a microspore-derived haploid embryo or embryo-like structure.
Petolino et al. teach methods for transforming androgenic-derived haploid maize cells and tissue with site-specific nucleases and regenerating plants from genetically modified haploid or doubled-haploid tissue. Petolino et al. expressly teach providing transformation-competent haploid tissue derived from a maize microspore, the tissue comprising a haploid genome, and delivering a polynucleotide encoding a site-specific nuclease to the haploid tissue to modify the haploid maize genome. Petolino et al. further teach that the transformation-competent haploid tissue derived from a maize microspore may be embryo or callus tissue. Petolino et al. further teach that, under appropriate experimental conditions, maize microspores can undergo altered development to produce haploid embryo-like structures without intervening fertilization. The reference identifies this androgenic process as the biological basis for anther or microspore culture. Petolino et al. additionally teach generating microspore-derived embryos by harvesting maize tassels containing microspores, isolating microspore-containing anthers, culturing the anthers to generate microspore-derived embryos, and culturing the resulting embryos to generate transformation-competent haploid tissue. Petolino et al. also teach delivering a polynucleotide encoding a site-specific nuclease to the microspore-derived haploid tissue by microparticle bombardment or Agrobacterium-mediated transformation. The reference further teaches treating genetically modified haploid tissue with a chromosome-doubling agent, obtaining doubled-haploid maize tissue containing the genomic modification, and regenerating the doubled-haploid tissue into a maize plant homozygous for the genomic modification. See in particular, abstract; detailed Description; claims 1-3 and 10-11, Figure 5; paragraphs [0025]-[0284], examples 1-10.
It would have been obvious to one of ordinary skill to employ Petolino et al’s microspore-derived haploid embryo or embryo-like structure as the haploid plant-cell population in the method resulting from the combination of Lowe et al., Svitashev et al., and Kelliher et al.
Petolino et al. expressly identifies microspore-derived haploid embryos and embryo-like structures as transformation-competent maize material suitable for delivery of a site-specific nuclease, genome modification, chromosome doubling, and plant regeneration. Lowe et al. teach enhanced embryogenesis and regeneration through Bbm or Wus2, Svitashev et al. teach targeted Cas9-guide RNA modification of maize embryo cells, and Kelliher et al. establish the recognized utility of haploid and doubled-haploid technology. A skilled artisan therefore would have had reason to apply the collective teachings of Lowe et al., Svitashev et al., and Kelliher et al. to Petolino et al’s expressly disclosed microspore-derived haploid embryo material. The technical motivation would have been to obtain the combined advantages of targeted genome editing, enhanced embryogenic growth and regeneration, and rapid genetic fixation in transformation-competent haploid maize material.
The proposed combination of these teachings represents application of known morphogenic-regeneration, gene-editing, and doubled-haploid techniques to transformation-competent haploid maize tissue that Petolino et al. expressly identifies as suitable for site-specific nuclease-mediated modification, chromosome doubling, and plant regeneration. Each technique would perform its established function.
A reasonable expectation of success existed because Petolino et al. itself teach site-specific nuclease modification of microspore-derived haploid maize tissue, chromosome doubling, and plant regeneration; Lowe et al. demonstrates morphogenic-regulator-assisted embryogenesis and regeneration in maize; Svitashev et al. demonstrates Cas9-guide RNA editing of maize embryo cells; and Kelliher et al. demonstrates maternal haploid induction and establishes the utility of doubled-haploid technology.
Under KSR, applying the collective teachings of Lowe et al., Svitashev et al., and Kelliher et al. to Petolino et al’s known transformation-competent microspore-derived haploid tissue would have amounted to the use of known techniques on closely related biological material to achieve their predictable functions.
Accordingly, claims 40, 39, 42 and 47 are rejected under 35 U.S.C. § 103 as being unpatentable over the combined teachings of cited art.
6. Claims 39 and 51 are rejected under 35 U.S.C. § 103 as being unpatentable over Lowe et al. in view of Svitashev et al. and Kelliher et al., as applied to claim 39 to the underlying method, and further in view of Czakó et al.(Plant Physiology, 104:1067–1071, 1994).
Lowe et al. teachings are discussed supra.
Svitashev et al. teachings are discussed supra.
Kelliher et al. teachings are discussed supra.
Lowe et al., Svitashev et al. or Kelliher et al. do not teach that somatic embryos comprises a negative selection method or a conditional selection method.
Czakó et al. expressly teach use of the herpes simplex virus thymidine kinase type 1 gene (“HSVtk”) as a conditional negative-selection marker in plants. Czakó et al. explain that the HSVtk-encoded enzyme phosphorylates certain nucleoside analogs, including ganciclovir, thereby converting them into toxic inhibitors of DNA replication. Accordingly, plant material expressing HSVtk becomes susceptible to the otherwise tolerated selection compound when ganciclovir is applied. Czakó et al. introduced HSVtk into Arabidopsis thaliana by Agrobacterium-mediated transformation and subsequently applied ganciclovir to HSVtk-positive plant explants and cultures to conditionally inhibit regeneration and growth of the HSVtk-expressing material.
Czakó et al. further teach that ganciclovir at concentrations of 10⁻⁵ to 10⁻⁴ M drastically reduced shoot regeneration from HSVtk-positive root explants and callus formation from HSVtk-positive leaf explants, while wild-type cultures were not affected. The reference further teach that approximately a 35-fold reduction in shoot regeneration eight days after transfer of HSVtk-positive plant material to shoot-induction medium containing ganciclovir. Czakó et al. additionally teach combining negative selection against HSVtk activity with positive kanamycin selection in Agrobacterium-mediated gene-transfer experiments. Shoot regeneration on media containing both ganciclovir and kanamycin was substantially reduced relative to media containing kanamycin alone. Czakó et al. therefore expressly establishes HSVtk/ganciclovir as a conditional negative-selection method for plant transformation and regeneration. Plant material expressing HSVtk is selectively inhibited by ganciclovir, while material lacking HSVtk expression can survive and regenerate. See in particular, abstract, materials and methods, Figures 1-3, results and discussion, pages 1068-1070.
Lowe et al., Svitashev et al., and Kelliher et al. collectively teach producing gene-edited embryogenic haploid plant material and recovering a genetically fixed modified plant through morphogenic-regulator-assisted embryogenesis, targeted genome editing, and doubled-haploid technology. Lowe et al. particularly teach the desirability of obtaining regenerated plant material that benefits from Wus2 activity without itself retaining or persistently expressing the Wus2 transgene. Lowe et al. addresses this objective through non-cell-autonomous Wus2 activity and excision strategies as discussed above. Czakó et al. teach an established conditional negative-selection system for selectively inhibiting plant cells and tissues that contain and express an undesired genetic marker. Thus, one of ordinary skill would have been motivated to apply Czakó et al’s HSVtk/ganciclovir conditional negative-selection method when selecting somatic embryos produced according to the combined teachings of Lowe et al., Svitashev et al., and Kelliher et al. More particularly, a skilled artisan would have recognized that an HSVtk expression cassette could be genetically associated with the morphogenic-regulator construct. After the desired morphogenic stimulation and targeted genome editing had occurred, treatment with ganciclovir would inhibit plant cells, tissues, or embryos retaining and expressing the HSVtk-associated construct, while permitting recovery of material lacking or no longer expressing that construct. The technical motivation for this modification would have been to facilitate selection of the desired edited somatic embryo that did not express the morphogenic polypeptide, consistent with Lowe et al.’s objective of obtaining the developmental benefit of Wus2 without persistent Wus2 expression in the recovered plant material. Conditional negative selection would enrich for material having the desired genetic status and reduce the burden associated with screening undesired material.
The proposed modification constitutes use of a known conditional negative-selection technique for its established function. Czakó et al’s HSVtk/ganciclovir system would perform its known function of selectively inhibiting regeneration of plant material expressing the HSVtk marker. Lowe et al’s morphogenic-regulator system would perform its known function of stimulating embryogenic growth and regeneration; Svitashev et al’s Cas9-guide RNA system would perform its known function of modifying a selected genomic target; and Kelliher et al’s haploid and doubled-haploid methodology would perform its known function of providing haploid material and rapidly fixing the modified genome.
A reasonable expectation of success existed because Czakó et al expressly demonstrates operation of the HSVtk/ganciclovir conditional negative-selection system in plant transformation and regeneration. Czakó et al reports selective suppression of regeneration and callus formation in HSVtk-positive plant material while wild-type cultures were not similarly affected. Czakó et al. also demonstrates use of the conditional negative-selection system in Agrobacterium-mediated plant gene-transfer experiments.
Although Czakó et al. demonstrate the system in Arabidopsis rather than maize, the conditional-selection mechanism depends upon expression of HSVtk and conversion of ganciclovir into a toxic DNA-replication inhibitor rather than upon a species-specific developmental mechanism. A person of ordinary skill therefore would have reasonably expected the established selection principle to be useful in another plant-transformation and regeneration system, particularly where the purpose was to suppress regeneration of plant material retaining an undesired marker-associated genetic construct.
Under KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417–18 (2007), application of a known technique to a similar method may be obvious where the technique would predictably perform its established function. Here, Czakó et al. expressly identify HSVtk as a conditional negative-selection marker and demonstrates selective inhibition of regeneration in HSVtk-positive plant tissue. Applying that known selection technique to somatic embryos generated through the combined plant-transformation method would predictably facilitate selection against material retaining and expressing an undesired HSVtk-associated construct.
Accordingly, claims 39 and 51are rejected under 35 U.S.C. § 103 as being unpatentable over the combined teachings of cited art.
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.
7. Claims 39-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 12,146,147 (‘147 thereafter). Although the claims at issue are not identical, they are not patentably distinct from each other because instant method is encompassed by the method step of US Patent ‘147.
US Patent ‘147 claim 1 recites a method of producing a transgenic plant substantially identical in structure to instant claim 39: providing a trait/morphogenic cassette pair (analogous to the gene-editing component and morphogenic-polypeptide-encoding sequence) to a population of first and second haploid embryos, where only the first expresses the morphogenic polypeptide, inducing somatic embryogenesis by translocation of that polypeptide to the non-expressing second embryo, selecting a somatic embryo lacking the morphogenic cassette, obtaining a doubled haploid embryo, and regenerating a modified plant therefrom.
The sole nominal difference — substituting a generic “trait gene expression cassette” for a “gene-editing component” that modifies a DNA target site — is already taught within the same US patent ‘147 claims 14-19 which recite that the trait or morphogenic cassette further comprises a site-specific nuclease (ZFN, meganuclease, TALEN, or CRISPR-Cas9/Cpf1) with a guide RNA forming a ribonucleoprotein complex, i.e., a gene-editing component effecting insertion/deletion/substitution at a target site. It would have been obvious to a person of ordinary skill to combine US Patent ‘147 claim 1 with claims 14–19 to arrive at instant claim 39, since the patent itself expressly contemplates using the nuclease-based cassette in place of (or in addition to) the general trait cassette, merely reciting the same doubled-haploid gene-editing method with different but obvious verbiage. The “obtaining a doubled haploid embryo” step of claim 39 is an obvious genus of the patent’s species step (contacting with a chromosome doubling agent, claim 1). Accordingly, instant claims 40 and 41 are rejected over US Patent’147 claims 2-4, instant claims 42 is rejected over US Patent’147 claim 6, instant claim 43 is rejected over US Patent’147 claim 7, instant claim 44 is rejected over US Patent’147 claims 8-10, instant claim 45 is rejected over US Patent’147 claim 30, instant claim 46 is rejected over US Patent’147 claim 31, instant claim 47 is rejected over US Patent’147 claims 33-34, instant claims 48 and 49 are rejected over US Patent’147 instant claims 14-16 and instant claim 50 is rejected over US Patent’147 claims 18-19,
In summary, each limitation of instant claims 39-51 is either expressly recited or renders obvious by US Patent’147 claims 1-34, alone or in combination, as they describe the same doubled-haploid, morphogenic-polypeptide-mediated somatic embryogenesis platform merely recited with different (obvious) terminology directed to gene editing rather than generic trait introduction. A terminal disclaimer over the referenced patent would overcome this rejection.
Conclusion
8. Claims 39-51 are rejected.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Vinod Kumar whose telephone number is (571) 272-4445. The examiner can normally be reached on 8.30 a.m. to 5.00 p.m.
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/VINOD KUMAR/Primary Examiner, Art Unit 1663
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