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
Amended claims were filed on 3/2/2026, such that claims 1,3-4 and 6-23 are under examination in this Office action. Claims 2 and have been cancelled.
Any rejection or objection not reiterated herein has been overcome by amendment. The Specification submission of 4/29/2026 overcomes the Specification objection (trademarks).
Applicant’s amendments and arguments have been thoroughly reviewed but are not persuasive to place the claims in condition for allowance for reasons that follow.
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 8, and 11are 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 pre-AIA the applicant, regards as the invention.
Claim 8 is indefinite in the recitation of comparing the modification in the plant polynucleotide to a modification that the editing system “is configured to make given the plant polynucleotide” because it is unclear how to interpret what is meant by “is configured to make given the plant polynucleotide”, which, as stated sounds incomplete (given the plant polynucleotide what?).
Claim(s) 11 may depend from claim 8, does not resolve the issue and is therefore, indefinite for the same reason.
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 1,3-4 and 6-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the method of transfecting a plant polynucleotide comprising a portion of the corn gene Glossy2, or the corn gene CenH3, or the blackberry SEEDSTICK gene, into a mammalian cell line (HEK293 cells) to provide transgenic cells using “a CRISPR-Cas system” or CRISPR-Cas12a, does not reasonably provide enablement for evaluating an editing system by introducing any plant polynucleotide into any mammalian cell to comprise a stably transformed transgenic cell. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. Notably, this is a scope of enablement rejection.
To address whether sufficient evidence supports the determination that the disclosure does not satisfy the enablement requirement and whether undue experimentation might be needed, the below factors are considered, per In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Nature of the Invention:
The claims are directed to a method of evaluating an editing system. The claims require introducing a plant polynucleotide with target nucleic acid into a mammalian cell such thus providing a stably transformed transgenic cell. A CRISPR editing system contacts the plant polynucleotide and the presence or absence of a modification is determined. Accordingly, enablement of the claims requires that one of ordinary skill in the art be able to stably introduce any plant polynucleotides into any mammalian cells to provide a stably transformed transgenic cell commensurate with the full scope of the claims without undue experimentation.
Breadth of the claims:
The claims broadly recite introducing any plant polynucleotide into any mammalian cell to generate stably transformed transgenic cell(s). A CRISPR-Cas protein and guide with spacer are used for editing and evaluation is through identification of presence/absence of a modification. Any "plant polynucleotide" encompasses a massive genus of possible plant polynucleotides, including all plants of all ploidy levels. The introduction is into any mammalian cell, another broad genus of all possible mammalian cells.
Teachings of the Specification:
The specification teachings are limited in scope, with one comparative editing example in mammalian transgene cells and in plant cells, and very limited use of the significant system components, including an engineered HEK293 mammalian cell line, four plant polynucleotides from two plant species, four polynucleotides edited in the mammalian cell line but just one edited in corn as the singular example of conceptual efficacy, comparing mammalian cells and plants. There is ample room for unpredictability in overall success and reproducibility across invention systems, when system components change, and when editing comparisons are made.
Transfection for introduction of plant polynucleotides into quite a particular mammalian cell line is presented (Example 1), transfection occurs of a few targets, where a HEK293T-based cell line is employed, with use of Flp recombinase to integrate the target polynucleotide into the engineered Flp-in293TM cells with a FRT site, such that, unusually, the target polynucleotide integration occurs only at a single site (site-specific integration at the landing pad), which is unlike integration in classical (e.g.HEK293, CHO) cell lines (FLP-in239 cells, thermofisher.com/us/en/home/products-and-services/services/custom-services/assay-development-services/cell-line-development/flp-in-cell-line-development), where in the latter cell lines, there would be much more unpredictable integration behavior regarding integration site locations, numbers of integration, repeatability in performance for the same attempted integration (e.g. more than one) (Burgio 2020, Trends Gene 36: 905-914, Abstract, Pg 2, para 3-4).
Four total polynucleotides (three in corn, one berry) were empirically edited (Glossy2, CenH3, Fea2 Pg 61, lines 4-5, and Seedstick) in mammalian cells, where for the first two “293Gl2 and 293CenH3” cell lines were transformed to introduce a Cas-CRISPR, employing six and four spacers, respectively. Indels were quantified after editing, with Glossy2 indel results varying, with a mean of ~42% to ~18% with different spacers (Fig1). The CenH3 result ranged from a mean of ~79% to 20% with four spacers in these HEK-cells.
Glossy2 was the only polynucleotide with empirical editing performance comparison in corn and mammalian cells, where a singular spacer (PWsp104) had high editing efficiency in corn of 80%+ (93.8% and 80% in two experiments, Ex 2) and in the mammalian system it was ~40% (~37-42%). This singular comparative example is insufficient evidence to make other systems enabled, or predictable for comparative editing performance.
SEEDSTICK angiosperm gene was inserted into mammalian cell line. Use of Cas12a and cRNA with spacer identified two active spacers (%indel: 82%, 73%, Ex 4) but editing efficiency was not compared in flowering plants to determine predictability from the model cell line to the plants/germplasm. Similarly, FEA2 corn polynucleotide in a model cell line, showed a range of editing efficiencies (max. of 44%) but efficiency was not compared to corn plants, and prediction regarding what editing would be like in the plants/germplasm is not possible since there is not enough empirical data for the prediction.
The specification does not describe other means for introducing any other plant polynucleotides, including other plant Genera, into any other mammalian cells, including standard cell lines (e.g. CHO), so there is not rationale to suggest all cell lines are enabled as comparative data on variability is lacking, and the particular modified cell-line used here was actively altered to differ in a specific manner from conventional cell lines to optimize single insert site, which is not typical of other cell lines. The specification only teaches introducing a portion of just four plant genes (Glossy2, CenH3, Fea2 and Seedstick) into mammalian cells, with different editing efficiencies and ranges, and with only the singular comparisons between mammalian cell line and plant indel counts. There are no other working examples in which any other plant polynucleotide was successfully introduced into any other mammalian cell to generate stably transformed transgenic cell lines, and thus nothing to base predictability of editing correlations between cell lines and plants upon.
State of the Art:
The state of the art was such that introducing plant polynucleotides into mammalian cells to generate stably transformed transgenic cells for evaluating editing would be highly unpredictable, in-part based on the lack of guidance. Extensive search for identification of art where plant polynucleotides were introduced into mammalian cell lines to generate stable transgenic cells used to evaluate editing did not produce direct guidance from the art. ThermoFisher (thermofisher.com/order/catalog/product/R75007) discloses publications of use of the Flp-InTM cell-line (used by applicant). None of these references incorporate the use of plant genes in this cell-line. Nor were obvious equivalent examples identified in art searches of introductions into mammalian lines to generate stable lines for this purpose. Burgio (2020, Trends Genet. 36: 905-914) generally discusses unpredictability in on target vs away from target insertions which are relevant to genome editing (Abstract) comparisons in particularly optimized cell lines versus other cell lines not optimized for inserts or typical plant genomes. Chakrabati (2019 Molecular Cell 73, 699-713) recently pointed out that target sites are not all edited in a predictable manner (Abstract) and that “careful selection of a predictable target is critical to induce a desired modification in a cell-type independent manner” (Pg 1) but that even so, evaluation of off-target sites demonstrates that prediction of these is not straightforward and is incomplete (Pg 2, right col para 2). The authors examined indels in human cells at over 1,000 sites to evaluate CRISPR mediated editing and determined that recurrences of particular indels varies among sites with some targets showing one highly preferred indel and others displacing numerous indels, which may be influenced by chromatin (Abstract). They particularly address inferences of efficacy based upon quantifying indels, where the association between predicted and empirically measured indels is only moderate (Pg 4, left col, para 1) and our understanding of CRISPR use and mechanisms of indel formation is limited (Pg 4, left col, final para), which is to say drawing inference from indel likelihood in a plant polynucleotide insert in a particular mammalian line to extrapolate to plant polynucleotides in plants likely has multiple elements of upredictability.
Work related to the stability of plant-mammalian cell associations came from examples such as Wada (Wada et al. (2017) ACS Synthetic Biology, 6:301-310) who teaches that interkingdom fusions between human cells and tobacco hybrid protoplasts were not viable beyond 6 days and that several more attempts to make fusion cells between human and plant cells have not been successful (see page 301, column 2). Similarly, Liu (Liu et al. (2021) Scientific Reports, 11:7160, pages 1-13) teaches attempting to study a fusion of plant genetic material in human cells and determined that "Most of the introgressed Arabidopsis DNA was eliminated during the culture" (abstract). Liu reiterates that cell fusion often induces chromosomal instability (page 1, paragraph 2).
These teachings, in the absence of more similar disclosures, indicate that the claims which broadly encompass introduction of any plant polynucleotides into any mammalian cells to generate stable transformations are also likely to be unpredictable with respect to stability of transgenic cells derived from heterologous human/plant cells.
The level of one of ordinary skill:
Artisans in biotechnology are generally considered highly-skilled and hold a relevant PhD, where the courts have considered this person at least a junior faculty member with one or two years of relevant experience or a postdoctoral student with several years of experience Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362, 1373 (Fed. Cir. 1999) (citing Enzo Biochem, Inc. v. Calgene, Inc., 14 F. Supp. 2d 536, 567 (D. Del 1998)).
Amount of Experimentation:
Given the limited number of teachings and their limited scope provided by the specification and given the unpredictability and lack of relevant support in the art, substantive experimentation would be necessary to practice the full scope of the claimed invention, particularly when invoking use of any cell line for stably transformed transgenic cells that can be used to evaluate an editing system. The invention would necessitate empirical support for predictability surrounding testing of many different plant polynucleotides in many mammalian cell lines, where results yielding stable transformation of transgenic cells would be unpredictable, and use of alternate cell lines would be anticipated to generate different and unpredictable effects on the claimed inventions, given the particularity of the cell line used here. Given the lack of teachings in the art directly related to evaluating editing systems using stably transformed transgenic cells after introduction of plant polynucleotide into mammalian cells, Wada’s and Liu’s showings of the difficulties associated with stability of other mammalian cell-plant cell associations are relevant, and undue experimentation would have been necessary to establish predictability of the invention as claimed.
In conclusion, the preponderance of evidence speaks to the lack of guidance and unpredictable nature of successfully stably integrating any plant polynucleotide into any mammalian cell line to generate stably transformed transgenic cells for evaluating editing systems, and these factors weigh strongly against patentability of the scope of claims, as presented.
Claims 22 and 23 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. This is a written description rejection.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the 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”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the invention: Broad. Since claim 22 and 23 depend from claim 1 it is presented here: Claim 1 recites a method of evaluating an editing system, introducing a plant polynucleotide comprising a target nucleic acid into a mammalian cell to provide a transgenic cell wherein introducing the plant polynucleotide into the mammalian cell comprises stably introducing the plant polynucleotide into the mammalian cell to provide the transgenic cell and wherein the transgenic cell is a stably transformed transgenic cell; contacting the plant polynucleotide in the transgenic cell with an editing system comprising a CRISPR-Cas effector protein and a guide nucleic acid comprising a spacer sequence that is complementary to the target nucleic acid and responsive to contacting the plant polynucleotide in the transgenic cell with the editing system, determining the presence or absence of a modification in the plant polynucleotide thereby evaluating the editing system.
Claim 22, the method of claim 18, introduces the editing system of claim 1 into a plant cell, wherein the modification in the plant cell is the same as the modification in the transgenic cell and/or wherein the editing efficiency for the Cas editing system in the plant cell is substantially the same as in the stably transformed transgenic mammalian cell line.
Claim 22 therefore requires possession of a CRISPR-Cas editing system that meets the functional limitation of having substantially the same editing efficiency for any plant polynucleotide introduced into any mammalian cell wherein the transgenic cell formed is a stably transformed transgenic cell, and upon contact with CRISPR-Cas effector protein and guide with spacer, has substantially the same editing efficiency in plant cells. It is therefore expected that the instant application will provide substantive disclosure of a method where such as system can be used and will demonstrate editing efficiency that is substantially the same when the editing system is used in mammalian stably transformed transgenic cells or in plants.
Claim 23 introduces the CRISPR-Cas editing system of claim 1 into a plant cell, wherein the editing system has the functional limitation of an editing efficiency of 80% or more in plant cells. It is therefore expected that methods employing CRISPR-Cas editing systems, where the editing efficiency is ≥80% when editing plant cells, will be sufficiently described.
State of Art: Currently challenging with unpredictability in editing efficiency.
Zhang (Zhang Y et al, CRISPR ribonucleoprotein-mediated genetic engineering in plants, March 2021, Plant Comms 2, 1-13) disclosed that editing efficiency in plants is highly dependent upon expression cassette design and its genomic insertion site (Abstract), and further while CRISPR ribonucleoprotein (RNP) mediated genetic engineering editing efficiency is only modest, and its application in many plant species is limited by difficulties in plant regeneration and selection (Abstract). Plasmid-based CRISPR editing requires efficient species-specific editing systems with optimal promotors, terminators and codon optimization (Pg 1 left col, para 1). Particle bombardment (to deliver RNPs) into plants, without selection, typically has an editing efficiency of less than 10% (Pg. 4 left col, para 2). When this is improved using plasmids with selective markers co-transformed with RNPs into plants, then a higher frequency of random inserts may also occur (Pg. 4 left col, para 2). Editing efficiency of ~6% was obtained when RNPs were delivered into tobacco by lipofection, where notably, for plants, this also requires cell wall degradation (Pg 4, left col, para 3) but for LbCas12a, editing efficiency was <1% (Pg. 4, right col, para 1). In soybeans editing efficiency was 1.6% max, using AsCas12a, but improved to 17.5% using LbCas12a. Problems recognized included formation of secondary structures, low activity in some species, and temperature sensitivity impacting Cas12a, and impacting results (Pg 4, right col para 1). Editing efficiencies for different plant species, using RNP delivered CRISPR reagents were presented in Table 1 and range widely (with most however, <10%), Zhang indicating “room for improvement to achieve much higher editing efficiencies” to make RNP based CRISPR genome editing more practical for plants (Pg 4 right col, para 1; Pg 8 Table 1). Variation occurred within species where editing systems varied, with editing efficiency of up to 3.4% with electrotransfection /Cas9 in cabbage ((Pg 4, left col, para 3) and up to 1.8-2% with other transformation methods/Cas9, though with one cabbage subspecies using PEG and Cas9, editing efficiency ranged from 3.7-24.5% for one gene, and differed for another gene and was 1.1-12.5% (Table 1). Soybean editing efficiency appeared as much as 10% higher with LbCas12a then with AsCas12a (Pg 6 Table 1), also reflecting differences with different systems.
Javaid (Javaid N and Choi S, CRISPR/Cas System and Factors Affecting Its Precision and Efficiency, Nov 2021, Front Cell & Dev Biol, 9 761709 ) generally addressed precision and efficiency issues using CRISPR-Cas system(s), pointing out challenges to obtaining maximum genome editing efficiency with minimal off-targets still remain (Abstract end). Javaid points out that spacers, in plants, with GC content 30-80% have been validated, but that editing efficiency in plants decreases with 40% GC content relative to higher amounts (Pg 5 right col, first full para), while in mammalian cells, very low or very high GC content is less effective, with 40-60% GC content favorable for efficient editing (Pg 5, right col, first full para). This difference points to reasons for anticipation of expected differences in editing efficiency using the same spacer in plant vs mammalian cell types that may result in some unpredictability in rank importance of a spacer in a given system.
Malzahn (Malzahn A, et al., Application of CRISPR-Cas12a temperature sensitivity for improved genome editing in rice, maize, and Arabidopsis, 2019, BMC Biol 17:9 1-14) identified that CRISPR-Cas12a provided new opportunity in genome editing but that only a few plant species had been edited, noting one study could not detect any activity in rice plants with AsCas12a, another barely found induced mutations in soybean protoplasts (Pg 2, left col, final sentence to right col first para). Editing efficiency in maize ranged, up to 60% with LbCas12a (Pg 2, right col first para). Malzahn does not have any comparative data for editing any berry plant polynucleotides but does point out that plant transformation and growth typically occur at ambident temperature and difficulty applying Cas12 nucleases in plants may be due to Cas12a nuclease temperature sensitivity (Pg 3 left col, para 1). Malzahn noted adoption of Cas12a systems to a wide collection of plant species has been slow, suggesting barriers impact editing (Pg 2, right col, final para), and demonstrating Cas12a nucleases also behave differently in different plant species (Pg 3, left col, first para), indicating experimental work would be necessary when moving from one plant system to another plant system and particularly moving to another non-plant system. Some nucleases (e.g. AsCas12a) had not even been successfully applied for generating heritable mutations in plants (Pg 5 left col, para 1), prior to Malzahn’s first-time work garnering success (Pg 8, right col, final para). This would also suggest comparison with mammalian lines not maintained at ambient temperature may impact Cas12a nuclease performance differentially relative to Cas12a nuclease performance in plants grown at ambient temperature (e.g. Pg 3 left col para 1). Even the Cas9 nuclease demonstrated optimal activity under different conditions for human genome editing (37-39 degrees C) relative to plants, where heat stress was applied to improve Cas9 editing in plants (Pg 10, left col second para). Malzahn believed further exploration of different conditions would probably result in more robust genome editing in plants (Pg. 10, left col, final para).
Bernabe-Orts (Bernabe-Orts, JM et al, Assessment of Cas12a-mediated gene editing efficiency in plants, 2019, Plant Biotechnology Journal (2019) 17, pp. 1971–1984) compared efficiency of Acidaminoccoccus (As), Lachnospiraceae (Lb) Cas12 variants with S. pyogenes Cas9 in CRISPR/Cas12a as an editing system for plants, comparing editing efficiency of these two Cas12a variants with SpCas9 in benth (N. benthamiana) (Abstract). All three nucleases showed ‘drastic target-dependent differences in efficiency’ (Abstract). Genome editing was conducted in three plants tobacco, tomato and Arabidopsis thaliana and Bernabe-Orts concluded that while Cas12a may be used as a viable alternative to Cas9 for plant genome editing, more work is needed to make editing efficiency more predictable. (Pg. 1972, left col, first full para last line). Bernabe-Orts also did point out that Cas12a orthologs have been proven effective in mammalian cells (Pg. 1971, right col final para).
What the specification does and does not teach:
The specification teaches one reduction to practice that is relevant to but that does not meet the method of claim 22 which depends from claim 1, wherein the editing efficiency for the editing system in a plant cell is substantially the same as the editing efficiency of the editing system in the transgenic cell. For clarity, in the prior Office action 1.21.26), “substantially the same” was recited in the claim interpretation, based upon the specification, as being within about ±10% of the same editing activity in a different cell.
The only editing comparison is for Glossy2, where a singular spacer (PWsp104) had high editing efficiency in corn, of 93.8% and 80% in two experiments, Ex 2) and in the mammalian system it was ~40% (~37 and 42% fwd and rev, respectively). By definition the values are not “substantially the same”. No other comparison can be made of empirical data since no other introduction into plants was made to provide editing data in plants. Further, this singular example is much narrower in scope than the disclosure of claim 22, even if it were to meet the “substantially the same” limitation.
The specification therefore does not describe a reduction to practice of any complete system, or the physical (or chemical) properties of a system that is shown to document the performance of the function if “substantially the same” editing systems as recited in claim 22.
Re: claim 23, which depends from claim 1, wherein any CRISPR-Cas editing system in the plant cell has an editing efficiency of 80% or more. The claimed function (80% editing efficiency) is described for “a CRISPR-Cas” construct with a singular spacer of the several tested, where the others all failed to produce the claimed editing efficiency, and this is for a singular plant polynucleotide Glossy2, in a singular ‘species’ (corn) of plant. A narrow scope, relative to the claim.
The specification does not sufficiently describe the structural features and/or physical properties of the editing system, plant polynucleotide and plant cell species that provide for performing the function of generating 80% or more editing efficiency, such that a correlation would be disclosed between these structural features and this editing efficiency function that could then be generalized to produce this function as claimed, for the large genus of any target polynucleotides, in the large genus of any plant with any CRISPR-Cas system as claimed.
Instead, the Specification does point to the issue that plant genome editing is difficult for many specialty crops, making it challenging to identify promising genome editing strategies that produce a desired edit in the context of the plant genome (Pg 1). The art demonstrates that editing comes with challenges in plants beyond specialty crops as disclosed above. The Specification further discloses that identification of optimal gRNA, assessing editing outcomes and estimating editing efficiency at targets cannot be easily determined (Pg 1), and yet just a singular example of success is presented. The specification also broadly recognizes the limitations affecting testing, as explanation why varied systems are not tested. The Specification points to feasibility issues, where it indicates that many specific editing enzymes and gRNAs could be employed, but due to “laborious” (nature of the work) and expensive cost, extensive testing of reagents is not feasible (Example 1, Pg 60, lines 25-29). In three of four polynucleotide examples presented, the comparative work to identify editing efficiency in plants was not conducted, therefore these examples also do not contribute to our knowledge regarding the structures required to generate the claimed 80% editing efficiency. They are summarized here: Ex.2 discloses edited Glossy2, generated in corn, by plant transformation using “CRISPR-Cas editing components”, with one spacer (PWsp104) evaluated twice demonstrated editing efficiency of 93.8% and 80% in corn. Prophetic Ex. 3: considers editing the CenH3 gene in corn with no results provided. Ex. 4: Blackberry SEEDSTICK gene: No work in plant cells. Prophetic Ex. 5: Edited SEEDSTICK allele constructs are proposed to be generated. No results provided. Ex. 6: corn fea2, in HEK but no work in plants. Prophetic Ex. 6 edited fea2 alleles in corn with spacers of Table 3 for fea2. No data presented.
Conclusion regarding possession:
Taking into consideration the factors outlined above, including the nature of the invention, the state of the art, the guidance provided by the applicant, the breadth of the claims, lack of working example for claim 22, and singular working example for claim 23, narrow in scope relative to the claim, and where the claim is defined by particular functional editing efficiency such that disclosure should therefore correlate to the necessary and sufficient structural features needed to demonstrate possession, and absent sufficient disclosure of a relationship demonstrating the correlation of structure and function, it is the conclusion that Applicant does not possess the invention as recited in the claims.
There is not sufficient specific written example in the Specification that would lead one with ordinary skill in the art to a different conclusion. Written description (possession) for claims 22 and 23 is not supported, given the absent or narrow and/or fractional disclosures in Specification, relative to the breadth of the claim scope.
Response to Remarks
Applicant comments that Claim 1 is amended to incorporate claims 2 and 5. It is noted that this amendment does narrows the scope of claim 1. It is also noted that the limitations of claims 2 and 5 were previously included in the enablement rejection
Applicant explains rationale for 112b rejection amendments, however “a modification that the editing system is configured to make given the plant polynucleotide” is unclear in it’s meaning (given the plant polynucleotide….what?). The claim sounds incomplete. The claim 16 amendment has an antecedent basis issue described above.
Applicant explains rationale for enablement amendments and it is agreed that claim 1 has a more narrow scope than it previously did with the amendment to incorporate claims 2 and 5 into it. However, the claim remains broad in scope and recites several genera (e.g. any plant polynucleotide, any mammalian cell line). It is stated that claim 1 is related to stably introducing a plant polynucleotide comprising a target nucleic acid into a mammalian cell using an editing system to provide a stably transformed transgenic cell. This is understood, though there is disagreement on the issue that the claim is enabled, for the reasons recited in the Office Action(s). Wada and Liu were not intended to be used to describe the exact same method as the claimed invention but rather, absent other findings nearer to the recited claim, to point to the unpredictability in generating stable fusions which also combine plant and animal cells. Additional art and thorough evaluation of the specification demonstrate why the claims are not enabled, including a number of unpredictable factors, along with a few claimed genera, for which there is not sufficient support, and for which there is evidence of unpredictability.
It is understood that the purpose of the invention is to test various plant polynucleotides, though why the Applicant believes undue experimentation would not be necessary is unclear (though Applicant may be saying this based upon the Remarks provided regarding the amended claim(s), description of the first claim provided, and references-based comments). In this Office action, relevant information is presented about cell lines, the unique features of the engineered HEK cell line used in this work that provide for unpredictability in several factors addressed that would arise were one to swap in a different cell line, as the breadth of claim 1 allows for, presently. Substantive presentation of the reasons for lack of enablement are found in the present Office action.
Regarding undue experimentation, for one: the genus of plants is vast; the number of plant species nearly 400,000. Relative to the data presented in the specification for just two plant species, it is unlikely to determine predictability for the scope of the claim relative to all species in this genus alone. The use of just four polynucleotides, three from one plant “species”, demonstrate in the specification that different plant polynucleotides each produce wide and distinctly different ranges (some wider, some narrower) and different means, in one mammalian cell line, without evidence of predictability. This does not take into account for example, different cell lines, where other cell lines are likely to add complexity for reasons addressed in the Office action. Undue experimentation would be necessary for this and other reasons as supported by the art beyond simply Wada and Liu, and described in this Office action. While it is understood that Applicant desires to use the invention to test different polynucleotides, the invention must first be enabled to do so.
Regarding the written description rejection,., the argument is not persuasive because while the claims do address methods for evaluating the editing system they also require the editing systems to have particular efficiencies as recited in claims 22-23. These editing efficiencies are functional limitations, namely an editing efficiency that is functionally ‘substantially the same’ in plant cell and transgenic cell and an editing efficiency in the plant cell that is functionally ‘80% or more’. The claims do not limit the structure of the editing system and therefore broadly encompass any editing system having the required editing efficiency recited in the claim(s). However, the editing efficiency of the editing system is not known, which is why the independent claim (claim 1) recites “A method of evaluating an editing system” and these, therefore, are further unpredictable.
While it is agreed spacer PWsp104 was demonstrated to have an editing efficiency of at least 80% in corn and was tested in mammalian cell line, this singular example is narrower than the recitation in the claims and is not sufficient to show possession of the genus of any such editing system with the required editing efficiency for the reasons articulated.
Conclusion
All claims rejected.
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.
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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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/LISA HORTH/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights