DETAILED ACTION
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 .
Claims 1-17 are under consideration in this office action.
Claim Objections
Claim 1 is objected to because of the following informalities:
(i) Claim 1 recites “bovine animal or offspring thereof or a bovine cell or gene” is grammatically incorrect because of the multiple recitations of “or” in the list. Amending the recitation to state, “bovine animal, an offspring thereof, a bovine cell, or gene”, would be remedial.
(ii) Claim 1 also recites, “animal/cell/gene” appears to be short-hand and informal language. Amending this to recite, “said animal, cell, or gene”, would be remedial. Appropriate correction is required.
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 1-17 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.
Claim 1 recites, “gene comprising a modified chromosome”. It is not apparent how a gene can comprise a chromosome because it is well established in the prior art that gene are comprised in chromosomes but the other way around. As such, the metes and bounds of this alternative are not apparent.
Further claim 1 also recites, “impairs the ability of said animal/cell/gene to encode said protein”. This recitation is indefinite for multiple reasons. First, it does not recite “the offspring thereof” in the list of said animal/cell/gene. As such, it is not apparent if the impairment claimed is only intended to apply to the bovine animal, cells, or gene but to the exclusion of the offspring or is the limitation intended to limit the offspring as well. Second, animal and cells do not have an ability to encode a protein, only genes or nucleic acids do. As such, it is not apparent how this claimed ability is intended to related to said animal or cell.
Claim 1 also recites, “A bovine animal or offspring thereof or a bovine cell or gene”. It is apparent that the animal of the claims is intended to be bovine because the descriptive “bovine” is placed directly before “animal”. It is also apparent that the offspring is bovine because of the recitation “thereof” refereeing back to animal. It is apparent that the cell is bovine as well because the descriptive “bovine” is placed directly before “cell”. However, the term “gene” has no descriptive or term that refers it back to the animal, offspring, or cell. As such, it is not apparent if the gene is intended to be limited to a bovine gene or if it is intended to be a gene of any species. Thus, the metes and bound of claim 1 are not apparent. For purposes of finding and applying relevant art, “gene” will be broadly interpreted as a gene from any species.
Claims 2-8 recite, “the animal, cell or gene” in reference to its base claim 1 which recites “A bovine animal or offspring thereof or a bovine cell or gene”. The recitations in claim 2-8 render the scope indefinite of these dependent claims because it leave out reference to the “offspring thereof”. As such, it is not apparent if the limitations of these claims are intended to apply to the offspring or not.
Claim 5 recites, “said chromosomal sequence comprises cleaving”. “Cleaving” is a verb and describes an action that is occurring, like in a method. However, the claim is to a product as such it is not apparent how the action of cleaving can be comprised by a sequence.
Claim 6 recites, “said chromosomal sequence comprises enzymatic or physical modulation”. It is not apparent how a sequence can “comprise” modulation, which is an action.
Claim 7 recites, “said chromosomal sequence comprises adenoviral, lentiviral, or other viral vectors”. Viral vector as claimed are viruses or virions or viral particles. As such, it is not apparent how a chromosomal sequence can “comprise” such viral vectors.
Claim 8 recites, “said chromosomal sequence comprises homology directed repair”, aka HDR. However, HDR is a process not a structural element. As such, it is not apparent how a sequence can comprise the action of HDR.
Claim 9 recites, “the chromosomal sequence of said gene”. Genes do not have “chromosomal sequence” because gene are found within chromosomes and do no comprise chromosomal or chromosomal sequences as claimed. As such, the metes and bound of this recitation are not apparent.
Claim 9 also recites, “a) obtaining a bovine cell, wherein the genomic DNA of the cell preferably comprises a wild-type ACTN3 gene”. “Preferably comprises” that one would like but does not require that genome of the cell to have the ACTN3 gene. In other words, it appears that the ACTN3 gene as claimed is optional. However step b recites, “Altering the chromosomal sequence of said gene” is implies that the ACTN3 gene as claimed is required and not optional to the claimed method. As such, the metes and bounds of the claim are not apparent because it is not apparent if the ACTN3 gene as claimed is required or optional.
Claim 9 also is indefinite because steps a and b result sole recite “obtaining a bovine cell” having a an ACTN3 gene and “altering…said gene…”. While these two active steps will result in the claimed gene and the claimed cell, it is not apparent how a method that solely has the end result of producing the gene and the cell can be considered “a method of producing a modified bovine animal” as claimed.
Regarding claims 13 and 15, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The remainder of the claims depend upon claim 1 or 9. As such, these dependent claims also comprise the above indefinite subject matter.
Claim Rejections - 35 USC § 112
Claims 1-17 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Regarding the product claims of claims 1-8, the Markush grouping of “bovine animal or offspring thereof, a bovine cell or a gene” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: an animal or offspring thereof, a cell, and a gene are teach structurally different entities. An animal a complex multiple organ living entity that has a myriad of distinct structures and functions that come from that structure, that are not present in cells or genes. Similarly cell are a complex multi-organelle comprising living entity that has a myriad of distinct structures that genes do not have and thus function that come from those structures that the gene does not have. As such, that lack a single structural similarity from which a common function flows.
Regarding the method claims 9-17, the Markush grouping of animal, cell, or gene” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: an animal, a cell, and a gene are teach structurally different entities. An animal a complex multiple organ living entity that has a myriad of distinct structures and functions that come from that structure, that are not present in cells or genes. Similarly cell are a complex multi-organelle comprising living entity that has a myriad of distinct structures that genes do not have and thus function that come from those structures that the gene does not have. As such, that lack a single structural similarity from which a common function flows.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without significantly more.
Claim Interpretation: Claim 1, and thus dependents, recite(s), in the alternative, “gene comprising a modified chromosomal sequence in at least one allele of a gene encoding an alpha-actinin-3 protein, wherein said modified chromosomal sequence partially or completely impairs the ability of said …gene to encode said protein”. Since the relationship between the modified chromosomal sequence and the gene are not apparent (see the 112(b) rejection above), the above recitation is interpreting “modified chromosomal sequence in at least one allele of a gene encoding” ACTN3 to mean a modification in the ACTN3 gene. Also “gene” is being interpreted as an ACTN3 of any species. Claims 4-8 recite additional limitations that do not necessarily impart a structural or functional distinction to the base claim. As such, these claims are being included in the rejection.
According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories of invention (i.e. process, machine, manufacture, or composition of matter). Claims 1-8 drawn to a composition of matter comprising an ACTN3 gene. Thus claims 1-8 meet the requirements for step 1 of the analysis.
Second, the claim is assessed to determine if it is directed to a judicial exception under step 2A. Under 2019PEG, “directed to” is determined via a two-prong inquiry: (1) Does the claim recite a law of nature, a product of nature, a natural phenomenon, or an abstract idea; and (2) Does the claim recite additional element(s) that integrate the judicial exception into a practical application. The phrase, “integration of a practical application”, requires the presence of an additional claim element(s) or a combination thereof to apply, rely on or use the judicial exception in a manner that imposes a meaningful limitation on the judicial exception, such that the claim does not monopolize the judicial exception. (See MPEP § 2106.05 for examples of integration of practical application).
Regarding the first prong (1), claims 1-8 are expressly directed to an ACTN3 gene having a modification/mutation in its sequence that partially or completely impairs said gene. MacArthur (MacArthur et al. Nature Genetics 39(10):1261-1265, 2007) reports, “More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein a-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that a-actinin-3 deficiency influences the function of fast muscle fibers.” See abstract. Thus, MacArthur teaches that a mutant form of the ACTN3 gene comprising a premature stop codon, as recited in claim 2, which is also a type of missense mutation as recited in claim 3, exists in humans in nature. As such, the claimed gene comprises embodiments that are a product of nature, and thus a judicial exception. Thus, the first prong of the inquiry demonstrates that claims 1-8 do recite are directed to a judicial exception.
Regarding the second prong (2), claims 1-8 are products and do not recite any additional limitations that could be interpreted as an application. As such, prong (2) is not applicable and claims 1-8 meet the requirement of step 2A as being directed to a judicial exception.
Third, if a judicial exception is present in the claim, it is further assessed to determine if the claim recites any additional elements or steps that are sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception. As discussed above, in the interpretation, the claims solely recite the gene comprising the mutated ACTN3 gene that has impair ability to product ACTN3 protein (claim 1), particularly the impairment cause by a premature stop codon (claim 2), a type of missense mutation (claim 3). Further claims 4-8 recite language that appears to be product by process type language and does not further limit base claim 1 structurally or functionally. As such, embodiments of the claims to a “gene” as claimed does not recite any additional elements that distinguish it from the natural counterpart, exemplified in MacArthur. As such, claims 1-8 do not meet the requirements of step 2B.
In conclusion, claims 1-8 are deem patent ineligible subject matter because the gene embodiments of the claims do not meet all the requirements of the 2019PEG. The gene embodiments of the claims read upon a human ACTN3 polymorphic allele that exists in nature, causing the claims to be directed to a judicial exception. The claims do not further recite any additional elements that integrate this judicial exception into an application or that distinguish the judicial exception from its natural counterpart. As such claims 1-8 are patent ineligible.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-8 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by MacArthur (MacArthur et al. Nature Genetics 39(10):1261-1265, 2007).
The claims are being interpreted as discussed above in the 101 rejection.
Regarding claim 1, MacArthur discloses that more than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein a-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that a-actinin-3 deficiency influences the function of fast muscle fibers. See abstract.
Regarding claim 2, MacArthur discloses a premature step codon or nonsense mutation as discussed above.
Regarding claim 3, MacArthur discloses a missense mutation as discussed above.
Regarding claims 4-8, these claims do not further structurally or functionally limit these claims. As such, the disclosure above by MacArthur discloses the requisite limitations of claims 4-8.
In conclusion, the prior art of MacArthur anticipates the claims because it expressly discloses of the requisite limitations of the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 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 following:
A) a bovine cell comprising in its genome a disruption of the ACTN3 gene;
B) a bovine ACTN3 gene comprising a modification that impairs ACTN3 expression;
C) a method of producing a genetically modified bovine animal comprising: (i) a bovine cell comprising in its genome a disruption of the ACTN3 gene, wherein said disruption reduces or ablates expression of the ACTN3 gene, and introducing said bovine cell into an enucleated bovine oocyte to product a SCNT embryo, transferring said embryo into a recipient bovine female, and gestating said embryo to produce a bovine animal; or (ii) providing a bovine embryo comprising in its genome of all its cells a disruption of the ACTN3 gene, wherein said disruption reduces or ablates expression of the ACTN3 gene, transferring said embryo into a recipient bovine female, and gestating said embryo to produce a bovine animal
The specification does not reasonably provide enablement for the following:
(1) A bovine animal or offspring thereof comprising a modified ACTN3 gene that impairs ACTN3 protein product and has any phenotype or no phenotype at all; and
(2) a method of producing a genetically modified bovine animal that does not require provide a genetically modified bovine embryo or bovine nuclear transfer embryo comprising the claimed genetic modification, transfers bovine embryo or bovine nuclear transfer embryo into a recipient female bovine animal, and gestating the embryo or the nuclear transfer embryo to produce a bovine animal.
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 use the invention commensurate in scope with these claims.
When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
Nature of Invention: The invention include multiple produce a genetical modified bovine animal, cell, and gene comprising a modification of an ACTN3 gene that impairs its ability to be result in expression of an ACTN3 protein.
Breadth of the Claims: The breadth of the animal and it offspring and the cell encompasses any bovine species, including but not limited to a bos taurus, bos indicus. The breath of the gene is to a gene of any species of origin. The genetic modification encompasses modification of one or both alleles of an ACNT3 gene (wild type or otherwise mutant or isoform). The modification is defined by the functional limitation of partially or completely impairing the ability of the gene to be expressed and result in a protein product. Thus the breadth encompasses any by transient or germline modification to the genome, episomally, epigenetically or by temporary or permanent inhibitor or antagonist. As such, the breadth of the modification that impairs genetic function is broad. Regarding the genetically modified animal, the claims do not recite that any particular phenotype that results from the genetic modification of the bovine animal. As such, the breadth of the resultant phenotype in the animal is one that has any phenotype or no phenotype at all.
Regarding the claimed method, the broadest claim is a method of producing a genetically modified animal, cell, or gene comprising obtaining a bovine cell and altering the gene sequence to impair ACTN3 gene partially or completely. The claims do no define the nature of said altering or impairing. As such, the ACTN3 can be altered in any way to impair any type of partial or complete impairment. “Impaired” as claimed in the method comprises reducing express at the transcriptional level, translational level, protein activity level by directly or indirectly impacting the ACTN3, which does not necessarily require a change in the genetic sequence of the ACTN3 gene. As such, the breadth of the impairment of the ACTN3 gene is broad and diverse in nature. The claims do not recite any other steps but results in a gene, cell, and animal. As such the breadth of the method of making the animal encompasses altering the gene, cell, bovine animal in any way and those are the only steps required to result in an animal.
Specification Guidance: The specification states the following (citation from the Pregrant publication):
[0044] The invention provides genetically engineered beef cattle having, within their genome, a modified chromosomal sequence within the ACTN3 gene that impairs or eliminates expression of the Alpha-actinin-3 protein.
[0045] In one embodiment, the modified chromosomal sequence comprises one or more premature termination codon(s) inserted within the ACTN3 gene, preferably within one of twenty available exons (FIG. 1). An example of this embodiment is presented below. Exon 605694 is selected due to its comparatively large size and significant distance from either the initiation or termination of the wild-type gene.
[0046] The sequence as naturally occurring in the wild-type gene is illustrated first (SEQ ID NO. 2). The sequence as occurring in the modified gene is illustrated beneath the wild-type gene (SEQ ID NO. 3). The modified sequence replaces the thirty-sixth amino acid—Arginine (GCG)—with a Premature Termination Codon (TAG), resulting in a nonsense mutation.
[0053] The invention provides any method of modifying a chromosomal sequence in vitro or in vivo as currently practiced in the art for realizing the animal, cell, or gene in this invention.
[0054] In the preferred embodiment, the invention uses the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system to edit the target gene genomic DNA in order to introduce a disabling mutation. This is the best mode contemplated by the author for carrying out the invention.
[0060] If working with animal zygotes or embryos another implementation would be to microinject in vitro transcribed and purified Cas9 mRNA and sgRNA directly into the zygotes or embryos.
[0070] In another embodiment, the invention uses Transcription activator-like effector nucleases (TALEN) to disrupt the genomic DNA sequence of the target gene.
[0072] In another embodiment, the invention uses RNAi methodology as would otherwise be practiced by people skilled in the art.
Working Examples: No working examples or reductions to practice were provided.
State of the Art: At the time of effective filing of the instant application, little information regarding the ACTN3 and modifications to the gene encoding ACTN3 was described. The earliest reportings on alterations of the ACTN3 gene and deficiency of expression of this gene were found as a naturally occurring missense mutation in the a significant portion of the human population, with a premature stop codon polymorphism that results in an R557X substitution and a non-function human ACTN3 protein. This polymorphism was found to be present in a significant number of elite athletes that have altered fast muscle fibers (abstract and p 1261 of MacArthur et al.) Garton et al (Human Molecular Genetics, 2014, Vol. 23, No. 7 1879–18930) reports, “Homozygosity for a common null polymorphism (R577X) in the ACTN3 gene results in the absence of the fast fibre-specific protein, a-actinin-3 in ∼16% of humans worldwide.a-Actinin-3 deficiency is detrimental to optimal sprint performance and benefits endurance performance in elite athletes. In the general population, a-actinin-3 deficiency is associated with reduced muscle mass, strength and fast muscle fibre area, and poorer muscle function with age”. See page 1879 abstract.
Mouse models with homozygous knockout of the ACTN3 gene where produce to characterize any phenotypic consequences of a deficiency of ACTN3. In the knockout mice, “they showed normal sarcomere formation at the light and electron microscope level and they did not demonstrate substantial loss of fast glycolytic (2B) fibers…. Loss of a-actinin-3 in fast fibers seems to be compensated for by an upregulation of the related protein a-actinin-2 (Fig. 1c), which shifts from preferential expression in oxidative fibers to uniform staining in all fibers in Actn3–/– muscle (Fig. 1b). The Actn3–/– mouse thus mimics a-actinin expression in 577XX humans, who also show a-actinin-3 deficiency and a-actinin-2 expression in all muscle fibers. See page 1261 of MacArthur.
Garton et al reports, “The Actn3 knock-out (KO) mouse model mimics the human phenotype, with fast fibres showing a shift towards slow/oxidative metabolism without a change in myosin heavy chain (MyHC) isoform. We have recently shown that these changes are attributable to increased activity of the calcineurin-dependent signalling
pathway in a-actinin-3 deficient muscle, resulting in enhanced response to exercise training. This led us to hypothesize that the Actn3 genotype influences muscle adaptation to disuse, irrespective of neural innervation. Separate cohorts of KO and wild-type mice underwent 2 weeks immobilization and 2 and 8 weeks of denervation.
Absence ofa-actinin-3 resulted in reduced atrophic response and altered adaptation to disuse, as measured by a change in MyHC isoform. KO mice had a lower threshold to switch from the predominantly fast to a slower muscle phenotype (in response to immobilization) and a higher threshold to switch to a faster muscle phenotype (in response to denervation). We propose that this change is mediated through baseline alterations in the calcineurin signalling pathway of Actn3 KO muscle. Our findings have important implications for understanding individual responses to muscle disuse/disease and training in the general population.” See abstract.
The only art found that addresses ACTN3 gene polymorphisms in bovine animals was reported by Vaughn et al (Frontiers in Genetics vol 13 Article 796038. 2022 pages 1-11). Vaughn et al report, “Based on these residual intake observations, individuals were ranked from most efficient to least efficient. Skeletal muscle samples were analyzed from 54 steers in three groups of 18 (high efficiency, low efficiency, and a statistically average group). ACTN3, which encodes a muscle-specific structural protein, was previously identified as a candidate gene from a microarray analysis of RNA extracted from muscle samples obtained from a subset of steers from each of these three efficiency groups. The expression of ACTN3 was evaluated by quantitative
reverse transcriptase PCR analysis. The expression of ACTN3 in skeletal muscle was 1.6-fold greater in the inefficient steer group than in the efficient group (p = 0.007). In addition to expression measurements, blocks of SNP haplotypes were assessed for breed or parent of origin effects. A maternal effect was observed for ACTN3 inheritance, indicating that a maternal B. indicus block conferred improved residual feed efficiency relative to the B. taurus copy (p = 0.03). A SNP haplotype analysis was also conducted for m-calpain (CAPN2) and fibronectin 1 (FN1), and a significant breed effect was observed for both genes, with B. indicus and B. taurus alleles each conferring favorable efficiency when inherited maternally (p = 0.03 and p = 0.04). Because the ACTN3 structural protein is specific to fast-twitch (type II) muscle fibers and not present in slow-twitch muscle fibers (type I), muscle samples used for expression analysis were also assayed for fiber type ratio (type II/type I). Inefficient animals had a fast fiber type ratio 1.8-fold greater than the efficient animals (p = 0.027). Because these fiber-types exhibit different metabolic profiles, we hypothesize that animals with a greater proportion of fast-twitch muscle fibers are also less feed efficient.” See page 1. While Vaughn et al provides interesting insight into the function of ACTN3 in cattle, and one could see a possible utility for producing a ACTN3 knockout bovine animal that could lead from the hypothesis of Vaughn. However, Vaughn et al and all the prior art falls short of producing a ACTN3 bovine animal.
The unpredictability of a phenotype in a genetically modified animal has been long established in the prior art, especially between different species of animal. Suva et al (Bone 2020 130: doi:10.1016/j.bone.2019.115119. pp 1-16) reports, “Historically, genetically modified mice, in particular mice in which a specific gene has
been inactivated (knockouts), have served as a cornerstone for models of animal and human disease and as the ultimate test for the determination of gene function. However, mice are not completely representative of human physiology, metabolism, genetics, lifespan, or size and many times engineered mice do not exhibit the same phenotype or reveal the same gene function(s) observed in humans.”. See page 1, last paragraph. As such, Suva et al provides phenotype in a knockout mouse model will not predictably translate into the same phenotype in other animals species such as human, livestock, or bovine animals.
Henning et al (Nature Research (2020) 10:22309. Pages 1-9) reports, “CRISPR-mediated genome editing in livestock zygotes offers an attractive approach to introduce useful genetic variation into the next generation of cattle breeding programs. However, genetic mosaicism is particularly problematic for CRISPR-mediated genome editing in developing zygotes…. Genetic mosaicism complicates phenotypic analysis of F0 animals and may complicate screening multiple founders and breeding mosaic founders to produce an F1 generation… A limited number of genome editing studies have been reported in bovine zygotes.., and indicate the frequent production of mosaic embryos. The frequency of mosaicism varies depending upon the type of site-directed nuclease used, the timing of editing relative to embryonic development, the form and efficiency of the targeting regents, the intrinsic properties of the target locus, and the method of delivery…”. See page 1. As such, Henning teaches that even in producing targeted knockouts or knockin of bovine embryos, the methodology does not predictably provide the same genotypes between different bovine animal, particularly in part due to mosaicism, which causes phenotype to be unpredictable as well.
Thus state of the art teaches a high degree of unpredictability. The specification of the instant application provides generic guidance to making the claimed ACNT3 knockout bovine animal that essentially relies upon the teaching of the prior art methods to make and use the claimed genetically modified bovine animal. However, the prior art teaches that making a genetically modified bovine animal is unpredictable. Even further, the breadth of the claims encompasses a genetically modified bovine animal that has any and all possible phenotypes because the claims do not limit the bovine animal any particular phenotype. However, the state of the art teaches that phenotype is highly unpredictable in bovine knockout animals due in part to genetic mosaicism. Further, while the art provides ACTN3 knockout mouse model that have a particular phenotype, the art teaches that findings in mouse models to not predictably translating into the same finding in other species of knockout animals. The specification fails to provide specific guidance to any specific targeting sequence or gRNAs that would overcome issues of impart unpredictabilites described in the prior art in making the claimed bovine ACNT3 knockout animal or one with any particular phenotype. It is further noted that the breadth of the claimed bovine animal encompasses no phenotype, which has not disclosed enabled use. As such, the breadth of the claims to a bovine ACNT3 animal is not enabled by the specification and the prior art does not supplement the shortcoming of the specification. Further, the art teaches a high degree of unpredictability that the specification does not address.
The method claims have been included in this rejection as well, mostly because the recited steps would only produce a modified bovine cell or gene, but would fall short of producing a bovine animals. As such the breadth of the claims is not enabled.
Therefore at the time of filing the skilled artisan would need to perform an undue amount of experimentation without a predictable degree of success to implement the invention as claimed.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632