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 .
Applicant’s amendment filed on 12/04/2025 has been entered.
Claims 69-74, 76-81, 115, 118, 121-126 and 129 are pending in the present application.
Applicant’s election without traverse of the following species in the reply filed on 12/04/2025 is acknowledged.
Applicant elected: (i) a nuclease as a species of a toxin; (ii) Barnase as a species of a nuclease; (iii) chicken as a species of a non-human vertebrate animal.
Accordingly, claims 73-74, 80-81 and 125-126 are withdrawn from further consideration because they are directed to non-elected species.
Therefore, claims 69-72, 76-79, 115, 118, 121-124 and 129 are examined on the merits herein with the above elected species.
Claim Rejections - 35 USC § 112 (Lack of Written Description)
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 69-72, 76-79, 115, 118, 121-124 and 129 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.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc). Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1117. The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed. ”Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1116.
Claims 69-72 encompass a method of producing a single sex population of non-human vertebrate animals, the method comprising: crossing (i) a first non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) having a first genotype comprising one or more sequence variants of any gene, and heterozygous allosomes, wherein one of the allosomes is modified to express one or more expression cassettes comprising any promoter, a nucleotide sequence of any type, a splice site (e.g., a donor splice site or an acceptor splice site), an open reading frame encoding any transgenic protein (e.g., not necessarily limited to a toxin such as a nuclease (e.g., the elected Barnase, an RNase, a restriction endonuclease), a ribosome toxin (e.g. diptheria, ricin, abrin), or a protease (e.g., a caspase, proteinase K, trypsin, chymotrypsin, or papain), and a polyadenylation signal; with (ii) a second transgenic non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) having a second genotype comprising a wildtype genome with homozygous allosomes; wherein the resulting progeny having a genotype comprising a wildtype gene and the allosome engineered to express the one or more transgenes is not viable; thereby creating a single sex population.
Claims 76-79 encompass a method of producing a single sex population of non-human vertebrate animals, the method comprising: obtaining (i) a first non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) comprising one or more sequence variants of any autosomal gene, and a modified allosome comprising one or more expression cassettes, wherein the one or more expression cassettes comprise the following elements in 5’ to 3’ orientation: any promoter; operatively linked thereto a nucleic acid sequence of any type; a splice site (e.g., a donor splice site or an acceptor splice site); an open reading frame encoding any transgenic protein (e.g., not necessarily limited to a toxin such as a nuclease (e.g., the elected Barnase, an RNase, a restriction endonuclease), a ribosome toxin (e.g. diptheria, ricin, abrin), or a protease (e.g., a caspase, proteinase K, trypsin, chymotrypsin, or papain); and a polyadenylation signal; obtaining (ii) a second non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) comprising a wildtype genome; and crossing the first non-human vertebrate animal and the second non-human vertebrate animals, wherein a resulting progeny comprising a wildtype gene and the modified allosome expressing the transgenic protein is not viable; thereby creating a single sex population.
Claims 115, 118, 121-124 and 129 encompass a method of producing a single sex population of non-human vertebrate animals, the method comprising: crossing (i) a first non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) comprising one or more nucleotide modifications in a sequence of an intron of a gene; one or more expression cassettes comprising any promoter, a splice site (e.g., a donor splice site or an acceptor splice site), an open reading frame encoding any transgenic protein (e.g., not necessarily limited to a toxin such as a nuclease (e.g., the elected Barnase, an RNase, a restriction endonuclease), a ribosome toxin (e.g. diptheria, ricin, abrin), or a protease (e.g., a caspase, proteinase K, trypsin, chymotrypsin, or papain), and a polyadenylation signal, wherein the one or more nucleotide modifications in the sequence of the intron cannot splice to the splice site and wherein the intron of the gene and the one or more expression cassettes are located on a single allosome; with (ii) a second transgenic non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) having a second genotype comprising a wildtype sequence of the intron of the gene, wherein the wildtype sequence of the intron of the gene is capable of splicing to the splice site and homozygous allosomes; wherein a resulting progeny having a genotype comprising the wildtype sequence of the intron of the gene and the one or more expression cassettes is not viable.
The instant specification discloses an exemplary genetic cross diagram showing how to generate single sex offspring such as chicken using the claimed methods, and the Punnett Square of possible genotypic outcomes of offspring from genetic crossing of A*A* and Z1W with AA and ZZ chicken as shown in Figs. 1 and 2, respectively, below. A* refers to an autosome having a mutated sequence that is not capable of base pairing with a trans-splicing accepting gene; and Z1 refers to an allosome that is integrated with one or more RNA trans-splicing expressing cassettes.
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Apart from disclosing generically that trans-splicing is a special molecular process of RNA or protein wherein exons (in mRNA) or exteins (in proteins) from two different primary mRNA transcripts or proteins are cleaved to remove introns (in mRNA) or inteins (in protein) and joined end to end via ligation, resulting in fusion mRNA or protein; and in this application generation of single sex offspring in animal is described by utilizing trans-splicing process to express a transgene or gene of interest, e.g., toxin, in which when expressed is lethal to the cell (see at least paragraphs [0042], [0066], [0072], [0080]-[0087]; and Figs. 1-6); the instant specification failed to describe sufficiently in detail any first non-human vertebrate animal having a first genotype comprising one or more sequence variants of any kind in a gene or autosomal gene, not necessarily limited to one or more nucleotide modifications in a sequence of an intron of a gene, wherein the one or more nucleotide modifications in the intron cannot splice to the splice site that is present in one or more expression cassettes, and any modified allosome comprising one or more expression cassettes comprising any promoter, any nucleic acid sequence, not necessarily limited to a nucleic acid sequence that is capable of base pairing to a wildtype intron sequence of a gene for trans-splicing, a splice site, an open reading frame encoding any transgenic protein, not even necessarily limited to a toxin, and a polyadenylation signal for crossing a second non-human vertebrate animal comprising a wildtype genome in the methods as claimed broadly to generate a single sex population; particularly the transgenic protein is not even a toxin. For example, apart from a toxin transgenic protein such as the elected Barnase (a potent, small bacterial ribonuclease from Bacillus amyloliquefaciens), what are the essential characteristics possessed by the other non-toxin, transgenic proteins that allow them to result in a generation of a single sex population as encompassed broadly by the instant claims via a trans-splicing process? Without a nucleotide sequence that is capable of base pairing to a wildtype intron sequence of a gene for trans-splicing (see Figs. 3-5 of the present application), what are the essential characteristics possessed by the other nucleotide sequences in one or more expression cassettes containing a splice site as encompassed broadly by the instant claims, such that they also result in a generation of a single sex population via a trans-splicing process? Similarly, apart from one or more nucleotide modifications in a sequence of an intron of a gene or an autosomal gene, wherein the one or more nucleotide modifications in the intron cannot splice to the splice site that is present in one or more expression cassettes; what are the specific characteristics possessed by the other one or more sequence variants of a gene or an autosomal gene as encompassed broadly by the instant claims, such that they also result in a generation of a single sex population via a trans-splicing process? In a review of Spliceosome-mediated RNA trans-splicing (SMaRT) for diagnostic and therapeutic purposes, Wally et al (J. Invest. Dermatology 132:1959-1966, 2012; IDS) disclosed that a target recognition sequence/binding domain (BD) that is able to hybridize specifically to an endogenous pre-mRNA of interest is of major importance for success of the trans-splicing process, with minor variations in sequence or target-binding position can have a major impact on the outcome of mRNA repair (third column at page 1960; and Figures 1 and 3). Wally et al also stated “Analysis of numerous RTM (RNA-trans-splicing molecule) libraries revealed the functionality of RTMs to be mainly related to length and binding position (Figure 4). However, it is also likely that the secondary structure formation, length of the targeted intron and other unknown factors influence trans-splicing efficiency. As these factors are hard to predict, identification of the most-efficient BDs by large-scale FACS screening is currently the best way to obtain high-quality RTMs” (first column at page 1961).
Importantly, even in the claimed embodiment wherein the transgenic protein is a toxin, the instant specification also fails to provide sufficient written description for a viable first non-human vertebrate animal having the recited features in independent claims 69, 76 and 115 for crossing with a second transgenic non-human vertebrate animal comprising a wildtype genome to generate a single sex population of non-human vertebrate animals as claimed broadly. This is because one or more expression cassettes comprising a promoter, a nucleotide sequence, a splice site and an open reading frame encoding a transgenic protein that is a toxin, and a polyadenylation signal express a pre-trans-splicing molecule (PTM) or RNA-trans-splicing molecule (RTM) carrying a transgene encoding a toxin that is translatable to a toxin (e.g., a nuclease such as the elected Barnase, an RNase, or a restriction endonuclease), which is lethal to cells of the first non-human vertebrae animal as encompassed broadly by the instant claims, regardless whether a trans-splicing process occurs or not. The instant specification stated specifically “In some cases, an intron is retained and the non-spliced mRNA is translated to a protein” (last sentence of paragraph [0045]). Additionally, Trapani et al (EMBO Molecular Medicine 6:194-211, 2014) already reported at least that truncated proteins are produced in HEK293 cells from the 5’- and 3’-halves of dual AAV vectors (e.g., the Hybrid AP (AP, alkaline phosphatase recombinogenic region) and Hybrid AK (AK, F1 phage recombinogenic region) dual AAV vectors) having the structures shown below (page 200, left column, last sentence; page 204, left column, second full paragraph; Figs. 1, S12 and S13). SD, splicing donor signal; SA, splicing acceptor signal.
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Moreover, Trapani et al (Human Molecular Genetics 24:6811-6825, 2015) also demonstrated that truncated proteins are produced in HEK293 cells and pig eyes from the 5’- and 3’-halves of dual AAV vectors (see at least section titled “Inclusion of the CL1 degron in the 5’-half vector decreases the production of truncated proteins” at page 6815; particularly Fig. 4A (lane 5’+3’) and Fig. 4B (lane 5’+3’)). Thus, the results of Trapani et al demonstrated that non-spliced RNAs are still translated to proteins in HEK293 cells and pig eyes.
Furthermore, it is also interesting to note that the Punnett Square of possible genotypic outcomes of offspring from genetic crossing of A*A* and Z1W with AA and ZZ chicken in Figure 2 of the present application, all male chicken offsprings (Z1Z) are not viable (indicating with a cross through a circle) since each of the male chicken offsprings carries a single allosome Z1 containing one or more expression cassettes for RNA trans-splicing process to express toxin protein; and this is the same Z1 allosome found in the A*A* and Z1W hen used for crossing. There is also no evidence of record indicating at least that an A*A* and Z1W hen has been successfully obtained or constructed that is viable for crossing in any of the claimed methods to generate a single sex population, let alone any first non-human vertebrate animal having the recited features used for crossing as encompassed by the instant claims.
Since the prior art before the effective filing date of the present application (09/16/2022) failed to provide sufficient guidance and/or written description for the above issues as evidenced at least by the teachings of Zhang et al (WO 2023/064895; IDS), Douglas et al (PLOS Genetics; doi.org/10.1371/journal.pgen.1008898, 19 pages, 2020), Lee et al (FASEB J. 33: 1-11, 2019; IDS), Riedmayr (Methods in Molecular Biology 2079:219-232, 2020; IDS), Blake et al (WO 2018/013759; IDS), Trapani et al (Human Molecular Genetics 24:6811-6825, 2015), Trapani et al (EMBO Molecular Medicine 6:194-211, 2014), Wally et al (J. Invest. Dermatology 132:1959-1966, 2012; IDS), and Alphey et al (US 9,125,388); it is incumbent upon the instant specification to do so. Furthermore, the instant specification also fails to provide and describe at least a representative number of species for a broad genus of a viable first non-human vertebrate animal having the recited features to be used for crossing with a second transgenic non-human vertebrate animal comprising a wildtype genome to generate a single sex population of non-human vertebrate animals in the methods as claimed broadly.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which are not conventional in the art as of Applicants’ filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998). The skilled artisan cannot envision at least a representative number of species for a broad genus of a viable first non-human vertebrate animal having the recited features to be used for crossing with a second transgenic non-human vertebrate animal comprising a wildtype genome to generate a single sex population of non-human vertebrate animals in the methods as claimed broadly; and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112 (Enablement)
Claims 69-72, 76-79, 115, 118, 121-124 and 129 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in the determination of an enabling disclosure have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims. Ex parte Forman, (230 USPQ 546 (Bd Pat. Appl & Unt, 1986); In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988)).
The instant specification is not enabled for the reasons discussed below.
1. The breadth of the claims
Claims 69-72 encompass a method of producing a single sex population of non-human vertebrate animals, the method comprising: crossing (i) a first non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) having a first genotype comprising one or more sequence variants of any gene, and heterozygous allosomes, wherein one of the allosomes is modified to express one or more expression cassettes comprising any promoter, a nucleotide sequence of any type, a splice site (e.g., a donor splice site or an acceptor splice site), an open reading frame encoding any transgenic protein (e.g., not necessarily limited to a toxin such as a nuclease (e.g., the elected Barnase, an RNase, a restriction endonuclease), a ribosome toxin (e.g. diptheria, ricin, abrin), or a protease (e.g., a caspase, proteinase K, trypsin, chymotrypsin, or papain), and a polyadenylation signal; with (ii) a second transgenic non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) having a second genotype comprising a wildtype genome with homozygous allosomes; wherein the resulting progeny having a genotype comprising a wildtype gene and the allosome engineered to express the one or more transgenes is not viable; thereby creating a single sex population. It is noted that the claims are not necessarily limited that first non-human vertebrate animal and the second transgenic non-human vertebrate animal are from the same animal species that are used for crossing.
Claims 76-79 encompass a method of producing a single sex population of non-human vertebrate animals, the method comprising: obtaining (i) a first non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) comprising one or more sequence variants of any autosomal gene, and a modified allosome comprising one or more expression cassettes, wherein the one or more expression cassettes comprise the following elements in 5’ to 3’ orientation: any promoter; operatively linked thereto a nucleic acid sequence of any type; a splice site (e.g., a donor splice site or an acceptor splice site); an open reading frame encoding any transgenic protein (e.g., not necessarily limited to a toxin such as a nuclease (e.g., the elected Barnase, an RNase, a restriction endonuclease), a ribosome toxin (e.g. diptheria, ricin, abrin), or a protease (e.g., a caspase, proteinase K, trypsin, chymotrypsin, or papain); and a polyadenylation signal; obtaining (ii) a second non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) comprising a wildtype genome; and crossing the first non-human vertebrate animal and the second non-human vertebrate animals, wherein a resulting progeny comprising a wildtype gene and the modified allosome expressing the transgenic protein is not viable; thereby creating a single sex population. It is noted that the claims are not necessarily limited that first non-human vertebrate animal and the second non-human vertebrate animal are from the same animal species that are used for crossing.
Claims 115, 118, 121-124 and 129 encompass a method of producing a single sex population of non-human vertebrate animals, the method comprising: crossing (i) a first non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) comprising one or more nucleotide modifications in a sequence of an intron of a gene; one or more expression cassettes comprising any promoter, a splice site (e.g., a donor splice site or an acceptor splice site), an open reading frame encoding any transgenic protein (e.g., not necessarily limited to a toxin such as a nuclease (e.g., the elected Barnase, an RNase, a restriction endonuclease), a ribosome toxin (e.g. diptheria, ricin, abrin), or a protease (e.g., a caspase, proteinase K, trypsin, chymotrypsin, or papain), and a polyadenylation signal, wherein the one or more nucleotide modifications in the sequence of the intron cannot splice to the splice site and wherein the intron of the gene and the one or more expression cassettes are located on a single allosome; with (ii) a second transgenic non-human vertebrate animal (e.g., a cow, a mouse, a pig, a chicken, a fish, a bird, a reptile) having a second genotype comprising a wildtype sequence of the intron of the gene, wherein the wildtype sequence of the intron of the gene is capable of splicing to the splice site and homozygous allosomes; wherein a resulting progeny having a genotype comprising the wildtype sequence of the intron of the gene and the one or more expression cassettes is not viable. It is noted that the claims are not necessarily limited that first non-human vertebrate animal and the second transgenic non-human vertebrate animal are from the same animal species that are used for crossing.
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application 09/16/2022), virtually nothing was known about a method for producing a single sex population of non-human vertebrate animals by utilizing trans-splicing process to express a transgene or gene of interest such as a toxin gene, in which when expressed is lethal to cells as evidenced at least by the teachings of Zhang et al (WO 2023/064895; IDS), Douglas et al (PLOS Genetics; doi.org/10.1371/journal.pgen.1008898, 19 pages, 2020), Lee et al (FASEB J. 33: 1-11, 2019; IDS), Riedmayr (Methods in Molecular Biology 2079:219-232, 2020; IDS), Blake et al (WO 2018/013759; IDS), Trapani et al (Human Molecular Genetics 24:6811-6825, 2015), Trapani et al (EMBO Molecular Medicine 6:194-211, 2014), Wally et al (J. Invest. Dermatology 132:1959-1966, 2012; IDS), and Alphey et al (US 9,125,388). Please note that the physiological art is already recognized as unpredictable (MPEP 2164.03).
3. The amount of direction or guidance provided
Apart from disclosing generically an approach to produce a single sex population of non-human vertebrate animals via a trans-splicing process along with prophetic examples (Summary of the Invention; Examples 1-2 and Figures 1-6); the instant specification failed to provide sufficient guidance for an ordinary skilled artisan on how to produce a single sex population of non-human vertebrate animals in the methods as claimed, particularly on how to make and use a first non-human vertebrate animal having a first genotype comprising one or more sequence variants of any kind in a gene or autosomal gene, not necessarily limited to one or more nucleotide modifications in a sequence of an intron of a gene, wherein the one or more nucleotide modifications in the intron cannot splice to the splice site that is present in one or more expression cassettes, and any modified allosome comprising one or more expression cassettes comprising any promoter, any nucleic acid sequence, not necessarily limited to a nucleic acid sequence that is capable of base pairing to a wildtype intron sequence of a gene for trans-splicing, a splice site, an open reading frame encoding any transgenic protein, not even necessarily limited to a toxin, and a polyadenylation signal for crossing a second non-human vertebrate animal comprising a wildtype genome to generate a single sex population; and especially the transgenic protein is not even a toxin. Apart from the use of a toxin transgenic protein such as the elected Barnase (a potent, small bacterial ribonuclease from Bacillus amyloliquefaciens), there is no evidence of record indicating that any non-toxin, transgenic protein has been successfully used in the generation of a single sex population as encompassed broadly by the instant claims via a trans-splicing process. In a review of Spliceosome-mediated RNA trans-splicing (SMaRT) for diagnostic and therapeutic purposes, Wally et al (J. Invest. Dermatology 132:1959-1966, 2012; IDS) disclosed that a target recognition sequence/binding domain (BD) that is able to hybridize specifically to an endogenous pre-mRNA of interest is of major importance for success of the trans-splicing process, with minor variations in sequence or target-binding position can have a major impact on the outcome of mRNA repair (third column at page 1960; and Figures 1 and 3). Wally et al also stated “Analysis of numerous RTM (RNA-trans-splicing molecule) libraries revealed the functionality of RTMs to be mainly related to length and binding position (Figure 4). However, it is also likely that the secondary structure formation, length of the targeted intron and other unknown factors influence trans-splicing efficiency. As these factors are hard to predict, identification of the most-efficient BDs by large-scale FACS screening is currently the best way to obtain high-quality RTMs” (first column at page 1961).
With respect to the claimed embodiment in which the transgenic protein is a toxin, there is no evidence of record indicating that a viable first non-human vertebrate animal having the recited features in independent claims 69, 76 and 115 has been successfully obtained or generated for crossing with a second transgenic non-human vertebrate animal comprising a wildtype genome to generate a single sex population of non-human vertebrate animals as claimed. This is because one or more expression cassettes comprising a promoter, a nucleotide sequence, a splice site and an open reading frame encoding a transgenic protein that is a toxin, and a polyadenylation signal express a pre-trans-splicing molecule (PTM) or RNA-trans-splicing molecule (RTM) carrying a transgene encoding a toxin that is translatable to a toxin (e.g., a nuclease such as the elected Barnase, an RNase, or a restriction endonuclease), which is lethal to cells of the first non-human vertebrae animal as encompassed broadly by the instant claims, regardless whether a trans-splicing process occurs or not. The instant specification stated specifically “In some cases, an intron is retained and the non-spliced mRNA is translated to a protein” (last sentence of paragraph [0045]). Additionally, Trapani et al (EMBO Molecular Medicine 6:194-211, 2014) already reported at least that truncated proteins are produced in HEK293 cells from the 5’- and 3’-halves of dual AAV vectors (e.g., the Hybrid AP (AP, alkaline phosphatase recombinogenic region) and Hybrid AK (AK, F1 phage recombinogenic region) dual AAV vectors) having the structures shown below (page 200, left column, last sentence; page 204, left column, second full paragraph; Figs. 1, S12 and S13). SD, splicing donor signal; SA, splicing acceptor signal.
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Moreover, Trapani et al (Human Molecular Genetics 24:6811-6825, 2015) also demonstrated that truncated proteins are produced in HEK293 cells and pig eyes from the 5’- and 3’-halves of dual AAV vectors (see at least section titled “Inclusion of the CL1 degron in the 5’-half vector decreases the production of truncated proteins” at page 6815; particularly Fig. 4A (lane 5’+3’) and Fig. 4B (lane 5’+3’)). Thus, the results of Trapani et al demonstrated that non-spliced RNAs are still translated to proteins in HEK293 cells and pig eyes.
Furthermore, it is also interesting to note that the Punnett Square of possible genotypic outcomes of offspring from an exemplary genetic crossing of A*A* and Z1W with AA and ZZ chicken as shown in Figures 1-2 of the present application which are reproduced below, all male chicken offsprings (Z1Z) are not viable (indicating with a cross through a circle) since each of the male chicken offsprings carries a single allosome Z1 containing one or more expression cassettes for RNA trans-splicing process to express toxin protein; and this is the same Z1 allosome found in the A*A* and Z1W hen used for crossing.
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Once again, there is also no evidence of record indicating at least that an A*A* and Z1W hen has been successfully obtained or constructed that is viable for crossing in any of the claimed methods to generate a single sex population, let alone any first non-human vertebrate animal having the recited features used for crossing as encompassed by the instant claims.
The instant specification also fails to provide sufficient guidance on how to generate a single sex population of non-human vertebrate animals by mating the first non-human vertebrate animal and the second transgenic non-human vertebrate animal, wherein the first animal and the second animal are not even from the same animal species as encompassed broadly by the instant claims. Mating unrelated species faces major hurdles like genetic incompatibility (different chromosome structures, DNA incompatibilities causing development issues, leading to sterile or unhealthy hybrids, e.g., mules), reproductive isolation (behavioral/physical barriers), and zygote mortality (genes not “playing well together”, halting development) as evidenced at least by the teachings of Dagilis et al (Science 368:710-711, 2020).
Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding to the aforementioned issues, it is incumbent upon the present application to do so. Given the state of the prior art, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use the instant invention as claimed.
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issues set forth above, the state and unpredictability of the relevant art, and the breadth of the instant claims, it would have required undue experimentation for one skilled in the art to make and use the instant claimed invention.
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 76-79 and 121 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 76 recites the limitation "the second non-human vertebrate animals" in lines 11-12 of the claim. There is insufficient antecedent basis for this limitation in the claim. This is because prior to this limitation, there is no recitation of second non-human vertebrate animals. Thus, which particular the second non-human vertebrate animals that the limitation refers to. Clarification is requested because the metes and bounds of the claim are not clearly determined.
In claim 121, it is unclear what is encompassed by the limitation “the non-human vertebrate animal”. Which one? The first non-human vertebrate animal or the second transgenic non-human vertebrate animal. Once again, clarification is requested because the metes and bounds of the claim are not clearly determined.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 69-72, 76-79, 115, 118, 121-124 and 129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 77-90 and 137-183 of copending Application No. 18/939,359 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because methods of producing a single sex population of non-human vertebrate animals in claims 77-90 and 137-183 of copending Application No. 18/939,359 anticipate and/or encompass methods of producing a single sex population of non-human vertebrate animals in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/
Primary Examiner, Art Unit 1631