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 .
Claim Status
Claims 1-7 were previously pending.
Receipt is acknowledged of the amendments to the claims filed on 11 September, 2025. Claims 1-7 are cancelled. Claims 8-20 are newly added. Claims 8, 16, 19 and 20 are independent claims.
Therefore, claims 8-20 are pending and are the subject of the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2020/047548, filed 18 December, 2020, which claims priority to United State Provisional Application No. 62,951,498, filed 20 December, 2019.
Therefore, the earliest possible priority for the instant application is 20 December, 2019.
Drawings
The drawings submitted on 13 June, 2022 are accepted by the Examiner.
Examiner’s Comment
Throughout the instant Official Action, where reference is made to the Instant Specification, the Examiner notes that the publication of the instant Application is being referenced (US 2023/0027317).
Withdrawn Objections/Rejections in View of Applicant’s Amendments/Arguments
Claim Objections
The objection to claims 1, and 3-4 because abbreviations need to be spelled out upon their first encounter in the claims is rendered moot in view of Applicant’s amendments. Applicant has cancelled claims 1, and 3-4.
Claim Rejections - 35 USC § 112
The rejection of claims 1-7 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 is rendered moot in view of Applicant’s amendments to the claims.
Applicant has cancelled claims 1-7.
Claim Rejections - 35 USC § 103
The rejection of claims 1-7 under 35 U.S.C. 103 as being unpatentable over Sato et al. (Cell stem cell 19.1 (2016): 127-138. (cited on the IDS filed: 08 September, 2022) (hereinafter, “Sato”)) in view of Jankowsky et al. (Human molecular genetics 13.2 (2004): 159-170. (cited on the IDS filed: 08 September, 2022) (hereinafter, “Jankowsky”)), Hiltunen et al. (European Journal of Human Genetics 8.4 (2000): 259-266. (cited in the IDS filed: 08 September, 2022) (hereinafter, “Hiltunen”)), and Cléry et al. (Journal of Neurophysiology 124.6 (2020): 1900-1913. (hereinafter “Cléry”)) is rendered moot in view of Applicant’s amendments to the claims.
Applicant has cancelled claims 1-7.
New Rejections in Response to Applicant’s Amendments
The amendments filed: 11, September, 2025 have necessitated the following new grounds of rejection. Applicant cancelled all previously rejected claims and has added new claims 8-20.
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 8-15 are rejected under 35 U.S.C. 101 because the claimed invention is not supported by either a credible asserted utility or a well-established utility. This is a new rejection necessitated by amendment of the claims in the response filed 9/11/2025.
Claims 8-15 are directed to a non-human primate model for Alzheimer's disease wherein the non-human primate comprises an endogenous mutation in the PSENl Gene wherein the mutation includes deletion of one or both of 2 nucleotides of 5 '-splice site GT of exon 9 of the PSENl gene or one or both of 2 nucleotides of 3' -splice site AG of exon 9 of the PSENl gene, and the deletion induces skipping of exon 9 during RNA splicing. The claims fail to recite any phenotype of the non-human primate model, which is not distinguishable from the corresponding wild-type non-human primate model. Absent any phenotype of the non-human primate model, the claimed non-human primate model lacks either a specific and substantial asserted utility or a well-established utility.
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 8-20 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 8 recites “2 nucleotides of 5’-splice site GT of exon 9” and “2 nucleotides of 3’-splice site AG of exon 9” in the third wherein clause of the claim. Each of these recitations is unclear insofar as it is unclear whether the two nucleotides of the splice site are the recited two letters following each statement (“GT” and “AG”) or whether “GT” and “AG” are part of the full identifiers for the splice sites and the claim is intended to encompass any two nucleotides within the respective splice sites. For the purpose of compact prosecution, this claim is interpreted consistent with the specification as referring to “AG” and “GT” nucleotide pairs within the respective splice sites. Claims 9-15, and 19-20 are further rejected for their dependency on a rejected base claim.
Claim 15 is confusing as written. Claim 15 is directed to the non-human primate model of claim 8, yet claim 15 recites methods steps. This is confusing because it is unclear whether Applicant intends claim 15 to be directed to a method or a product. For the purpose of compact prosecution, claim 15 is interpreted as reciting an intended use for the product of claim 8 and nothing more.
Claim 16 recites the limitation "the cultured embryos” in tenth line of the claim. There is insufficient antecedent basis for this limitation in the claim. Nowhere in claim 16 is there a recitation of “cultured embryos”. Thus, it is unclear what “the cultured embryos” is referencing.
Claim 16 recites the limitation "the resulting offspring” in eleventh line of the claim. There is insufficient antecedent basis for this limitation in the claim. Nowhere in claim 16 is there a recitation of “resulting offspring”. Thus, it is unclear what “the resulting offspring” is referencing.
Claim 16 recites the limitation "the deletion” in last line of the claim. There is insufficient antecedent basis for this limitation in the claim. Nowhere in claim 16 is there a recitation of “a deletion”. Claim 16 only recites “ a heterozygous deletion”. Thus, it is unclear what “the deletion” is referencing.
Claims 17-18 are further rejected for their dependency on a rejected base claim (claim 16).
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 8-20 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:
A non-human primate model for Alzheimer’s disease,
whose genome comprises a presenilin 1 (PSEN1) gene;
wherein the non-human primate comprises an endogenous mutation in the PSEN1 gene;
wherein the mutated PSEN1 gene has the nucleotide sequence encoded by SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 20; and
wherein the non-human primate is heterozygous for said mutation, wherein the non-human primate model exhibits deficient γ-secretase activity or increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio in its fibroblasts.
And
A method of generating a non-human primate model of Alzheimer’s disease of claim 8,
The method comprising:
Introducing a pair of TALEN mRNAs into ova of a non-human primate, wherein the pair of TALEN mRNAs are encoded by SEQ ID NO: 1 and SEQ ID NO: 2;
Fertilizing the ova after step (a) and in vitro culturing the fertilized ova to produce cultured embryos; and
Transferring the cultured embryos into surrogate non-human primate females;
wherein an offspring resulting from the surrogate non-human primate females of step (c) comprises the nucleotide sequence encoded by SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 20 and
wherein the offspring resulting from the surrogate non-human primate females of step (c) exhibit exon 9 skipping during RNA splicing, wherein the offspring resulting from the surrogate non-human primate females of step (c) exhibit deficient γ-secretase activity or increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio in their fibroblasts.
does not reasonably provide enablement for (1) any mutation which includes deletion of one or both of AG of the 3’-splice site of exon 9 of PSEN1 and which induces exon skipping of exon 9 during RNA splicing, (2) any mutation at all of the 5’-splice site of exon 9 of PSEN1 which induces exon skipping of exon 9 during RNA splicing, (3) a method of generating a non-human primate model of Alzheimer’s disease utilizing any TALENs which target one or both of AG of the 3’-splice site of exon 9 of PSEN1 and which produce a deletion that results in exon 9 skipping during RNA splicing, (4) a method using any TALENs at all which target the 5’-splice site of exon 9 of PSEN1 and which produce a deletion that results in exon 9 skipping during RNA splicing, (5) a non-human primate model lacking a phenotype as a model for Alzheimer's disease , (6) endogenous mutations of the PSEN1 that are outside the genome of the non- human primate model or (7) any method of generating a heterozygous non-human primate model comprising introducing a genus of TALENs to fertilized ova. 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/use the inventions commensurate in scope with these claims.
Claim 8 broadly encompasses any mutation (wherein not all somatic and germ cells comprise the gene mutation) which includes deletion of one or both of AG of the 3’-splice site of exon 9 of PSEN1 and which induces exon skipping of exon 9 during RNA splicing, and any mutation of the 5’-splice site of exon 9 of PSEN1 which induces exon skipping of exon 9 during RNA splicing (reading on any sized deletion including one which encompasses most of the PSEN1 gene from the 5’ end to the end of intron 8 so long as it encompasses at least one base of the recited nucleotide pairs and results in skipping of exon 9). Claim 8 also broadly encompasses a non-human primate having any or no phenotype at all (see 101 rejection above) (reading on a non-human primate having even a single cell having the recited mutation and no resulting phenotype, as well as a non-human primate having genomic modification of every cell and yet still lacking a phenotype).
Claim 12 limits the size of the deletion insofar as it necessitates the use of the TALENs of SEQ ID NOs: 1 and 2. However, as shown in FIG. 1, these TALENs flank an approximately 16bp large segment at the junction between intron 8 and exon 9 and, as written, claim 12 continues to read on a deletion as small as 1 base in total (either A or G). It is noted that the TALENs recited in claim 12 do not flank the 5’-splice site. Claim 16 broadly encompasses a method of generating a non-human primate model of Alzheimer’s disease utilizing any TALENs (literally any TALENs) which target one or both of AG of the 3’-splice site of exon 9 of PSEN1 and which produce any deletion (reading on any sized deletion including one which encompasses most of the PSEN1 gene from the 5’ end to the end of intron 8 so long as it encompasses at least one base of the recited nucleotide pairs and results in skipping of exon 9) that results in exon 9 skipping during RNA splicing, and a method using any TALENs (literally any TALENs) which target the 5’-splice site of exon 9 of PSEN1 and which produce any deletion that results in exon 9 skipping during RNA splicing. Claim 16 also broadly encompasses generating heterozygous mutants by introducing TALENs to fertilized ova (encompassing somehow directing TALENs to modify the genome of the ova wherein after ferritization one chromosomal copy of a gene of the embryo is modified without modifying the other, resulting in a heterozygous non-human primate model). Claim 18 limits the TALENs to SEQ ID NOs: 1 and 2 just as claim 12 did above. However, the same issues exist here with respect to deletions as small as individual bases resulting in induced exon 9 skipping.
The specification provides working examples using TALENs encoded by SEQ ID NOs: 1 and 2 (Specification, [0044]). The instant specification specifically teaches the introduction of the above-referenced TALENs into the nuclei of fertilized marmoset ova (Specification, [0056]). The instant specification teaches that deficiency of the 3’-splice site was only seen in 2 out of 3 fertilized ova when assessed at the 4-cell stage ([0056]) and that introducing TALENs directly to fertilized ova resulted in homozygous deletion of exon 9 which was lethal ([0056]). Thus, as Example 1 of the instant specification explains, one cannot generate a heterozygous mutant by introducing TALENs to a fertilized ova, and such a process does not produce any “non-human primate model” because such a process is lethal to the embryos. The instant specification also teaches an alternative method whereby the TALENs discussed above are introduced to ova prior to fertilization and transfer to a surrogate mother marmoset to generate heterozygous offspring ([0057]). The results of this approach are embodied in FIG. 3 which shows one resulting heterozygous mutant possessing a PSEN1 gene having the sequence of SEQ ID NO: 13 which, compared to wild-type, possesses a deletion of the 6bp at the end of intron 8 including the final two nucleotides A and G (FIG. 3). The instant specification then teaches 3 other specific heterozygous mutant marmosets produced in the same way and which have the mutant PSEN1 genes of SEQ ID NOs: 16, 18, and 10 ([0060]). It is noted that the deletion embodied by SEQ ID NOs: 16 and 18 appear to be the same as that embodied by SEQ ID NO: 13 (FIG. 5). SEQ ID NO: 20 has a deletion of the same region as SEQ ID NOs: 13, 16, and 18 plus the first “CAA” of exon 9 for a total of 9 deleted nucleotides. Thus, the specification discloses only 4 mutant PSEN1 sequences, of which, only two deletions are taught (one 6-bp deletion and one 9-bp deletion) and all of which delete both the “A” and the “G” at the 3’-end of intron 8 (FIG. 5). The specification also teaches quantifying amyloid levels and that the 4 specific heterozygous mutant marmosets exhibit increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio (FIG. 4 and 6). The specification does not teach any methods of generating heterozygotes where TALENs are introduced to fertilized ova, any deletions other than the specific 6-bp or 9-bp deletions encompassing both the “A” and the “G” at the 3’-end of intron 8, nor any marmosets (or any other non-human primates for that matter) possessing anything other than a mutant PSEN1 gene having a sequence of 100% identity to SEQ ID NOs: 13, 16, 18, or 20 expressed heterozygously to result in skipping of exon 9 of PSEN1. The specification also does not teach any non-human primates possessing the mutant PSEN1 gene and not having an increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio.
The skilled artisan at the time of filing knew that the application of TALENs varies in efficiency of editing depending on a variety of factors including the species being edited, the type and amount of molecule delivered, TALEN architecture, target choice, and detection methods, among others (Wright et al. Biochemical Journal 462.1 (2014): 15-24., hereinafter “Wright”, at page 20, fourth full paragraph). Wright further teaches that the evaluation of TALEN systems depends on an evaluation of the literature that is most relevant to the species of interest (Wright, page 20, fourth full paragraph). Wright also teaches that DNA composition, half-site recognition lengths, and spacer length can affect TALEN performance (Wright, page 21, “Target Choice” heading). Thus, a skilled artisan at the time of filing understood that target binding sites for TALEN pairs are not equal and that designing TALENs to target a specific site is an experimental endeavor in which a variety of factors need to be considered to be able to effectuate TALEN-induced genomic modification. The skilled artisan at the time of filing also knew of at least one example for the genomic modification of marmosets using TALENs (Sato et al. Cell stem cell 19.1 (2016): 127-138., cited on the IDS filed: 08 September, 2022, hereinafter, “Sato”). Sato teaches that the design of TALENs targeting a single gene for knockout in marmosets (IL2RG) can be experimentally taxing in that multiple pairs need to be designed for evaluation, more than 60 oocytes may need to be injected resulting in only 42 embryos for transfer and culminating in only a single mutant marmoset per pair of TALENs (Sato, Figure 1, Table 1). Thus, a skilled artisan would understand a command to design TALENs targeting a specific site in marmosets to be an experimentally burdensome endeavor when the target is particularly described (as it was in Sato), and where, as here, the target requires only the A or G at the 3’-end of intron 8 to induce skipping of exon 9, a skilled artisan would understand the target site not to be particularly described in that it can be a deletion of any bases in between exon 1 and 9 which, when deleted, result in the skipping of exon 9. In fact, the applicant is on record as stating that the ordinary artisan would have had no reason to expect that “in a case of deleting exon 9 as a whole, it is necessary to break the double strand of the gene at least at two points to delete exon 9 as a whole (i.e. cut out exon 9 from the genome). For this purpose, it is necessary to introduce at least two sets of a genome editing tool into a fertilized ovum (or ovum) simultaneously so that they cause double-strand break of the gene at the same timing.” (page 9 of Applicant’s remarks) and that “the inventors of the present invention have found for the first time in the world that skipping of exon 9 can be caused by deleting a few bases and it allows for preparation of a non-human primate AD model” (page 9 of Applicant’s remarks). These remarks further highlight the unpredictably of skipping of exon 9 with by targeting only the A or G at the 3’-end of intron 8 to induce skipping of exon 9.
Alternatively, the claims 8-15 and 19-20 may be interpreted to read on somatic cell gene transfer, e.g., “introducing a pair of TALEN mRNAs into ova or fertilized ova of a non-human primate”. The claims, as written, do not specifically convey germline transmission of the deletion of exon 9 during RNA splicing and could also be interpreted as one cell in any non-human primate, for example, that have been transformed with a pair of TALEN mRNAs having a single cell deletion of exon 9. Therefore, it would be unpredictable if transgenic non-human animals created by somatic cell gene transfer to any cell could be created and used in accordance with the invention as claimed. The invention is enabling to a non-human primate model for Alzheimer’s disease, whose genome comprises a presenilin 1 (PSEN1) gene; wherein the non-human primate is heterologous for an endogenous mutation in the PSEN1 gene; wherein the mutated PSEN1 gene has the nucleotide sequence encoded by SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 20. However, the claims do not recite such a structural limitation. Thus, to the extent the claims fail to recite distinguishing features commensurate with the level of guidance presented, the claims are not considered enabled.
Therefore, in view of the breadth of the claims, the limitation of the specification to only marmosets possessing 4 mutant PSEN1 sequences, of which, only two deletions are taught (one 6-bp deletion and one 9-bp deletion) and all of which delete both the “A” and the “G” at the 3’-end of intron 8 (SEQ ID NOs: 13, 16, 18, and 20), the lack of specific guidance in the specification for any methods of generating heterozygotes where TALENs are introduced to fertilized ova, the lack of specific guidance for any deletions other than the specific 6-bp or 9-bp deletions encompassing both the “A” and the “G” at the 3’-end of intron 8, the lack of specific guidance for any marmosets (or any other non-human primates for that matter) possessing anything other than a mutant PSEN1 gene having a sequence of 100% identity to SEQ ID NOs: 13, 16, 18, or 20 expressed heterozygously to result in skipping of exon 9 of PSEN1 and an increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio, and the unpredictability evidenced by the prior art at the time of filing with respect to TALEN pairs, target sites, and the level of experimentation required to design TALEN systems for marmosets, it would require undue experimentation to make the non-human primate models and to use the methods instantly claimed.
Claims 8-20 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 claims contain 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.
Claim 8 broadly encompasses a genus of mutations which includes deletion of one or both of AG of the 3’-splice site of exon 9 of PSEN1 and which has the functional property of inducing skipping of exon 9 during RNA splicing, and a genus of mutations of the 5’-splice site of exon 9 of PSEN1 which has the functional property of inducing skipping of exon 9 during RNA splicing (reading on any sized deletion including one which encompasses most of the PSEN1 gene from the 5’ end to the end of intron 8 so long as it encompasses at least one base of the recited nucleotide pairs and results in skipping of exon 9). Claim 8 also reads on a genus of non-human primates having even a single copy of a mutant PSEN1 gene with the functional property of being a model for Alzheimer’s disease. Claim 12 limits the size of the deletion insofar as it necessitates the use of the TALENs of SEQ ID NOs: 1 and 2. However, as shown in FIG. 1, these TALENs flank an approximately 16bp large segment at the junction between intron 8 and exon 9 and, as written, claim 12 continues to read on a deletion as small as 1 base in total (either A or G). It is noted that the TALENs recited in claim 12 do not flank the 5’-splice site at all. Claim 16 broadly encompasses a method of generating a non-human primate model of Alzheimer’s disease utilizing a genus of TALENs (literally any TALENs) which target one or both of AG of the 3’-splice site of exon 9 of PSEN1 and which have the functional property of producing any deletion (reading on any sized deletion including one which encompasses most of the PSEN1 gene from the 5’ end to the end of intron 8 so long as it encompasses at least one base of the recited nucleotide pairs and results in skipping of exon 9) that results in exon 9 skipping during RNA splicing, and a method using a genus of TALENs (literally any TALENs) which target the 5’-splice site of exon 9 of PSEN1 and which have the functional property of producing any deletion that results in exon 9 skipping during RNA splicing. Claim 16 also broadly encompasses generating heterozygous mutants by introducing TALENs to fertilized ova (encompassing somehow directing TALENs to modify one chromosomal copy of a gene without modifying the other). Claim 18 limits the TALENs to SEQ ID NOs: 1 and 2 just as claim 12 did above. However, the same issues exist here with respect to deletions as small as individual bases resulting in induced exon 9 skipping. No claims are presented to narrow the scope of deletions having the claimed functional properties.
The specification provides working examples using TALENs encoded by SEQ ID NOs: 1 and 2 (Specification, [0044]). The instant specification specifically teaches the introduction of the above-referenced TALENs into the nuclei of fertilized marmoset ova (Specification, [0056]). The instant specification teaches that deficiency of the 3’-splice site was only seen in 2 out of 3 fertilized ova when assessed at the 4-cell stage ([0056]) and that introducing TALENs directly to fertilized ova resulted in homozygous deletion of exon 9 which was lethal ([0056]). Thus, as Example 1 of the instant specification explains, one cannot generate a heterozygous mutant by introducing TALENs to a fertilized ova, and such a process does not produce any “non-human primate model” because such a process is lethal to the embryos. The instant specification also teaches an alternative method whereby the TALENs discussed above are introduced to ova prior to fertilization and transfer to a surrogate mother marmoset to generate heterozygous offspring ([0057]). The results of this approach are embodied in FIG. 3 which shows one resulting heterozygous mutant possessing a PSEN1 gene having the sequence of SEQ ID NO: 13 which, compared to wild-type, possesses a deletion of the 6bp at the end of intron 8 including the final two nucleotides A and G (FIG. 3). The instant specification then teaches 3 other specific heterozygous mutant marmosets produced in the same way and which have the mutant PSEN1 genes of SEQ ID NOs: 16, 18, and 10 ([0060]). It is noted that the deletion embodied by SEQ ID NOs: 16 and 18 appear to be the same as that embodied by SEQ ID NO: 13 (FIG. 5). SEQ ID NO: 20 has a deletion of the same region as SEQ ID NOs: 13, 16, and 18 plus the first “CAA” of exon 9 for a total of 9 deleted nucleotides. Thus, the specification discloses only 4 mutant PSEN1 sequences, of which, only two deletions are taught (one 6-bp deletion and one 9-bp deletion) and all of which delete both the “A” and the “G” at the 3’-end of intron 8 (FIG. 5). The specification also teaches quantifying amyloid levels and that the 4 specific heterozygous mutant marmosets exhibit increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio (FIG. 4 and 6). The specification does not teach any methods of generating heterozygotes where TALENs are introduced to fertilized ova, any deletions other than the specific 6-bp or 9-bp deletions encompassing both the “A” and the “G” at the 3’-end of intron 8, nor any marmosets (or any other non-human primates for that matter) possessing anything other than a mutant PSEN1 gene having a sequence of 100% identity to SEQ ID NOs: 13, 16, 18, or 20 expressed heterozygously to result in skipping of exon 9 of PSEN1. The specification also does not teach any “model for Alzheimer’s disease” outside of the specific four heterozygous mutant marmosets possessing genomic modification of their PSEN1 genes.
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 inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
In this case, the instant specification has only described two TALENs (SEQ ID NOs: 1 and 2) and has only described 4 mutant PSEN1 sequences, of which, only two deletions are taught (one 6-bp deletion and one 9-bp deletion) and all of which delete both the “A” and the “G” at the 3’-end of intron 8 (FIG. 5), and has only described four examples of a “model for Alzheimer’s disease” all of which possess genomic modification of their PSEN1 gene and all of which exhibiting increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio (FIG. 4 and 6). There is no disclosure at all of TALENs targeting the 5’-splice site as claimed. There is no disclosure of any TALENs other than SEQ ID NOs: 1 and 2 having the functional property of producing a deletion that results in exon 9 skipping during RNA splicing. There is no disclosure of any mutant PSEN1 sequences other than SEQ ID NOs: 13, 16, 18, and 20 having the functional property of inducing exon 9 skipping during RNA splicing. There is also no description at all of a method of generating a heterozygous model comprising introducing TALENs to a fertilized ova (a possibility foreclosed by the explicit disclosure of the instant invention as discussed above).
The skilled artisan at the time of filing knew that the application of TALENs varies in efficiency of editing depending on a variety of factors including the species being edited, the type and amount of molecule delivered, TALEN architecture, target choice, and detection methods, among others (Wright et al. Biochemical Journal 462.1 (2014): 15-24., hereinafter “Wright”, at page 20, fourth full paragraph). Wright further teaches that the evaluation of TALEN systems depends on an evaluation of the literature that is most relevant to the species of interest (Wright, page 20, fourth full paragraph). Wright also teaches that DNA composition, half-site recognition lengths, and spacer length can affect TALEN performance (Wright, page 21, “Target Choice” heading). Thus, a skilled artisan at the time of filing understood that target binding sites for TALEN pairs are not equal and that designing TALENs to target a specific site is an experimental endeavor in which a variety of factors need to be considered to be able to effectuate TALEN-induced genomic modification.
Therefore, in view of the breadth of the claims, the lack of sufficient description for the entire genus of models and methods claimed, the lack of any description at all in the supporting disclosure of TALENs targeting the 5’-splice site as claimed, of any TALENs other than SEQ ID NOs: 1 and 2 having the functional property of producing a deletion that results in exon 9 skipping during RNA splicing, of any mutant PSEN1 sequences other than SEQ ID NOs: 13, 16, 18, and 20 having the functional property of inducing exon 9 skipping during RNA splicing, of any “model for Alzheimer’s disease” possessing anything other than genomic modification of their PSEN1 gene and exhibiting increased beta-amyloid-42 (Aβ42): beta-amyloid-40 (Aβ40) ratio (FIG. 4 and 6), nor of a method of generating a heterozygous model comprising introducing TALENs to a fertilized ova, and the unpredictability evidenced by the prior art at the time of filing, the disclosure is insufficient to show the inventor was in possession of the claimed genera.
35 U.S.C. 112, (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new rejection necessitated by Applicant’s amendments to the claims. Claim 10 depends from claim 8. Claim 8 newly requires that mutation “includes deletion of one or both of 2 nucleotides of 5 '-splice site GT of exon 9 of the PSENl gene or one or both of 2 nucleotides of 3' -splice site AG of exon 9 of the PSENl gene. Claim 10 broadens the scope of the claimed mutation, permitting that it may be “a 6-bp or 9-bp deletion at the 3'-splice site of exon 9.” which does not require to include the 2 nucleotides of 3' -splice site AG.
Applicant may cancel the claim, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Additional Comments
Zhou et al. (Available at SSRN 3299433 (2018) (hereinafter “Zhou”)) is another piece of relevant prior art. Zhou discusses the state of the art regarding genetic engineering of marmosets and specifically references Sato.
Conclusion
No claim is allowed.
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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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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