DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 8-20 were previously pending.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 18 February, 2026 has been entered.
Receipt is acknowledged of the amendments to the claims filed on 18 February, 2026. Claims 8, and 10-17 are amended. Claim 18 is cancelled.
Therefore, claims 8-17, and 19-20 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.
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).
Claim Objections
Claims 12 and 16 are objected to because of the following informalities: SEQ ID NOs are placeholders and are not sequences in themselves. The claims should be amended to recite “encoded by the nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 2”. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: in vitro should be italicized for consistency. Appropriate correction is required.
Withdrawn Rejections in View of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 101
The rejection of claims 8-15 under 35 U.S.C. 101 because the claimed invention is not supported by either a credible asserted utility or a well-established utility is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended the claims to recite a phenotype for the non-human primate models.
Claim Rejections - 35 USC § 112
The rejection of claims 8-20 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 withdrawn in view of Applicant’s amendments to the claims.
35 U.S.C. 112, (d)
The rejection of claim 10 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 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claim 10 such that it further limits claim 8 from which it depends.
Maintained Rejections in View of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 112(a)
Claims 8-17, and 19-20 remain 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 relative to a wild-type non-human primate.
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) endogenous mutations of the PSEN1 gene that are outside the genome or not in every cell of the non-human primate model or (4) 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, for example, encompasses non-human primates having the claimed mutations in many but not all of the cells of the model and mutations in which a vast swath of genomic DNA is deleted so long as it includes one or both of the recited nucleotides.
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 the TALENs encoded by SEQ ID NO: 1 and 2 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 down to a single nucleotide) 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 fertilization one chromosomal copy of a gene of the embryo is modified without modifying the other, resulting in a heterozygous non-human primate model).
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 transferred 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 in a heterozygous state to result in skipping of exon 9 of PSEN1. The working examples also do not teach any non-human primate possessing a deletion at the 5’ splice site of PSEN1 at all.
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 or only the G or T at the 5’ splice donor site of exon 9 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 by targeting only the A or G at the 3’-end of intron 8 or only the G or T at the 5’ splice donor site of exon 9 to induce skipping of exon 9.
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 in a heterozygous state 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 8-17, and 19-20 remain 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 acceptor 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 donor 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 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 the TALENS encoded by SEQ ID NOs: 1 and 2 which have the functional property of producing any deletion (reading on a deletion of even a single nucleotide as long as it is the A or the G) 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). No claims are presented to narrow the scope of deletions having the claimed functional properties and no claims narrow the method to ova instead of fertilized ova.
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 the 3’ splice acceptor site of their PSEN1 gene and all of which exhibit 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 donor 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.
Response to Arguments
Applicant argues that the amended claims are now fully enabled. Specifically, Applicant argues that “As amended, the claims are fully enabled by the present disclosure. Claim 16 is now expressly limited to the use of a specific TALEN pair having the sequences of SEQ ID NOs: 1 and 2, and to deletions at the 3' splice site of exon 9 of the PSEN1 gene. The specification describes in detail the construction of this TALEN pair, its introduction into ova or fertilized ova, the production of cultured embryos, and the production of resulting offspring. Example 1 further demonstrates that this TALEN pair reliably induces exon 9 skipping. Moreover, the submitted Referential Document 1 (TAB A) confirms that the deletions induced by this TALEN pair are not limited to the originally exemplified 6 bp and 9 bp deletions, but also include smaller deletions, such as a 1 bp deletion, while still producing AE9 skipping. Thus, the full scope of amended Claim 16 is supported by working examples and corroborating experimental evidence, and does not require undue experimentation.”(Remarks, page 9). This argument has been fully considered but has not been found persuasive for the following reasons.
Applicant is still broadly claiming mutations of any size so long as they encompass the A or G of the 3’ splice acceptor site of exon 9 of PSEN1. As discussed above, claim 8 is not limited to the specific TALEN pair of SEQ ID NO: 1 and 2. Therefore, any size deletion imaginable which produces the desired outcome is claimed. Applicant’s have only demonstrated SEQ ID NOs: 13, 16, 18, and 20 having the functional property of inducing exon 9 skipping during RNA splicing, and all of these delete both the A and the G at the 3’-splice acceptor site and encompass a mere 6 or 9 bp deletion. In addition, the claims still read on deletions at the 5’-splice donor site, which the Applicant has not demonstrated by way of working example and which the art does not exemplify to skilled artisans. Still further, Applicant’s disclosure expressly precludes the modification of fertilized ova in this context as this produces homozygotes and is lethal (see above discussion). As the development of marmoset models for Alzheimer’s disease by inducing PSEN1 exon 9 skipping is a nascent field and Applicant’s appear to be the first to accomplish it, the disclosure of only 4 examples, all of which delete both the A and G at the 3’ splice acceptor site of exon 9 of PSEN1 and of methods to produce heterozygotes from ova as opposed to fertilized ova is not sufficient to support the entire scope claimed and the skilled artisan would most certainly have to undergo undue experimentation to practice the scope of the invention here claimed. Particularly in view of the relative unpredictability and context-specific requirements of TALEN-based genome editing. In addition, TAB A only shows a hypothetical deletion of the G at the 3’-splice acceptor site and does not say anything about what was used to induce the mutation, what organism possesses the mutation, nor what phenotype the resulting organism exhibited. The question is not whether the disclosed TALENS could induce a single nucleotide deletion but whether Applicant’s have demonstrated that the breadth of mutations claimed which encompass single nucleotide deletions is sufficient to induce exon 9 skipping and to result in the claimed phenotype. Applicant’s arguments on the record that TAB A shows exon skipping and resulting phenotype are insufficient to establish as much. Accordingly, Applicant’s argument has been fully considered but has not been found persuasive.
Applicant also argues that the application demonstrates possession of the claimed subject matter. Applicant specifically argues that they have demonstrated possession of mutations as small as a single nucleotide having the functional properties claimed, possession of marmosets having the disease-relevant phenotype, and possession of the breadth of the methods of claim 16 (Remarks, pages 10-11). These arguments have been fully considered but have not been found persuasive for the following reasons.
With respect to Applicant’s arguments relying on TAB A, these are not found persuasive for identical reasons to those presented above in response to Applicant’s arguments in favor of enablement. Further, Applicant s still claiming mutations of any size so long as they encompass the A or G of the 3’ splice acceptor site of exon 9 of PSEN1. As discussed above, claim 8 is not limited to the specific TALEN pair of SEQ ID NO: 1 and 2. Therefore, any size deletion imaginable which produces the desired outcome is claimed. Applicant’s have only demonstrated SEQ ID NOs: 13, 16, 18, and 20 having the functional property of inducing exon 9 skipping during RNA splicing, and all of these delete both the A and the G at the 3’-splice acceptor site and encompass a mere 6 or 9 bp deletion. In addition, the claims still read on deletions at the 5’-splice donor site, which the Applicant has not demonstrated by way of working example and which the art does not exemplify to skilled artisans. Still further, Applicant’s disclosure expressly precludes the modification of fertilized ova in this context as this produces homozygotes and is lethal (see above discussion). As the development of marmoset models for Alzheimer’s disease by inducing PSEN1 exon 9 skipping is a nascent field and Applicant’s appear to be the first to accomplish it, the disclosure of only 4 examples, all of which delete both the A and G at the 3’ splice acceptor site of exon 9 of PSEN1 and of methods to produce heterozygotes from ova as opposed to fertilized ova is not sufficient to demonstrate to the skilled artisan that Applicants had possession of the entire genera claimed. Accordingly, Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant has additionally provided TAB B which “reports pathological analysis of the brain of a PSEN1-ΔE9 marmoset at four years of age” (Remarks, page 11). Applicant asserts that this marks “a remarkable and unexpected result that could not have been anticipated based on prior animal models relying on overexpression or homozygous introduction of multiple mutations” (Remarks, page 12). While this evidence may be sufficient to rebut a prima facie case of obviousness, it is unclear how this evidence is relevant to the 35 U.S.C. 112(a) written description analysis other than to prove the Office’s position that there is unpredictability in this field. Applicant has not sufficiently demonstrated possession of the genera of models and methods claimed and this argument is not persuasive to overcome that insufficiency.
New Rejections
Claim Rejections - 35 USC § 112
Claims 11 and 12 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.
Claims 11 and 12 have been amended to recite “the endogenous mutation in the PSEN1 gene is introduced”. Claims 11 and 12 both depend from claim 8 which is a composition claim not a method claim. It is unclear whether Applicant is intending the scope of claims 11 and 12 to encompass a step of introducing which would improperly claim both a method and a composition in the same claim or whether Applicant instead intends the scope of claims 11 and 12 to encompass past-tense product-by-process language. Applicant should amend claims 11 and 12 to refer to the introduction in the past-tense as it was originally presented.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MARIA G LEAVITT can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
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