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 .
Election/Restrictions
Applicant has elected group II, drawn to a fertile homozygous mutated female fish, crustacean, or mollusk for producing a sterile fish, crustacean, or mollusk (claims 11, 41-42, and 49-51).
Furthermore, Applicant has elected a mutation in a cis-acting 5’ or 3’ UTR regulatory sequence pf a primordial germ cell (PGC) development gene.
Applicant has elected nanos3 as the mutated PGC Development gene.
Claims 1-10, 21-40, and 43-51 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Election of Applicant’s invention(s) was made with traverse in the reply filed
on February 7, 2024.
DETAILED ACTION
The amended claims filed on February 26, 2026, have been acknowledged.
Claims 12-20 were cancelled. Claims 41, 44, and 50 were amended. Claims 1-11 and 21-51 are pending. Claims 1-10, 21-40, and 43-48 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Claims 11, 41-42, and 49-51 are pending and examined on the merits.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on November 6, 2025, and January 16, 2026, have been considered.
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed by Dr. John Buchanan on February 26, 2026, has been considered but is insufficient to overcome the rejections of instant claims based upon 35 U.S.C 112 as set forth in the current Office action for the following reasons:
The Buchanan declaration argues that the Application provides proper possession of nanos3 5’ and 3’ UTR regulatory mutations capable of modulating translation and that lead to fertile homozygous mutated female fish capable of producing sterile progeny. The Buchanan declaration cites to data from Figure 1 showing that the 8-base pair (D8/D8) and 32-base pair (D32/D32) mutations in the nanos3 3’ UTR show a significant reduction in PGC counts and data from Figure 2 showing these mutant fish have a sterile phenotype. Thus, this data demonstrates that mutations in the 3’ UTR lead to fertile homozygous mutated female fish capable of producing sterile progeny.
Furthermore, the Buchanan declaration argues that the Application expressly identifies mutations in cis-acting 5' UTR regulatory sequences of PGC development genes, including nanos3, as embodiments of the invention. The Buchanan declaration cites to five pieces of prior art to show that at the time of filing, it was well established in molecular biology that the 5' UTR of eukaryotic mRNA plays a critical role in translational regulation, including ribosomal recruitment, scanning efficiency, translational initiation, secondary structure formation, RNA-binding protein interactions, and in certain contexts mRNA stability. The Buchanan declaration argues that PGC specification depends on maternally deposited RNA and tightly regulated translation during early embryogenesis. Accordingly, alterations in nanos3 translational efficiency caused by 5' UTR regulatory mutations would reasonably be expected to reduce nanos3 protein levels during early maternal stages, disrupt PGC specification or survival, and potentially preserve sufficient zygotic expression later in development to maintain viability and fertility of the broodstock female. This regulatory principle is mechanistically analogous to the demonstrated 3' UTR mutations described in the Application, which selectively alter maternal contributions without abolishing later-stage viability. The Application further discloses a screening and propagation workflow enabling identification of regulatory alleles, including cis-acting 5' UTR mutations, that produce the claimed phenotype, namely reduction of maternal PGC development without impairment of zygotic viability or fertility
Based on the scientific understanding of 5' UTR regulatory function at the time of
filing, together with the Application's express disclosure of cis-acting 5' UTR
regulatory mutations as embodiments of the invention and its detailed phenotypic
screening methodology, the Application conveys possession of nanos3 5' UTR regulatory mutations capable of modulating translation in a manner consistent with the maternal-effect phenotype described in the Application (page 2, paragraph 4-page 6, paragraph 6).
Applicant's arguments and the cited prior art (where applicable) have been fully considered but they are not persuasive.
As a first matter, the prior art cited in Applicant’s remarks were not filed in an IDS. Applicant is respectfully reminded the individuals covered by 37 C.F.R. § 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge which are "material to patentability" of the application in question in the form of an Information Disclosure Statement. As set forth by the court in Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). See MPEP §2001.06(b). Careful search of each of the cited art failed to identify the relevant non-patent literature of the Lee and Hempel documents. Therefore, only the Hornig, Leppek, and Gu references have been considered.
Hornig relates to germline mutations in the 5’ UTR of the androgen receptor (whole document)
Leppek is a review related to how 5ʹ UTR structures in mRNAs may block or recruit ribosomes and other regulatory factors to enable a rapid, dynamic response to diverse cellular conditions to control gene expression (whole document)
Gu relates to the 5′ UTR secondary structure and how it performs multiple functions in regulating post-transcriptional processes. Although the local structure immediately upstream of the start codon is involved in translation initiation, RNA structure near the 5′ cap site, rather than the structure of the full-length 5′ UTR sequences, plays an important role in miRNA-mediated gene regulation (whole document).
Although each of these cited prior art relate to the 5’ UTR and protein regulation, none of them discuss nanos3. Thus, although these publications demonstrate that mutations within 5' UTR regulatory sequences can modulate protein output, none of them identify that the nanos3 5’ UTR can be modified to lead to fertile homozygous mutated female fish capable of producing sterile progeny
Regarding the 3’ UTR mutations, they recite two mutations in the same motif 1 region as being capable of causing the recited function (D8/D8 and D32/D32). As stated in the 112a rejection below, the two recited mutations in motif 1 of the nanos3 3’ UTR are not sufficient to show possession of the entire genera (any mutation within the nanos3 3’ UTR). The limited number of recited mutations specifically disclosed that lead to a fertile homozygous mutated female fish for producing a sterile fish are not representative of the genera because the genera are highly variant. Furthermore, Applicant’s arguments suggest that the only region in the 3’ UTR that would have a similar function is mutations in motif 1 as Applicant considers motif 1 as the sole functional hotspot (page 13, paragraph 3 of Remarks from May 5, 2025). Therefore, this would suggest that only mutations in Motif 1 would have this function and not any 3’ UTR mutation as presently claimed. However, Applicant was incorrect in stating that Motif 1 is the sole functional hot spot as mutations in the putative Dnd interaction sequence 2 (outside of motif 1, as shown in Figure 33) suppressed nanos3 expression levels while mutations in putative Dnd interaction sequence 1 did not, as identified by Kedde. Therefore, there are at least two regions that can be mutated to reduce nanos3 expression through post-translational regulation as both mutations are hypothesized to reduce the binding of an RNA binding protein that blocks the miR 430 seed region, opening up the seed site and allowing degradation of the nanos3 mRNA (Figure 6 of Kedde and paragraphs 0164-0165 of the specification). Furthermore, as stated below, Kedde teaches that 4 of 5 mutations of the 3’ UTR of nanos1 (also known as nanos3) did not cause a reduction in expression of nanos1. As such, the site of the mutations within the nanos3 3’ UTR region is important for producing fertile homozygous mutated female fish for producing a sterile fish. As these results show, only certain mutation sites can lead to fertile homozygous mutated female fish for producing a sterile fish.
Therefore, Applicant’s arguments regarding possession of any 3’ UTR mutation are not persuasive.
Regarding the 5’ UTR mutations, although Applicant cites to the art to establish that it was known that mutations in the 5’ UTR could have an impact on protein output, Applicant and the cited prior art doesn’t provide any examples of mutations of the 5’ UTR in nanos3 that have the required function in the specification. Furthermore, although the specification provides embodiments encompassing 5’ UTR mutations in nanos3, this does not provide possession as Applicant hasn’t shown any 5’ UTR mutations capable of generating fish with the required functional limitations. Additionally, although Applicant discloses a screening and propagation workflow enabling identification of regulatory alleles, including cis-acting 5' UTR mutations, it is worth noting that Applicant could have used their identified workflow to identify 5’ UTR mutations of nanos3 with the claimed function, but did not. As an example, Applicant discloses that one can use motif mapping as recited in Example 17, but Applicant doesn’t recite any motifs in the 5’ UTR of nanos3 that would be of interest.
Therefore, Applicant has not shown any 5’ UTR mutation in nanos3 that has the recited function and is not in possession of the recited mutated fish.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence fails to outweigh the evidence for the 112a written description rejection.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11, 41-42, and 49-51 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. This is a new rejection made in response to Applicant’s amendments to claims 41 and 50 that is substantially similar to a previous rejection of record. Any aspect of Applicant's traversal that is relevant to the new rejection of record is addressed below.
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 11 and 49 recites the functional limitation “wherein the mutation disrupts the post- transcriptional regulation of a primordial germ cell (PGC) development gene to reduce the maternal-effect of the PGC development gene, and wherein the mutation that disrupts the post-transcriptional regulation of a PGC development gene does not impair somatic (claim 11)/zygotic (claim 49) function of the gene, wherein the mutation is in a cis-acting 5' or 3' UTR regulatory sequence of nanos3.” Applicant does not teach any mutations in a cis-acting 5' UTR regulatory sequence of nanos3 that lead to fertile homozygous mutated female fish for producing a sterile fish. Furthermore, Applicant only teaches one example of a mutation in a cis-acting 3' UTR regulatory sequence of nanos3 by mutating nucleotides near the miR-430 binding site.
However, the applicant does not describe a structure capable of performing these functions. Vas-cath Inc. v. Mahurkar, 19USPQ2d 1111, 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.'' (See page 1117). The specification should “clearly allow persons of ordinary skill in the art to recognize that (he or she) invented what is claimed.'' (See Vas-cath at page 1116).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
Applicant teaches one example of a mutation in a cis-acting 3' UTR regulatory sequence of nanos3 that lead to fertile homozygous mutated female fish for producing a sterile fish. Applicant does not teach any mutations in a cis-acting 5' UTR regulatory sequence of nanos3 that lead to fertile homozygous mutated female fish for producing a sterile fish. As such, applicant provides limited examples of mutations in the 5’ or 3’ UTR of nanos3 that result in fertile homozygous mutated female fish for producing a sterile fish (paragraph 00134).
The applicant has provided limited description or reduction to practice of mutations that lead to fertile homozygous mutated female fish for producing a sterile fish. Based on the applicant's specification, the skilled artisan cannot envision the detailed mutations that would allow for fertile homozygous mutated female fish for producing a sterile fish.
The limited number of recited mutations specifically disclosed that lead to a fertile homozygous mutated female fish for producing a sterile fish are not representative of the genera because the genera are highly variant. Kedde et al. (Cell 131: 1273-1286. 2007) teaches that 4 of 5 mutations of the 3’ UTR of nanos1 (also known as nanos3) did not cause a reduction in expression of nanos1. As such, the site of the mutations within the nanos3 3’ UTR region is important for producing fertile homozygous mutated female fish for producing a sterile fish. As these results show, only certain mutation sites can lead to fertile homozygous mutated female fish for producing a sterile fish.
Furthermore, claims 11, 41, and 49-50 are claiming a genus of mutations based on the function of the mutations. This claim would encompass novel mutations not yet described in the literature. Additionally, while maternal-effect mutations were known, not all mutations, let alone maternal-effect mutations, result in the functional properties of claims 11 and 49. As an example, Kishimoto et al. (Mechanisms of Development 121: 79-89. 2004) teaches that their acytokinesis mutations are a maternal-effect mutation that causes sterility as embryos die during development (abstract and Figure 2).
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Therefore, conception is not achieved until reduction to practice has occurred. See Fiers v. Revel, 25 USPQ2d 1602 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
As such, there is a wide variety of mutations encompassed by the scope of claims 11 and 49. Accordingly, given that the specification only teaches one species of the broadly-defined genera of mutations that produce sterile offspring as recited in claims 11 and 49, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the required starting materials, that is a fertile homozygous mutated female fish for producing a sterile fish, at the time the application was filed. As such, the Applicant is not deemed to be in possession of the required starting materials, that is a fertile homozygous mutated female fish for producing a sterile fish with the requisite mutation, at the time the application was filed
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
Applicant is reminded that 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).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims fail to recite, and the specification fails to disclose, a nexus between the required fertile homozygous mutated female fish for producing a sterile fish and the corresponding recited functional properties of “wherein the mutation disrupts the post- transcriptional regulation of a primordial germ cell (PGC) development gene to reduce the maternal-effect of the PGC development gene, and wherein the mutation that disrupts the post-transcriptional regulation of a PGC development gene does not impair somatic (claim 11)/zygotic (claim 49) function of the gene, wherein the mutation is in a cis-acting 5' or 3' UTR regulatory sequence of nanos3.” Applicant does not teach any mutations in a cis-acting 5' UTR regulatory sequence of nanos3 that lead to fertile homozygous mutated female fish for producing a sterile fish. Furthermore, Applicant only teaches one example of a mutation in a cis-acting 3' UTR regulatory sequence of nanos3 by mutating nucleotides near the miR-430 binding site.
Claims 41-42 are also rejected because they fail to fix the 112(a) issues associated with claim 11. Claims 50-51 are also rejected because they fail to fix the 112(a) issues associated with claim 49.
Response to Arguments
Applicant's arguments filed February 26, 2026, are acknowledged.
Applicant argues that the specification reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter because the application: (i) expressly describes that class of mutations as part of the invention; and (ii) teaches a concrete identification, validation, and propagation workflow for isolating maternal-effect-specific alleles that do not impair later-stage function.
Regarding reason (i), Applicant argues that the specification explicitly describes the 5’ UTR class of mutation in multiple places and thus, the 5’ UTR mutation is repeated, consistent, and integrated into the described invention.
Regarding reason (ii-iii), Applicant argues that the application identifies the relevant structural class (cis-acting 5' UTR regulatory sequence mutations of nanos3) and discloses a detailed pipeline that selects alleles because they are maternal-effect-specific and do not impair later-stage viability/sex determination/fertility and thus, provides "identifying characteristics" and "structure/function correlation" the Office Action recites as relevant factors. Furthermore, Applicant argues that the Office Action cites Kedde for the proposition that only certain mutation sites in a UTR yield the desired effect, but that observation is not a written description defect where the application: (i) identifies the relevant structural class (cis-acting UTR regulatory mutations); and (ii) discloses a workflow that identifies which sites work by phenotypic selection and propagation (page 9, paragraph 7-page 13, paragraph 6).
Applicant's arguments have been fully considered but they are not persuasive.
Although the Applicant cites to multiple sections of the specification identifying different embodiments of their invention and the pipeline that can be used to identify the relevant 5’ UTR mutations, Applicant has not provided any examples of any mutations in the 5’ UTR region of nanos3 that lead to fish with the claimed function. Furthermore, although Applicant cites that one can use motif mapping as recited in Example 17, Applicant doesn’t recite any motifs in the 5’ UTR of nanos3 that would be of interest nor provide any examples of mutations of the 5’ UTR in nanos3 that have the required function in the specification. Furthermore, it is worth noting that Applicant could have used their identified workflow to identify 5’ UTR mutations of nanos3 with the claimed function, but did not. Therefore, Applicant has not shown any 5’ UTR mutation in nanos3 that has the recited function and is not in possession of the recited mutated fish.
Applicant further argues that the declaration provides data that ( a) rebuts "unpredictable/only certain sites work" and (b) reinforces that the application taught a workable, identifying approach for the 5' UTR class (page 13, paragraph 7).
Applicant's arguments have been fully considered but they are not persuasive.
As stated above, the Buchanan declaration was found unpersuasive.
Therefore, Applicant’s arguments are unpersuasive and the 112a rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 11, 41-42, and 49-51 are rejected under 35 U.S.C. 103 as being unpatentable over Draper et al. (Developmental Biology 305: 589-598. 2007), Kedde et al. (Cell 131: 1273-1286. 2007), NCBI (nanos homolog 3 [ Danio rerio (zebrafish) ]; Gene ID: 140631), and Skugor et al. (Mar Biotechnol 16: 256-264. 2014; referenced in IDS). This is a new rejection made in response to Applicant’s amendments to claims 41 and 50 that is substantially similar to a previous rejection of record. Any aspect of Applicant's traversal that is relevant to the new rejection of record is addressed below.
Regarding claims 11 and 49, Draper teaches a fertile homozygous mutated female fish for producing a sterile fish. Draper teaches that they mated Znos1 [nanos1] (nos1-/-) females to wild-type males and found that embryos derived from Znos1 mothers (fertile homozygous mutated female fish) developed into agametic adults that were phenotypically male (n=39/39). In contrast to embryos derived from Znos1 females, embryos derived from Znos1 males mated to wild-type females had normal numbers of PGCs at all stages examined. Thus, nos1(fh49) mutation results in a strict maternal effect-sterile phenotype (sterile offspring) (page 593, column 2, paragraph 1).
Draper does not teach wherein the mutation disrupts the post- transcriptional regulation of a primordial germ cell (PGC) development gene to reduce the maternal-effect of the PGC development gene.
However, Kedde teaches that mutating one URR [U-rich regions] (mut3, downstream of miR-430 site) of nos1 [nanos1] 3’ UTR reduced its expression. mut3 did not reduce gene expression when miR-430 target site was mutated, suggesting that also in this case Dnd1 effect is miRNA dependent (page 1279, column 2, paragraph 3). As can be seen in Figure 6, Dnd1 functions by blocking miR-430 binding sites in the 3’ UTR, preventing degradation of the nanos3 mRNA and Kedde teaches that Dnd1 binds to URRs to mediate miRNA based suppression (page 1279. Column 1, paragraph 2-column 2, paragraph 3). Based on the data of Kedde, the mut3 mutation in the URR region prevents Dnd1 from binding to the nanos3 mRNA to prevent miR-430 binding, thereby opening up the miR-430 binding site for miR-430 to bind and degrade the nanos3 mRNA, reducing nanos3 expression levels.
NCBI teaches that nanos1 and nanos3 are the same gene (See “Also known as” section).
Skugor teaches that the binding of the microRNA (miRNA) gene family miR-430 to target sites within the 3′UTR of zebrafish nanos caused mRNA degradation in somatic cells, but the mRNAs persisted in PGCs despite the presence of miR-430. In zebrafish germ cells, the RNA binding protein DnD was demonstrated to inhibit miRNA access to target 3′UTRs by binding to adjacent U-rich elements. Consistently, loss of DnD function or its target sequences made zebrafish nanos susceptible to miR-430-mediated degradation and resulted in failure of PGC migration and survival (page 257, column 1, paragraph 1). Skugor teaches that MO [morpholino]-induced DnD reduction on PGCs labeled by the cod gfp-nanos3 3′UTR in cod and zebrafish (Fig. 4d, e). In both species, the fluorescent cells expressing the GFP construct were completely abolished in DnD morphants. The results strongly indicate a DnD-dependent mechanism for stabilization of germ plasm factors, including nanos3 mRNA, required for germ cell survival, a mechanism previously reported in zebrafish (page 259, column 2, paragraph 2-page 260, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted null nanos1 (also known as nanos3) mutation of Draper with a mutation in the 3’ UTR region of nanos3 as identified by Kedde to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to substitute with a reasonable expectation of success because Draper, Kedde, and Skugor all focus on the role of nanos3 in the maintenance of primordial germ cells and fertility. Kedde teaches that mutating the 3’ UTR of nanos3 in the putative DnD interaction sequence 2 region caused DnD to be unable to bind to the 3’ UTR of nanos3, allowing miR-430 to bind to the nanos3 3’UTR. This caused degradation of nanos3 transcripts which lead to a reduction in expression of nanos3. Additionally, Skugor teaches that blocking DnD expression leads to loss of PGC cells. Therefore, it was well understood that one could mutate a region of the 3’ UTR of nanos3 to allow for degradation of nanos3 in primordial germ cells and Draper shows that nanos3 homozygous mutants still produced viable offspring that were sterile. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitations “does not impair somatic (claim 11)/zygotic (claim 49) function”, Applicant teaches that discrete mutations in a nos3 3'UTR conserved motif1 did not impair oocytes development. Instead, such mutations only appear to disrupt the post-translational regulation of nos3 mRNA in embryos progeny of mutant females (paragraph 00134). Additionally, Table 3 identifies that the deletion in the 3’ UTR likely corresponds to the motif protecting against miR-430 degradation (page 41). Kedde teaches that mutating one URR [U-rich regions] (mut3, downstream of miR-430 site) of nos1 [nanos1] 3’ UTR reduced its expression. mut3 did not reduce gene expression when miR-430 target site was mutated, suggesting that also in this case Dnd1 effect is miRNA dependent (page 1279, column 2, paragraph 3). Considering that the mutations of the instant application and Kedde affect the miR-430 binding site, the mutation of Kedde is likely to cause a similar effect as the mutation of the Applicant. As such, Kedde should also have the effect of disrupting the maternal activity of the PGC development gene, and not disrupting the function of the PGC development gene during later stages of development.
Regarding claims 41 and 50, Kedde mutated the putative Dnd interaction sequence 2 region in mut3 (the URR region) and this prevents Dnd1 from binding to the nanos3 mRNA to prevent miR-430 binding, thereby opening up the miR-430 binding site for miR-430 to bind and degrade the nanos3 mRNA, reducing nanos3 expression levels (Figure 5).
Skugor, as stated supra, teaches that the binding of the microRNA (miRNA) gene family miR-430 to target sites within the 3′UTR of zebrafish nanos caused mRNA degradation in somatic cells, but the mRNAs persisted in PGCs despite the presence of miR-430. In zebrafish germ cells, the RNA binding protein DnD was demonstrated to inhibit miRNA access to target 3′UTRs by binding to adjacent U-rich elements. Consistently, loss of DnD function or its target sequences made zebrafish nanos susceptible to miR-430-mediated degradation and resulted in failure of PGC migration and survival (page 257, column 1, paragraph 1).
Although Kedde did not delete the URR rich region, Skugor directly identifies that loss of its target sequences made zebrafish nanos susceptible to miR-430-mediated degradation and resulted in failure of PGC migration and survival. It would have been well understood by one of ordinary skill in the art that deletion of the whole or partial URR region would also lead to loss of the target sequence, preventing DnD binding and making zebrafish nanos susceptible to miR-430-mediated degradation. Therefore, it would have been obvious that the mutation could be a deletion of the whole or partial URR region to prevent DnD binding. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 42 and 51, Skugor teaches that the main target sequence GCACUU for the highly conserved seed of miR-430 was identified in zebrafish and tilapia (page 259, column 1, paragraph 1). As such, although Draper, Kedde, and Skugor focused on experimenting in Zebrafish and Cod, Skugor clearly identifies Tilapia as another potential experimental fish for disrupting miR-430 binding and it would have been obvious that one could perform the same experiments in tilapia. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed February 26, 2026, are acknowledged.
Applicant argues that substituting Draper's coding-sequence loss-of-function allele with a Kedde-type UTR modification in an endogenous nanos gene rests on a conclusory chain of assumptions: that a UTR alteration disrupting Dnd/Dndl binding would necessarily permit miR-430-mediated degradation of nanos mRNA in primordial germ cells, thereby reducing maternal effect while simultaneously preserving zygotic function and female fertility. That chain is not demonstrated in the cited references and is instead asserted to "naturally flow" or "should also have" the claimed outcome. Under§ 103, hindsight reconstruction of this type is insufficient. Claim 49 is particularly instructive because it requires, in combination, a fertile homozygous mutated female fish, a mutation in a cis-acting 5' or 3' UTR regulatory sequence of nanos3, a reduction of maternal effect, and the absence of impairment of zygotic function of the gene. The cited art does not support a reasonable expectation that all of these features would coexist.
Applicant argues that Draper teaches a fundamentally different biological outcome Draper demonstrates that maternal depletion can lead to sterile progeny, it also teaches that elimination of zygotic nanos function results in collapse of female fertility. Draper therefore does not suggest, and indeed cautions against, an expectation that homozygous females would remain fertile when nanos function is disrupted in a manner that affects zygotic activity.
Kedde does not provide an example of a fertile homozygous female carrying such a UTR mutation, nor does it establish maternal effect reduced without zygotic impairment would be expected to occur.
Skugor does not demonstrate that a Kedde-style UTR alteration, implemented as an endogenous, heritable allele, yields fertile homozygous females while selectively eliminating maternal nanos function and leaving zygotic function intact.
The Office's additional discussion of reporter repression in HEK-293 cells does not alter this analysis. Even if one accepts that HEK-293 cells express miR-430 and lack Dnd, such in vitro reporter behavior does not establish that an endogenous nanos UTR mutation in a living fish would preserve zygotic function, nor that homozygous females would remain fertile.
While KSR allows the use of common sense, it still requires more than assembling known elements with hindsight. Draper's documented progressive sterility of homozygous females, together with the absence in Kedde and Skugor of any demonstration that an endogenous UTR mutation yields maternal-only disruption with preserved zygotic function, undermines any assertion that a person of ordinary skill would have reasonably expected the proposed substitution to produce the specific, selective phenotype required by claim 49.
Accordingly, the Office has not established that, based on the combined teachings of Draper, Kedde, and Skugor, a person of ordinary skill in the art would have reasonably expected that substituting Draper's coding-sequence null allele with a Kedde-type UTR mutation would yield fertile homozygous females carrying a UTR mutation that reduces maternal effect while not impairing zygotic function, as required by the claims (page 14, paragraph 1-page 17, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to identify the same rationale as argued by the Applicant (produce the specific, selective phenotype required by the claims: an endogenous, heritable allele, yields fertile homozygous females while selectively eliminating maternal nanos3 function and leaving somatic/zygotic function intact), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In this case, it would have been obvious to have substituted null nanos1 (also known as nanos3) mutation of Draper with a mutation in the 3’ UTR region of nanos3 as identified by Kedde with a reasonable expectation of success because Draper, Kedde, and Skugor all focus on the role of nanos3 in the maintenance of primordial germ cells and fertility. Kedde teaches that mutating the 3’ UTR of nanos3 in the putative DnD interaction sequence 2 region caused DnD to be unable to bind to the 3’ UTR of nanos3, allowing miR-430 to bind to the nanos3 3’UTR. This caused degradation of nanos3 transcripts which lead to a reduction in expression of nanos3. Thus, there is a clear nexus between the null mutation of Draper and the 3’ UTR mutation of Kedde as they both reduce nanos3 expression through different means. Furthermore, Skugor teaches that blocking DnD expression leads to loss of PGC cells. Thus, there is a clear nexus between preventing DnD binding (as done by Kedde and Skugor) which leads to reduced nanos3 expression and loss of PGC cells. Therefore, it was well understood that one could mutate a region of the 3’ UTR of nanos3 to allow for degradation of nanos3 in primordial germ cells and loss of the primordial germ cells. As such, there is a reasonable motivation for substituting the mutations to generate the claimed invention even if it is not the same motivation as identified by the Applicant.
Furthermore, as stated supra, considering that the mutations of the instant application and Kedde affect DnD binding and opening the miR-430 binding site to miR-430 in primordial germ cells, it naturally flows that the mutation of Kedde will cause a similar effect as the mutation of the Applicant. As such, Kedde would also have the effect of disrupting the maternal activity of the PGC development gene, and not disrupting the somatic/zygotic function.
MPEP 2112(V) states that the express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983). Additionally, MPEP 2112(V) states that “[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977)).
Therefore, Applicant’s arguments are considered unpersuasive.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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/KEENAN A BATES/Examiner, Art Unit 1631
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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