DETAILED ACTION
The Response of 5 Feb. 2026 has been entered.
Claims 1-6, 10-20 and 24-26 are currently pending.
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’s election without traverse of the invention of Group I, claims 1-6 and 10-12, and the species of P. falciparum as the Plasmodium parasite, FKBP as the destabilization domain and Shld1 as the ligand, in the reply filed on 5 Feb. 2026 is acknowledged.
Claims 5, 13-20 and 24-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (claim 5) and invention (claims 13-20 and 24-26), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5 Feb. 2026.
Claims 1-4, 6 and 10-12 are considered here with respect to the elected species.
Claim Rejections - 35 USC § 103
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.
Claims 1-4, 6 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Kafsack et al., Nature 507.7491 (2014): 248-252 (cited in IDS of 20 Feb. 2024) in view of Avraham et al., Proceedings of the National Academy of Sciences 109.52 (2012): E3678-E3686 (cited in IDS of 20 Feb. 2024) and Bechtsi et al., International Journal for Parasitology 47.7 (2017): 425-434.
Regarding claims 1-4, Kafsack teaches a Plasmodium falciparum parasite, wherein the genome of said Plasmodium parasite comprises an exogenous nucleic acid encoding a FKBP destabilization domain fused to the 3' end of nucleic acid encoding an AP2-G polypeptide (p. 249, right col., 1st full ¶; Supp. Fig. 6; METHODS, under Parasites and strains). Kafsack teaches that P. falciparum is the parasite responsible for malaria, and that the AP2-G locus acts as a transcriptional switch that controls sexual differentiation that is essential for infection of mosquitoes and transmission to a subsequent host (p. 248, 1st ¶; p. 250, 1st ¶). Insertion of the FKBP destabilization domain allows for AP2-G function to be regulatable by providing an exogenous ligand (Shld1), such that the protein is targeted for degradation in the absence of the ligand but is functional in the presence of the ligand (p. 249, right col., 1st full ¶). Kafsack teaches that the FKBP-regulatable AP2-G construct provides a new tool for studying the sexual stage development of malarial parasites, and provides potential new targets for interrupting malarial transmission by preventing sexual maturation of the parasite (p. 250, last ¶ to p. 251, 1st ¶).
Regarding the pairing elements recited in claims 1 and 10-12, Kafsack teaches that the AP2-G gene is flanked by insulator-like pairing elements upstream and downstream of AP2-G which may play a role in gene silencing and/or render AP2-G expression mutually exclusive with other genes (var genes) (p. 250, right col., 1st full ¶; Supp. Figs. 9D and 10).
Regarding claim 6, Kafsack teaches that the nucleic acid encoding the FKBP destabilization domain further comprises an HA (hemagglutinin) peptide tag (Supp. Fig. 6A).
Claims 1-4, 6 and 10-12 differ from Kafsack in that: the FKBP-encoding nucleic acid further comprises at least one disrupted pairing element flanking the AP2-G sequence (claim 1); the disrupted pairing element is a 5' pairing element (claim 10); the disrupted pairing element is a 3' pairing element (claim 11); and the genome of the parasite comprises a disrupted 5' pairing element and a disrupted 3' pairing element (claim 12).
Avraham teaches that insulator-like pairing elements like those flanking AP2-G regulate expression of var genes via pairing interactions that influence chromatin structure (p. E3678, last ¶; p. E3679, 1st ¶ to p. E3683, 2nd full ¶; Discussion; Figs. 1 and 3). Avraham further teaches that disrupting the pairing elements (via either deletion or insertion of an additional copy) disrupts the gene silencing and allows for full activation of the var gene (p. E3679, right col., 2nf full ¶; Fig. 3).
Bechtsi teaches that the hypothesis put forward by Kafsack regarding the potential regulation of expression of AP2-G by insulator-like pairing elements and linkage to expression of var genes is "worth investigating, as even a partial mutual regulation of these transcriptional programmes would mechanistically link parasite transmissibility and virulence, having significant implications in the context of disease control" (p. 432, 1st full ¶). Bechtsi further teaches that studies relating to AP2-G gene regulation "not only provided the first model for sexual commitment in Plasmodium, but also gave invaluable information for the discovery of transmission-blocking antimalarial agents. AP2-G is a plausible drug target candidate due to its conservation throughout the phylum and its lack of orthologues in humans" (p. 432, 2nd full ¶).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to make a modified P. falciparum parasite comprising an FKBP-regulated AP2-G gene as taught by Kafsack wherein the modified parasite further comprises at least one disrupted pairing element flanking the AP2-G sequence as taught by Avraham because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to include at least one disrupted pairing element flanking the AP2-G sequence in the parasite of Kafsack because Kafsack teaches that the AP2-gene is flanked by pairing elements that are known to regulate gene expression, and Bechtsi teaches that the role of such pairing elements in regulating AP2-G expression is worthy of investigation since such regulation could mechanistically link parasite transmissibility and virulence and have significant implications in the context of disease control. Bechtsi further teaches that AP2-G is a plausible drug target candidate and that investigating AP2-G regulation can give invaluable information for the discovery of transmission-blocking antimalarial agents. Including at least one disrupted pairing element flanking the AP2-G sequence in the parasite of Kafsack would have led to predictable results with a reasonable expectation of success because Avraham teaches that disruption of similar pairing elements (e.g., via deletion) disrupts the silencing effect. Moreover, Kafsack teaches that the location of the pairing element sequences flanking the AP2-G gene are known (Kafsack, Supp. Figs. 9D and 10) and disruption of such sequences as taught by Avraham could be incorporated into the organism of Kafsack using similar genetic engineering techniques as used for the FKBP insertion (e.g.,, Kafsack, Supp. Fig. 6).
Regarding claims 10-12, Kafsack teaches that there are multiple pairing element sequences located 5' and 3' of the AP2-G gene (Kafsack, Supp. Figs. 9D and 10), and it would have been obvious to disrupt any one or more of such sequences in order to study their effects on gene regulation. Kafsack further teaches that the nucleic acid encoding the FKBP destabilization domain is integrated into the host genome (Supp. Fig. 6A), and it would have been obvious to incorporate the pairing element disruptions in a similar integrated construct.
Conclusion
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657