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 .
Status of Claims
The response submitted on 06/16/2026 has been entered. Claims 1-4, and 8-22 are pending.
Claims 3-4 and 8-22 remain withdrawn.
Claims 1 and 2 have been amended.
Claims 1-2 are examined in this Office Action.
Objections and Rejections that are Withdrawn
The rejection of claims 1 and 2 under 35 USC 112(b) Indefiniteness has been withdrawn in light of Applicant’s amendments to the claims.
The rejection of claim 2 under 35 USC 112(d) Failure to Further Limit has been withdrawn in light of Applicant’s amendments to the claims.
The text of those sections of Title 35, U.S. Code, not included in this action, can be found in a
prior Office action.
Claim Rejections - 35 USC § 112
Written Description
Claims 1-2 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 claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. All dependent claims are included in these rejections unless they include a limitation that overcomes the deficiencies of the parent claim.
The claims are broadly drawn to a modified insecticidal protein comprising an insecticidal
protein, wherein the insecticidal protein has been modified to include at least one stink bug gut binding peptide.
The instant invention is based on the discovery that modification of an insecticidal protein to include a gut binding peptide enhances the efficacy of the insecticidal protein against stink bugs (page 3, paragraph 0011).
Example 4 of the instant specification describes the modification of insecticidal protein ARP147-MBP. As there was little information on domains of ETX/Mtx2 proteins that are important for toxicity, a wide range of sites including alpha helices, beta sheets and loop regions that are predicted to be on the exterior of ARP147 were selected for modification. The sites and the mode of peptide addition were selected on the basis of modeling with 1) the peptide predicted to be displayed on the
surface of ARP147 rather than folded in, and 2) the stability of the predicted modified structure (page 10, 0035).
BONNING (Bonning et al., Pub. No.: US 2018/0127771 A1; Pub. Date: May 10, 2018) further demonstrates the importance of site selection for the gut-binding protein within the insecticidal protein. BONNING describes that gut binding peptides may be incorporated into multiple loops of a Bt toxin; and one or more gut-binding peptides can be substituted in place of certain surface loops of an insecticidal protein (0014).
BONNING describes that modifications of the toxins include the N-terminal and C-terminal regions of the Cry1Ba toxic core (0017).
BONNING describes a method of making a modified insecticidal toxin comprising a gut binding peptide portion and a toxin portion, by fusing the nucleotide sequence encoding the gut binding peptide in frame with a Bt coding sequence, advantageously as an addition to the external loop of the toxin (0020).
BONNING describes a modified insecticidal toxin that specifically binds to a receptor in a sap-sucking insect gut via a peptide incorporated within the modified insecticidal toxin, for example as an N-terminal extension of the toxin or incorporated within surface domains of the toxin (0140).
BONNING describes that the N terminal of Domain I has previously been modified, showing a toxicity increase (0196). Domain II has been clearly shown to be involved in the toxin binding to the receptors present in the midgut cells, in particular, the Cry1Ac loop 2; Cry1Ac loop3 was also involved in receptor binding; and Domain III has also been involved in receptor binding (0198).
BONNING describes that only peptide 15 bound to ACP BBMV proteins specifically [0204]. The structures of Cry1Ab and Cry1Ba were modeled; residues corresponding to the site of trypsin cleavage in Domain I and loops 2 and 3 of Domain II were determined and will be used as sites for introduction of peptide 15 sequence into the toxin (see Figures 11A and 11B below) (0205).
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To further elucidate the importance of site selection for the gut-binding protein within the insecticidal protein , BONNING (Bonning et al., Pub. No.: US 2013/0097729 A1, Pub. Date: Apr. 18, 2013; see IDS dated 01/14/2024) describes the construction of novel, aphicidally active Cyt2Aa by introducing an aphid gut binding peptide into the toxin. Constructs for addition to, or substitution of, the Cyt2Aa loops with the 12 amino acid GBP3.1 or variants thereof were made (Bonning, page 9, paragraph 0093).
Two addition mutants, Cyt2Aa-His-Ek-GBP-AL1 (CGAL1) and Cyt2Aa-His-Ek-GBP-AL3 (CGAL3) were tested for gut binding and toxicity (Bonning, page 9, paragraph 0094).
BONNING describes that changes in the ability of Cyt2Aa to bind to pea aphid gut proteins following introduction of GBP3.1 were examined. Very strong binding was seen for active CGAL1 to the whole aphid BBMV whereas binding of active CGAL3 was barely detectable. It is believed that the difference in the abilities of active CGAL1 and active CGAL3 to bind to whole aphid BBMV proteins may result from differences in the accessibility of the GBP3.1 peptide; and that the peptide within loop3 in CGAL3 may be buried within the core structure of Cyt2Aa (Bonning, page 11, paragraph 0103).
Furthermore, BONNING describes mosquitocidal activity of the substitution mutants, CGSL1, CGSL2, CGSL4, CGSL5 and CGSL7 on A. aegypti. CGSL1 and CGSL4 maintained toxicity; however, the remaining three mutants, CGSL2, CGSL5 and CGSL7 showed a decrease in toxicity against A. aegypti (Bonning, page 15, paragraph 0138).
In regard to the decrease in functional activity of the three substitution mutants, CGSL2, CGSL5 and CGSL7, it is believed that any changes to loops 2, 5 and 7 affect the control toxicity of Cyt2Aa. In fact, structure-function studies on Cyt2Aa implicated amino acids in loops 2, 5, and 7 in pore formation. Addition or substitution of GBP3.1 to these loops is believed to have altered the pore forming toxin structure to the extent that the toxin loses its pore forming ability. Structure-function studies of Cyt2Aa indicated that (i) amino acids in loop 2 and the loop 2 flanking helices (aA and aB) are important for pore formation; (ii) amino acids in loop 5 and the loop 5 flanking β5 and β6 are involved in pore formation and are inserted into the membrane; (iii) two amino acids from β7, which is at the N-terminal end of loop 7 are inserted into the membrane during pore formation. The loss of CGAL7 toxicity may result from the fact that GBP3.1 is located next to β7 which may affect the pore forming ability of the toxin (Bonning, page 15, paragraph 0139).
The claims encompass an extremely large genus of compositions comprising all possible modifications to said insecticidal proteins. Applicants have reduced to practice NvBP1-modified constructs with modifications at AA172-178, 207-214 and 269-275 increasing binding, and modifications of NvBP1 at AA70-76, 172-178, 207-214, and 224-230 increasing toxicity; ABP5-modified constructs with modifications at AA70-76, 172-178 and 269-275 increasing binding, and modifications of ABP5 at AA43, 207-214, 224-230, and 269-275 increasing toxicity. As the instant Specification and the two studies cited by BONNING show, the insecticidal protein cannot be modified by inserting the gut-binding peptide just anywhere in the insecticidal protein and still retain the function of an insecticidal protein. Certain modifications may even decrease binding and/or toxicity as shown in the prior art. Given that there have not been an adequate number of species reduced to practice to be representative of the broad genera of claimed compositions, and there is no description of structures that are correlated with the required function, there is not an adequate written description to support the breadth of the claims.
Response To Applicant’s Arguments
Applicant's arguments filed 06/16/2026 have been fully considered but they are not persuasive.
Applicant argues that the disclosure demonstrates possession of modified insecticidal proteins comprising an insecticidal protein modified to include the specifically claimed stink bug gut binding peptides. The written description requirement does not require reduction to practice of every possible species within the claim. Rather, the specification must reasonably convey to those skilled in the art that the inventors had possession of the claimed subject matter. Here, the specification describes the structural feature that defines the claimed modified proteins - the inclusion of the specific stink bug gut binding peptide in an insecticidal protein - and provides representative working examples demonstrating how that structural feature is implemented and why it provides the desired biological effect.
Additionally, Applicant argues that the Office Action also relies on variability in binding and toxicity among different modification sites. Applicant respectfully submits that such variability does not undermine written description support.
The Examiner respectfully disagrees. The MPEP states that “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) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.')”. In the instant case, the Specification does not support that the inventor possessed the entire scope of the claimed invention, namely how to modify an insecticidal protein (other than insecticidal protein ARP147) to increase gut binding and/or toxicity.
The MPEP further states that 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."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when…the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.) In the instant case, it is unpredictable whether or how the location of the gut-binding protein in a modified insecticidal protein (other than insecticidal protein ARP147) would affect the capability of the insecticidal protein to increase gut binding and/or toxicity.
Given the unlimited number of possible modifications and the unpredictability of each modification on the capability of the insecticidal protein to increase gut binding and/or toxicity, the Applicant has not demonstrated possession of the broad scope of possible modified insecticidal proteins.
Summary
No claim is allowed.
However, claims 1 and 2 are deemed free of the prior art to the extent that the claims read on sequence SEQ ID NO: 1 or 7. A thorough search of the prior art did not disclose an amino acid sequence at least 95% identical to the full-length amino acid sequence as set forth in SEQ ID NO: 1 or 7.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MEADOWS whose telephone number is (703)756-1430. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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/CHRISTINA L MEADOWS/Examiner, Art Unit 1663
CHRISTINA MEADOWS
Examiner
Art Unit 1663
/Amjad Abraham/SPE, Art Unit 1663
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