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 .
Election/Restrictions
Applicant's election without traverse of species of SEQ ID NO: 139, SEQ ID NO: 145, and SEQ ID NO: 161 in the reply filed on 11/19/2022 is acknowledged.
Since applicant has amended claims to add new insecticidal polypeptide sequences 10-41, 43-45, 235-255, or 258- 273. They are subjected to election of species. Furthermore, applicant has not separated into groups that has common structure or the common use from the common structure. Therefore for following analysis first five sequences of SEQ ID NOs: 10-15 are examined in this office action.
Therefore claims 18-20, 22-23, 27, 40-43, 45-51, 53-54, 72-75 and 77-79 are pending and the claims among with the species of SEQ ID NO: 139 from claim 24, SEQ ID NO: 145 from claim 25, and SEQ ID NO: 161 from claim 27 are examined in this office action.
Rejections that are withdrawn
Objection to specification has been withdrawn in light of applicant’s amendment of specification to claim benefit for the provisional patent application No. 63/812,550 filed after the PCT.
35 USC § 102 rejection has been withdrawn in light of applicant’s amendment of claims 18, 40, 47 and 72 to recite domain I and II from SEQ ID NO: 1 and heterologous domain III derived from a Cry1C, Cry1D or Cry1F or 90% sequence identity to a domain III region of any one of SEO ID NOs: 10-41 or toxin having an amino acid sequence of any one of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273. The amendment require specific heterologous domain III and specific polypeptide sequences.
Claim Interpretation
Claims 41 and 48-49, recite the term “Cry89Aa”, the phrase has been interpreted since applicant has not defined the term “Cry89Aa”. Furthermore, there are no art standard to define the term. Therefore, the term is interpreted to refer to any protein that has insecticidal property.
Claims 18-19, 27, 40-42, 50 and 72 recite the term “heterologous”, the term has been interpreted as applicant defines “The term "heterologous" as used herein refers to nucleic acid comprising two or more subsequences that are not found in the same relationship to each other in nature.” Therefore, it is interpreted that any fusion proteins within or across species are interpreted to comprise heterologous region.
Following Improper Markush Groups rejection has been added since applicant has recited diverse poplypeptide sequences of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273 in claims 18, 40, 47 and 72 in the amendments of 03/03/2026.
Improper Markush Groups
Claims 40-43, 45-51, 53-54, 72-75 and 77-79 are rejected under the judicially-created basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-722 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. and Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or common use that flows from the substantial structural feature and/or common use that flows from the substantial structural feature for the following reasons:
Claims 40, 47 and 72 recite an engineered insecticidal polypeptide of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273. Specification provides the description of the sequence in Tables 1-4, and it is clear there are numerous different proteins that do not appear to be from the same family of proteins, and therefore they do not have the same function for example Tables 1-4 showed that they have different insecticidal activity to insects corn earworm (CEW), European corn borer (ECB) and Fall army worm (FAW). There are some engineered variants among the sequences to have no insecticidal activity or are not tested for insecticidal activity for either CEW, ECB or FAW or other insects. Therefore, they constitute proteins that does not have common use as have insecticidal activity against the common insects. Furthermore, sequence alignment in Figures 6-7 showed the polypeptides has various identity to each other ranging from about 83%-99%. This shows that the recited proteins of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273 do not share a substantial feature and/or common use that flows from the substantial structural feature and/or common use that flows from the substantial structural feature.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or groupings of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 USC 134 and 37 CFR 41.31 (a)(1).
Claim Rejections - 35 USC § 112 - written description requirement
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 18-20, 22-23, 27, 40-43, 45-46, 48-51, 53-54, 72-75 and 77-79 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The 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.
Following analysis has been modified since applicant’s claim 18 now recite any heterologous domain III derived from Cry1C, Cry1D, or Cry1F family insecticidal polypeptide and claims 40 and 72 recite heterologous domain III having at least 90% sequence identity to a domain III region of any one of SEQ ID NOs: 10-41.
Analysis of Breadth of Claims
Domain III derived from any Cry1C, Cry1D, or Cry1F family insecticidal polypeptide would comprise large number of polypeptide sequences (claim 18).
Applicant has not described the structure of border II region (claim 18).
Cry89Aa family insecticidal polypeptide encompass any structure (claims 41, 48, and 49).
Any heterologous domain III having at least 90% sequence identity to a domain III region of any one of SEO ID NOs: 10-41 comprise large variants of amino acid sequences.
What is Described in the Specification
Applicant describes:
Engineered polypeptide sequences were designed in silico using a previously identified native Cry89Aa class toxin, originally found in a Bacillus thuringiensis species (PCT/US2022/028078; SEQ ID NO: 1 as disclosed herein) (page 44, paragraph 135).
engineering method altered SEQ ID NO: 1 by exchanging domain III (SEQ ID NO: 151) of SEQ ID NO: 1, a Cry89Aa class native polypeptide (formerly Cry1N class, as disclosed in U.S. Provisional Patent Application No. 63/665,914 and International Patent Application No. PCT/US2025/014957) (page 43, paragraph 135).
SEQ ID NO: 139 is domain I region, SEQ ID NO:145 is the domain II region and SEQ ID NO:161 is the border/linker II region and SEQ ID NO:s:146-151 is domain III region (page 44, paragraph 137).
Engineered Variant 0871.1.1 (SEQ ID NO: 91) was generated using domain swapping techniques between a native Cry1N-like protein (NCBI Accession# WP 170924498 (EntDB 01628); SEQ ID NO: 3) and a native non-Cry1N protein, Cry1Ca5 wherein domain I (SEQ ID NO: 135) and domain II (SEQ ID NO: 141) of the Cry1N were joined to domain III of Cry 1 Ca5 to generate the engineered protein of Engineered Variant 0871.1.1 (SEQ ID NO: 91) (FIG. 4B) (pages 44-45, paragraph 138).
Engineered Variant 00309A (SEQ ID NO:11) comprises domains I (SEQ ID NO: 139) and II (SEQ IDNO: 145) (dld2) from the native Cry89Aa protein AFG02511.1 (SEQ ID NO: 1) from Bacillus thuringiensis (Figure 1) (pages 45, paragraph 139).
Engineered Variant 00309A (SEQ ID NO:11) showed insecticidal activities in Table 1 and Table 3 where Table 3 showed it does not have insecticidal activity against European com borer (ECB).
Corn plants were stably transformed to express either the Engineered Variant Engineered Variant 0309A (SEQ ID NO: 11) insecticidal protein (page 55, paragraph 156).
Difference Between What was Described and What is Claimed
Applicant has not described any other domain I and domain II amino acid sequence of SEQ ID NO: 1 other than SEQ ID NOs: 139 and 145 respectively (claim 18).
Applicant has not described domain III derived from any Cry1C, Cry1D, or Cry1F family insecticidal polypeptide (claim 18) when heterologously combined with domain I and II of SEQ ID NO:1 would cause insecticidal property other than domain I and II as SEQ ID NOs: 139 and 145 and domain III of Cry 1 Ca5 leading to variants as SEAQ ID NO:11.
Applicant has not described domain III having at least 90% sequence identity to a domain III region of any one of SEQ ID NOs: 10-41 (claims 40 and 72).
Applicant has not described “Cry89Aa family insecticidal polypeptide” (claims 41 and 48-49).
Analysis
The purpose of the written description is to ensure that the inventor had possession at the time the invention was made, of the specific subject claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
Applicant has not described any other domain I and domain II amino acid sequence of SEQ ID NO: 1 other than SEQ ID NOs: 139 and 145 respectively (claim 18). Furthermore, Applicant has not described any domain III derived from any Cry1C, Cry1D, or Cry1F family insecticidal polypeptide other than SEQ ID NO:151 when exchanged would cause insecticidal properties (claim 18). Applicant provides examples of sequences identified as CRY89 in Figure 1 wherein domain I and domain II have various structures from B. thuringiensis. However applicant has not described the structure of any domain I , II or II from B. thuringiensis that is required to have function of the protein to have insecticidal polypeptide functions other than certain combination of domains that would have insecticidal properties for example provided in Table 1. Applicant describes Engineered Variant 00309A (SEQ ID NO:11) comprises domains I (SEQ ID NO: 139) and II (SEQ ID NO: 145) (d1d2) from the native Cry89Aa protein AFG02511.1 (SEQ ID NO: 1) from Bacillus thuringiensis (Figure 1) (pages 45, paragraph 139).
Applicant teaches engineered Variant 0871.1.1 (SEAQ ID NO:91) and Engineered Variant 0309A (SEQ ID NO:11) share a common domain III (that of Cry1Ca5) as showed in common amino acids from 500-655 in Figure 4C wherein the two proteins differ in that Engineered Variant 0871.1.1 comprises domains I (SEQ ID NO: 135) and II (SEQ ID NO: 141) (dld2) from Cry1N (EntDB 01628; SEQ ID NO: 3), whereas Engineered Variant 0309A comprises domains I (SEQ ID NO: 139) and II (SEQ ID NO: 145) (dld2) from the native Cry89Aa protein AFG02511.1 (SEQ ID NO: 1) (page 45, paragraph 000139). Furthermore, table 3 (page 51, paragraph 000147) showed SEQ ID NO:11 has insecticidal activity against CEW, CL, SBL etc. and does not have activity against ECB. There is no data showing that the other engineered variant of SEQ ID NO:91 have any insecticidal activity. Therefore, there is dearth of description of any domain III from Cry1C, Cry1D, or Cry1F family insecticidal protein when replaced in SEQ ID NO:1 would cause insecticidal properties.
Therefore, if amino acid positions 500-655 i.e. 155 amino acid comprise the domain III of SEQ ID NO:11, the any amino acid comprising 90% identity to the domain III would have 15 amino acids changes (i.e., substitutions, deletions, insertions, or additions) relative to domain III of SEQ ID NO: 11 encompasses a genus of amino acid sequences that includes at least ~2015 different molecules. For this reason, the genus of amino acid molecules having at least 90% identity to domain III region of SEQ ID NO: 11 is a very large genus of molecules.
Furthermore, the state of the art at the time of the instant invention was that although the skilled artisan would appreciate the engineered protein comprising specific domain III of SEQ ID NO:11, one would not be able to readily predict function of amino acid which has at least 90% identity to domain III of the SEQ ID NOs: 11 and it is impossible to predict such a broad sequence variation will have any required function of having insecticidal properties. For example, Guo et al. (Published Year: 2004, Journal: Proceedings of the National Academy of Sciences, Vol. 101(25), pages: 9205-9210) teaches that while proteins are fairly tolerant to mutations resulting in single amino acid changes, increasing the number of substitutions additively increases the probability that the protein will be inactivated (page 9209, right. col., paragraph 2).
Applicant teaches engineered variant 00309A (SEQ ID NO:11) showed insecticidal activities in Table 1 and Table 3 where Table 3 showed it does not have insecticidal activity against European com borer (ECB). Furthermore, in Spec, Table 1 there are other variants that has no insecticidal activity against ECB and FAW (see Table 1, paragraph 144). Karlova et al. (Published: 2005, Journal of Invertebrate Pathology 88: 169–172) teaches different hybrids with different structures and combinations of domain I, II and III have various toxicity for example hybrid pRK6 (Cry1Ba-Cry1Ac) has showed considerable activity only as a protoxin wherein the lack of trypsin activated toxin of Cry1Ba and its hybrid is due to trypsin processing in domain 1 (page 171, right first paragraph, see other examples in Table 1 below). Furthermore, Sakai et al. (Published: 2007, Journal: Journal of Bioscience and Bioengineering 103(4):381–383 DOI: 10.1263/jbb.103.381) teaches when domain III of Cry1C was replaced with that of Cry1Aa or Cry4A, the hybrid Cry1C protein retained the cytotoxicity showing that domain III of Cry1C is not crucial in determining the cytocidal specificity of Cry1C against Sf9 (page 381, Abstract). Sakai et al. teaches various cytotoxicity in hybrids of different combinations of domains (See Figure 3 below). This showed that any combination of domain I, II and III would not cause the engineered protein to have property of being insecticidal and it would require specific domain combinations. Therefore, there is dearth of description of domain I and domain II amino acid sequence of SEQ ID NO: 1 other than SEQ ID NOs: 139 and 145 respectively (claim 18) and description of domain III from any Cry1C, Cry1D, or Cry1F family insecticidal polypeptides (claim 18) to have an insecticidal property.
Applicant tests many variants of paragraph 147, Table 3 wherein the data showed few variants were effectively insecticidal against many of the tested insects. For example, Bosch et al. (US patent No.: US 6,780,408 Bl, Date of Patent: Aug. 24, 2004) teaches their disclosed proteins each protein has different specificity for example Cry1C is particularly active against S. exigua and M. brassicae (col. 2, lines 1-5). Furthermore, Sakai et al. teaches Cry1C, one of the lepidopteran-specific insecticidal proteins from Bacillus thuringiensis (page 381, Abstract). Therefore, there is dearth of description of any of the domain III of the not described Cry89Aa family insecticidal polypeptide would be effectively insecticidal against all of the insects.
Applicant has not described “Cry89Aa family insecticidal polypeptide” (claims 41 and 48-49). Applicant describes engineering method altered SEQ ID NO: 1 by exchanging domain III (SEQ ID NO: 151) of SEQ ID NO: 1, a Cry89Aa class native polypeptide (formerly Cry1N class, as disclosed in U.S. Provisional Patent Application No. 63/665,914 and International Patent Application No. PCT/US2025/014957). However, the term “Cry89Aa” has not been expressly defined on what percentage of similarity or any other properties/structures or functions are required to be the “Cry89Aa family insecticidal polypeptide”. Therefore, there is dearth of description of an “Cry89Aa family insecticidal polypeptide” and their domains I and II within the B. thuringiensis.
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Applicant has not described any domain III having at least 90% sequence identity to a domain III region of any one of SEQ ID NOs: 10-41 (claims 40 and 72) would cause insecticidal property. Applicant has not described the domain III of SEQ ID NOs:10-41. Furthermore, applicant has not described any sequence having 90% sequence identity to domain III of the sequences would cause insecticidal activity to any insects. For example, Xu et al. teaches there are variations in the domain III regions of for example Cry1A wherein the domain position ranges from 463 to 679 (page 2735, Table 1, see table below). For example, Cry1Ac has large variations in the domain III residues (see figure 4 below). Furthermore, specific residue changes are important to have function of receptor binding, recognition and toxicity (page 2742, first paragraph). Therefore, there is dearth of description of described any sequence having 90% sequence identity to domain III of the sequences would cause insecticidal activity to any insects.
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Given the large structural variable associated with these embodiments, the claims read on an extremely broad and highly diverse structures that would require to have specific function activity against any insects as being insecticidal. Thus, in view of the analysis presented above, a skilled artisan would appreciate that the claims are directed to extremely broad and highly diverge genus of sequence variants that are required to have the specific function activity against any insects as being insecticidal.
Applicant states Domain III (C-terminal domain) is made up of two anti-parallel β-sheets and is also involved in receptor binding (page 39, paragraph 000119).
Given the large size and structural diversity associated with the claimed genus, Applicant’s disclosure is not representative of the claimed genus as a whole. This point is particularly relevant because, as discussed above, the prior art speaks to the disconnection between the structure of the broadly claimed variants in any plants and the recited specific function.
The test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to one skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Pharm, Inc, v EH Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010). To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Lockwood v. Amer. Airlines, ina, 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). "An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations. Lockwood, 107 F.3d at 1572, 41 USPG2d at 1966". While the written description requirement does not demand either examples or an actual reduction, actual "possession" or reduction to practice outside of the specification is not enough. Ariad Pharm, Inc. v. Eli Lilly & Co., 598 F,3d 1336,1352 (Fed. Cir. 2010). Rather, it is the specification itself that must demonstrate possession. Id.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. The court stated that, “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNAs, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F. 3d 1559; 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
Thus, based on the analysis above, Applicant has not met either of the two elements of the written description requirement as set forth in the court's decision in Eli Lilly. As a result, it is not clear that Applicant was in possession of the claimed genus at the time this application was filed.
Response to Arguments
Applicant's arguments filed 03/03/2026 have been fully considered but they are not persuasive.
Applicant argues regarding claim interpretation solely to advance prosecution, claims 18, 40, and 72 are amended to remove the phrase "Cry89Aa family insecticidal polypeptide." Applicant argues each of the independent claims is amended to recite specific sequence and structural features that are sufficiently supported by the specification (Response to rejection, page 8, paragraph 2).
Applicant argues specification expressly discloses "engineered insecticidal polypeptides comprising a domain I and a domain II from a Cry1N or Cry89Aa family insecticidal polypeptide, and a heterologous domain III from a Cry1F or a Cry1C family insecticidal polypeptide." See Specification at paragraph 19 (emphasis added). Applicant argues the specification further discloses "an insecticidal hybrid delta-endotoxin protein, wherein the insecticidal hybrid delta-endotoxin protein comprises domains I and II of a native Bacillus thuringiensis delta-endotoxin Cry1N or Cry89Aa protein, and domain III of a native Bacillus thuringiensis delta-endotoxin Cry1F or Cry1C protein." See Specification at paragraph 20 (emphasis added). Applicant argues the domain I and domain II amino acid sequences of SEQ ID NO: 1, as specified in amended claim 18, correspond to the domain I and II regions of the AFG02511.1 sequence, which is a native Bacillus thuringiensis delta-endotoxin Cry89Aa family insecticidal polypeptide. See FIG. 1 and Sequence Listing (Response to rejection, page 8, last paragraph).
Applicant agues regarding the claimed "heterologous domain III derived from a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide," the specification expressly discloses "domains may be swapped between different Cry family toxin pesticidal polypeptides (e.g., Cry89Aa, Cry1N, Cry1F, Cry1C, Cry1D, etc.) resulting in hybrid or chimeric fusion protein toxins having altered insecticidal activity or target spectrum." See Specification at paragraph 61 (emphasis added). Applicant argues effectively then, as amended, the claims are focused on structural claiming, not claiming by genus. Applicant argues this also serves to distinguish the instant claims from Juno, which involved purely functional gene claims that were found to be without sufficient structural commonality. Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021. Applicant argues the claimed genus is not defined by function alone, but by a conserved structural framework comprising fixed domain I and domain II sequences, with domain III constrained by structural origin and sequence identity thresholds. Applicant argue the specification identifies common structural characteristics shared across the genus (Response to rejection, page 9, first paragraph).
Applicant argues the scope of amended claim 18 is further supported by the specific example sequences and insecticidal data provided in the specification and the sequence listing. Applicant argues for example, each of the engineered sequence variants of SEQ ID NOs: 10-41 disclosed in the application has a structure comprising domains I and II from SEQ ID NO: 1, and a heterologous domain III derived from either a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide, wherein the heterologous domain III is connected within 10 amino acids of a border II region positioned between the domain II and the heterologous domain III, as recited in amended claim 18. Applicant argues this is further supported by the sequence alignment in FIG. 2 between SEQ ID NO: 12-39, and in the sequence alignment in FIG. 5 between SEQ ID NOs: 1, 10 and 11. Applicant argues these specific engineered variants of SEQ ID NOs: 10-41 also exhibit measurable insecticidal activity against various pests using different assays, as demonstrated in the Examples of the application. See Specification at Tables 1 and 3-4 (Response to rejection, page 9, second to last paragraph).
Applicant teaches engineered Variant 0871.1.1 (SEAQ ID NO:91) and Engineered Variant 0309A (SEQ ID NO:11) share a common domain III (that of Cry1Ca5) wherein specifically SEQ ID NO:11 comprise domain I and II of SEQ ID NO:1 as variant 0309A. Furthermore, table 3 (page 51, paragraph 000147) showed SEQ ID NO:11 has insecticidal activity against CEW, CL, SBL etc. and does not have activity against ECB. There is no data showing that the other engineered variant of SEQ ID NO:91 have any insecticidal activity. Therefore, there is dearth of description of any domain III from Cry1C, Cry1D, or Cry1F family insecticidal protein or a sequence having 90% sequence identity to the domain III region of any one of SEQ ID NOs: 10-41 (claim 40) when replaced in SEQ ID NO:1 would cause insecticidal properties.
Applicant argues the instant specification discloses by actual reduction to practice at least 32 different species of engineered polypeptide variants (e.g., SEQ ID NOs: 10-41) that have a reasonable structure-function correlation - i.e., each polypeptide having a domain I and a domain II amino acid sequence from SEQ ID NO: 1, and a heterologous domain III derived from a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide, wherein the heterologous domain III is connected within 10 amino acids of a border II region positioned between the domain II and the heterologous domain III; and exhibiting insecticidal activity. Applicant argues for example, as discussed above, the instant specification demonstrates that the engineered polypeptide variants of SEQ ID NOs: 10-41 were found to have measurable insecticidal activity (i.e., function) against various pests using different assays. See Specification at Tables 1 and 3-4. Applicant argues this adequately reflects the structural diversity of the claimed genus not only through the disclosure of sufficient species that are representative of the full variety or scope of the genus, but also by the establishment of a reasonable structure-function correlation. Applicant argues also, as shown above, the MPEP does not require "individual support for each species that the genus embraces." (Response to rejection, page 10, second to last paragraph).
Applicant argues thus, the instant specification sufficiently describes by actual reduction to practice a representative number of species sharing a reasonable structure-function correlation to support the full scope of amended claim 18. Applicant argues therefore, the engineered polypeptide of claim 18 is fully supported by the written description of the original specification (Response to rejection, page 10, last paragraph).
Applicant argues regarding claim 40, scope of amended claim 40 is sufficiently supported by the specification at least by the sequences of SEQ ID NOs: 1, 139, 145, and 10-41; the insecticidal activity data in Tables 1 and 3-4; the sequence alignments of FIG. 2 and FIG. 5; and the homology tables of FIG. 6-7 (Response to rejection, page 11, second paragraph).
Applicant argues the claimed sequences of SEQ ID NOs: 139 and 145 correspond to the domain I and domain II regions of the AFG02511.1 native Cry89Aa sequence disclosed in SEQ ID NO: 1. See FIG. 1 and Sequence Listing. Applicant argues each of SEQ ID NOs: 10-41 comprises a domain I having the amino acid sequence of SEQ ID NO: 139 and a domain II having the amino acid sequence of SEQ ID NO: 145, with different heterologous domain III regions derived from either a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide 7 (Response to rejection, page 11, paragraph 3).
Applicant argues FIG. 6 of the instant application shows that SEQ ID NOs: 10 and 11 share 84.8% sequence homology, while FIG. 7 of the instant application shows that SEQ ID NOs: 12- 39 share between about 81-99% sequence homology, with the differences being in their respective heterologous domain III sequences. Applicant argues this is also shown and supported by the sequence alignment in FIG. 2 between SEQ ID NO: 12-39, and in the sequence alignment in FIG. 5 between SEQ ID NOs: 1, 10, and 11 (Response to rejection, page 11, paragraph 4). Applicant argues the specific engineered variants of SEQ ID NOs: 10-41 having distinct heterologous domain III regions were also found to exhibit measurable insecticidal activity against various pests using different assays, as demonstrated in the Examples of the application. See Specification at Tables 1 and 3-4 (Response to rejection, page 11, last paragraph).
Applicant argues the instant specification discloses by actual reduction to practice a sufficient number of species that are representative of the full variety or scope of the claimed genus of amended claim 40. Applicant argues the sequence alignments, homology data, and insecticidal activity data provided in the instant application demonstrate that there is a link between sequence identity and functionality, and therefore it can be reasonably inferred that variants showing a high degree of sequence similarity to the claimed polypeptides would exhibit the functional effect of insecticidal activity. Applicant argues the MPEP does not require "individual support for each species that the genus embraces." (Response to rejection, page 12, first paragraph).
Applicant agues the instant specification sufficiently describes by actual reduction to practice a representative number of species sharing a reasonable structure-function correlation to support the full scope of amended claim 40. Applicant argues therefore, the engineered insecticidal polypeptide of claim 40 is fully supported by the written description of the original specification (Response to rejection, page 12, second paragraph).
Applicant argues regarding claim 47, the scope of the claim is sufficiently supported by the specification at least by the insecticidal activity data in Tables 1-4. Applicant argues the Examples of the instant specification demonstrate that the claimed polypeptide variants comprising an insecticidal Bacillus thuringiensis toxin having the sequence of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273 were found to exhibit insecticidal activity against various pests using different types of assays. See Specification at Tables 1-4. Applicant agues therefore the written description of the original specification provides sufficient support for the scope of amended claim 47 (Response to rejection, page 12, paragraphs 5 and 6).
Applicant argues the scope of amended claim 72 is sufficiently supported by the specification for at least the same reasons provided above for amended claim 40. Applicant argues amended claim 72 is sufficiently supported by the specification at least by the sequences of SEQ ID NOs: 1, 139, 145, and 10-41; the insecticidal activity data in Tables 1 and 3-4; the sequence alignments of FIG. 2 and FIG. 5; and the homology tables of FIG. 6-7. Applicant argues the written description of the original specification provides sufficient support for the scope of amended claim 72 (Response to rejection, page 12, first paragraph).
Applicant's arguments have been fully considered but they are not persuasive since:
Regarding argument on 18, 40 and 72 are amended to remove the phrase "Cry89Aa family insecticidal polypeptide." Claims 41, 48-49 still recite undescribed phrase “non-Cry89Aa” cry family insecticidal polypeptide, wherein applicant has not described the term Cry89Aa, applicant has not described the phrase “non-Cry89Aa”. Therefore the claim interpretation and written description requirements has been maintained.
Regarding argument on domain I, II and III has been described in paragraph 00019 is not found persuasive since the paragraph only discloses one aspect of the disclosure among many. The domain I and II of native B. thuringiensis delta-endotoxin Cry1N or Cry89Aa protein, and domain III of a native B. thuringiensis delta-endotoxin Cry1F or Cry1C protein would have lots of structure and functions associated with the structures. Instead applicant has not described any other domains other than the SEQ ID NOs: 139 and 145 as domain I and II and all the Cry89Aa or non - Cry89Aa B. thuringiensis domain III protein other than SEQ ID NO: 151 (page 44, paragraph 000136).
Regarding argument on domain III constrained by structural origin and sequence identity thresholds, the argument was not found persuasive since applicant has not described adding any heterologous domain III from any Cry1C, Cry1D or Cry1F family insecticidal polypeptide (claim 18) or a sequence having 90% sequence identity to the domain III region of any one of SEQ ID NOs: 10-41 (claim 40) to the domain I or domain II of SEQ ID NO:1, would cause insecticidal property in the engineered insecticidal polypeptide. Applicant teaches engineered Variant 0871.1.1 (SEAQ ID NO:91) and Engineered Variant 0309A (SEQ ID NO:11) share a common domain III (that of Cry1Ca5) wherein specifically SEQ ID NO:11 comprise domain I and II of SEQ ID NO:1 as variant 0309A. Furthermore, table 3 (page 51, paragraph 000147) showed SEQ ID NO:11 has insecticidal activity against CEW, CL, SBL etc. and does not have activity against ECB. There is no data showing that the other engineered variant of SEQ ID NO:91 have any insecticidal activity. Therefore there is dearth of description of any domain III from Cry1C, Cry1D, or Cry1F family insecticidal protein or a sequence having 90% sequence identity to the domain III region of any one of SEQ ID NOs: 10-41 (claim 40) when replaced in SEQ ID NO:1 would cause insecticidal properties.
Regarding argument on each of the engineered sequence variants of SEQ ID NOs: 10-41 disclosed in the application has a structure comprising domains I and II from SEQ ID NO: 1, and a heterologous domain III derived from either a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide, the argument was not found persuasive since it is not clear which of the domain III derived from either a Cry1C, Cry1D, or Cry1F has effect against which of the insects as showed in Table 1, paragraph 000144 where some variants has no effect against ECB. Furthermore, applicant has not described in specification that SEQ ID NOs: 10-41 or any of the variants showed in Tables 1 and 3-4 comprises domain III of either a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide in specification and which sequences has which of the domain or their derivation comprises how many changes in the domain III sequences from the original Cry1C, Cry1D, or Cry1F family insecticidal polypeptide. Therefore there is dearth of description of variants of SEQ ID NO:1 comprising any of the domain III of either a Cry1C, Cry1D, or Cry1F would have insecticidal properties.
Regarding argument on claim 40 that engineered variants of SEQ ID NOs: 10-41 having distinct heterologous domain III regions were also found to exhibit measurable insecticidal activity, the argument was not found persuasive since applicant has not described any heterologous domain III having at least 90% sequence identity to a domain III region of any one of SEO ID NOs: 10-41. Applicant has not described deletion, addition or substitution which of the amino acids motif or domains on the variants comprising 90% sequence identity to a domain III region of any one of SEQ ID NOs: 10-41 would have insecticidal activity against any insects. Therefore the written description rejection has been maintained. Furthermore, these sequence comprise distinct domain III and their modifications.
Regarding argument on SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273 were found to exhibit insecticidal activity against various pests using different types of assays, since the sequences are structurally different and their uses varies as different insecticidal proteins as showed in Tables 1-4 they does not constitute members of a Markush group. The sequence comprises different origins for example SEQ ID NO:1, SEQ ID NO:3 that has different domains I and II combined with various domain III showing the sequence to not have structural similarity.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 18-20, 22-23 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kelly et al. (US patent Application Pub. No.: US 2024/0240200 A1, Date of Patent: Jul. 18, 2024) and further in view of by Bosch et al. (US patent No.: US 6,780,408 Bl, Date of Patent: Aug. 24, 2004).
Claims are drawn to an engineered insecticidal polypeptide comprising a domain I and II from a SEQ ID NO:1 and a heterologous domain III from a Cry1C, Cry1D or Cry1F family insecticidal polypeptide. Claims are further drawn to the polynucleotide encoding the protein is linked to heterologous regulatory element and plant cell or bacteria comprising the polynucleotide.
Applicant discloses an engineering method to alter SEQ ID NO: 1 by exchanging domain III (SEQ ID NO: 151) of SEQ ID NO: 1, a Cry89Aa class native polypeptide (formerly Cry1N class, as disclosed in U.S. Provisional Patent Application No. 63/665,914 and International Patent Application No. PCT/US2025/014957) (page 44, paragraphs 135-136). Therefore, SEQ ID NO: 151 is domain III region. Applicant describes SEQ ID NO: 139 is domain I region, SEQ ID NO:145 is the domain II region and SEQ ID NO:161 is the border/linker II region and SEQ ID NOs:151 is domain III region (page 44, paragraph 137).
Regarding claims 18, alignment of SEQ ID NO: 139, 145, 161 and 151 showed that the regions have 100% identity to SEQ ID NO:12 of Kelly et al. (see alignment below). Therefore, the polypeptide of SEQ ID NO:12 comprises domain I, domain II, border II and domain III.
Kelly et al. claim 1 teaches SEQ ID NO:12 has pesticidal activity.
Alignment of SEQ ID NOs: 139, 145, 161 and 151 to Kelly et al.’s SEQ ID NO:12.
Query: unnamed protein product Query ID: lcl|Query_4971823 Length: 634
>unnamed protein product
Sequence ID: Query_4971825 Length: 593
Range 1: 1 to 593
Score:1220 bits(3157), Expect:0.0,
Method:Compositional matrix adjust.,
Identities:593/633(94%), Positives:593/633(93%), Gaps:40/633(6%)
Query 2 NQNNQNVTPDNSVKYPLADDQTTPLAENNQDVTSDNKENSKVINCLSDPNSDLEKSGGGV 61
NQNNQNVTPDNSVKYPLADDQTTPLAENNQDVTSDNKENSKVINCLSDPNSDLEKSGGGV
Sbjct 1 NQNNQNVTPDNSVKYPLADDQTTPLAENNQDVTSDNKENSKVINCLSDPNSDLEKSGGGV 60
Query 62 ALDITMSLISELLGAVPVAGSYIQFVFDKLWSIFGPSDWDSLMEHVEALIDSKIQEHVKR 121
ALDITMSLISELLGAVPVAGSYIQFVFDKLWSIFGPSDWDSLMEHVEALIDSKIQEHVKR
Sbjct 61 ALDITMSLISELLGAVPVAGSYIQFVFDKLWSIFGPSDWDSLMEHVEALIDSKIQEHVKR 120
Query 122 NAQNELEAIQRNLETYLKFLYAWENDSNNLRARAVVKDQFVGLEQTLERKMVSVFGSTGH 181
NAQNELEAIQRNLETYLKFLYAWENDSNNLRARAVVKDQFVGLEQTLERKMVSVFGSTGH
Sbjct 121 NAQNELEAIQRNLETYLKFLYAWENDSNNLRARAVVKDQFVGLEQTLERKMVSVFGSTGH 180
Query 182 EVHLLPIFAQAANLHLMLLRDAEKYGNRWGWTDREIQVYYDNQVRYIHEYTDHCVKYYNQ 241
EVHLLPIFAQAANLHLMLLRDAEKYGNRWGWTDREIQVYYDNQVRYIHEYTDHCVKYYNQ
Sbjct 181 EVHLLPIFAQAANLHLMLLRDAEKYGNRWGWTDREIQVYYDNQVRYIHEYTDHCVKYYNQ 240
Query 242 GLSKLKGSTYQDWDKYNRYRREMTLTVLDLISIFPSYDTRTYPIDTIGQLTREVYSDLLI 301
GLSKLKGSTYQDWDKYN LLI
Sbjct 241 GLSKLKGSTYQDWDKYN----------------------------------------LLI 260
Query 302 ANSSGIQPFTNTDFDNILIRKPHLMDFLRHLEIFTDRHNASRHNVYWGGHRVHFSRAGDN 361
ANSSGIQPFTNTDFDNILIRKPHLMDFLRHLEIFTDRHNASRHNVYWGGHRVHFSRAGDN
Sbjct 261 ANSSGIQPFTNTDFDNILIRKPHLMDFLRHLEIFTDRHNASRHNVYWGGHRVHFSRAGDN 320
Query 362 TYHISPLYGSEANVEPTTYLSFGDSQVYRIHSKPEWDRGSTAISGSYEFRGVTGCSFYRM 421
TYHISPLYGSEANVEPTTYLSFGDSQVYRIHSKPEWDRGSTAISGSYEFRGVTGCSFYRM
Sbjct 321 TYHISPLYGSEANVEPTTYLSFGDSQVYRIHSKPEWDRGSTAISGSYEFRGVTGCSFYRM 380
Query 422 GNFPGTVALTYRQFGPELTELPWGKNGPSHRLCHVTYFRRSQAVGATSRQTLTSGLLFSW 481
GNFPGTVALTYRQFGPELTELPWGKNGPSHRLCHVTYFRRSQAVGATSRQTLTSGLLFSW
Sbjct 381 GNFPGTVALTYRQFGPELTELPWGKNGPSHRLCHVTYFRRSQAVGATSRQTLTSGLLFSW 440
Query 482 THSSAAETNNIDPEKITQIPMVKASSLGSGTSVIEGPGFTGGDILRRSSPGSTGTLRVNV 541
THSSAAETNNIDPEKITQIPMVKASSLGSGTSVIEGPGFTGGDILRRSSPGSTGTLRVNV
Sbjct 441 THSSAAETNNIDPEKITQIPMVKASSLGSGTSVIEGPGFTGGDILRRSSPGSTGTLRVNV 500
Query 542 NSPLSQRYRIRIRYASTTDLEFLVTCGGRTVNNFFPFTKTMNKGDSLTLEKFKFASFSTP 601
NSPLSQRYRIRIRYASTTDLEFLVTCGGRTVNNFFPFTKTMNKGDSLTLEKFKFASFSTP
Sbjct 501 NSPLSQRYRIRIRYASTTDLEFLVTCGGRTVNNFFPFTKTMNKGDSLTLEKFKFASFSTP 560
Query 602 FTFTQNEDTLEIFVQRFSSGEEVYIDRIEVIPV 634
FTFTQNEDTLEIFVQRFSSGEEVYIDRIEVIPV
Sbjct 561 FTFTQNEDTLEIFVQRFSSGEEVYIDRIEVIPV 593
Furthermore, Kelly et al. teaches modification in their disclosed Cry toxins can be made in their disclosed polypeptides for example by domain III swapping resulting in hybrid toxins with improved toxicities against certain insect pests. Kelly et al. teaches domain III swapping is an effective strategy to improve toxicity of Cry toxins or to create novel hybrid toxins with toxicity against pests that show no susceptibility to the parental Cry toxins (page 8, paragraph 0046). Kelly et al. teaches position of different N-terminal, central and C-terminal domain of their pesticidal protein of SEQ ID NO:12 wherein their C-terminal portion is location at from 497-634 (see table 12). Kelly et al. furthermore teaches many of the Cry1C and Cry1A pesticidal polypeptides and their different N-terminal, central, and C-terminal domain (i.e. domain III) (page 9, Table 2).
Furthermore, Bosch et al. claim 1 teaches Bacillus thuringiensis hybrid toxin fragment comprising a domain III of a first Cry protein and domains I and II of second Cry protein different from the first Cry protein. Since domain III is different from I and II, domain III would have been heterologous domain.
Bosch et al. teaches Cry1G can be made considerably more toxic to S. exigua by substituting its domain III with that of Cry1C and hybrid toxins produced comprising domain III of CryIC and the N-terminal region, including domains I and II of any other Cry protein (col. 12, lines 32-36, lines 41-44). Bosch et al. teaches of other insecticidal protein from B.t. of being CryIC, CryID and CryIF (col. 2, lines 60-66).
Bosch et al. teaches the reciprocal hybrid of G27, in which domain III of Cry1C has been exchanged by domain III of Cry1E is toxic to M. sexta (col. 9, lines 36-45). Bosch et al. discloses a heterologous promoter and terminator operably linked to the hybrid G27 (Col. 10, lines 57-67).
Thus it would have been obvious to a skilled in the art before the effective date of filling of the invention from teaching, suggestion, or motivation in the Kelly et al. to swap the domain III of their disclosed SEQ ID NO:12 that comprise the domain I, II and the border II of SEQ ID NO:161 of SEQ ID NO:1 with the domain III of Cry1C or combining the teaching of Bosch et al. such that the exchanging domain III that would led one of the skilled in the art to arrive at the claimed invention of a insecticidal polypeptide comprising domain I, II of SEQW ID NO:1, border II region and domain III of Cry1C, Cry1D and Cry1F with predictable result of insecticidal properties.
Regarding claims 19, Kelly et al. claim 10 teaches the polynucleotide encoding the Kelly et al.’s SEQ ID NO:12 operably linked to a heterologous promoter.
Regarding claims 20, 22, 23, Kelly et al. claims 11 and 21 teaches plant comprising the polynucleotide encoding the Kelly et al.’s SEQ ID NO:12.
Regarding claim 27, Alignment showed the heterologous domain is connected within 10 amino acids of a border II region positioned between the domain II and the heterologous domain III.
Response to Arguments
Applicant's arguments filed 03/03/2026 have been fully considered but they are not persuasive.
Applicant argues regarding claim 18, Kelly fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues Kelly does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009) (Response to rejection, page 13, last paragraph). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from the proteins disclosed in Kelly (Response to rejection, page 14, first paragraph).
Applicant argues Kelly does not provide any teaching or motivation to combine domains I and II from its disclosed polypeptide sequence of SEQ ID NO: 12 with a heterologous domain III derived from a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide. Applicant argues instead, Kelly merely discusses in paragraph 46:
"Modification of Cry toxins by domain III swapping has resulted in some cases in
hybrid toxins with improved toxicities against certain insect species. Thus,
domain III swapping could be an effective strategy to improve toxicity of Cry
toxins or to create novel hybrid toxins with toxicity against pests that show no
susceptibility to the parental Cry toxins."
Applicant argues these broad statements by Kelly are purely speculative and generic. Applicant argues Kelly fails to provide any actual teaching or guidance for making such domain III swapping modifications between Cry toxins, let alone swapping modifications between the specifically claimed domains I and II of SEQ ID NO: 1 (a Cry89Aa protein) and a heterologous domain III derived from a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide (Response to rejection, page 14, paragraphs 1-4).
Applicant argues Kelly fails to provide any teaching or guidance for the specific structural configuration and connectivity between swapped domain regions of Cry proteins, including the border region positioning and amino acid spacing between domains. Applicant argues nothing in Kelly would teach or motivate a person skilled in the art to connect a heterologous domain III within 10 amino acids of a border II region positioned between the domain II and the heterologous domain III, as recited in claim 18 (Response to rejection, page 14, paragraph 5).
Applicant argues domain swapping in Bacillus thuringiensis (Et) Cry proteins can often destroy or substantially alter their functional activity, and Et Cry protein structure-function relationships are highly unpredictable. Applicant argues therefore, minor sequence and structural alterations can drastically affect toxicity and pesticidal efficacy. Applicant argues this is supported by the activity data in the instant application, showing that certain engineered sequences do not exhibit insecticidal activity. Applicant argues for example, the engineered variants 0640A (SEQ ID NO: 256) and 0641A (SEQ ID NO: 257) did not show insecticidal activity against CEW and FAW pests, while the AFG02511 native Cry89Aa control (SEQ ID NO: 1) and other engineered variants exhibited measurable insecticidal activity against both pests. See Specification at Table 2 (Response to rejection, page 14, last paragraph). Applicant argues each of the each of engineered variants 0640A (SEQ ID NO: 256) and 0641A (SEQ ID NO: 257) differ from SEQ ID NO: 1 by having swapped domain I regions from other Cry toxin proteins (Response to rejection, page 15, first paragraph).
Applicant argues the disclosure of Kelly does not anticipate claim 18 because Kelly fails to teach or disclose, either expressly or inherently, each and every element of amended claim 18, as required for anticipation under 35 U.S.C. § 102. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from any protein disclosed in Kelly. Applicant argues in addition, a person skilled in the art would not have had any reasonable expectation of success in producing the claimed engineered insecticidal polypeptide based on the broad teachings of Kelly. Applicant argues therefore, claim 18 and the claims that depend therefrom are also nonobvious over the disclosure of Kelly. Applicant argues the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to rejection, page 15, paragraph 2).
Applicant argues regarding claim 40, Kelly fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues therefore, Kelly does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from the proteins disclosed in Kelly (Response to rejection, page 15, second to last paragraph).
Applicant argues Kelly does not provide any teaching or motivation to combine domains I and II from its disclosed polypeptide sequence of SEQ ID NO: 12 with a heterologous domain III having at least 90% sequence identity to a domain III region of any one of SEQ ID NOs: 10-41 of the instant application. Applicant argues instead, as discussed above, Kelly merely makes broad and generic statements for domain III swapping but does not provide any actual teaching or guidance for making such domain III swapping modifications between Cry toxins, let alone swapping between the specifically claimed domain I and II sequences from a Cry89Aa protein and a heterologous domain III having at least 90% sequence identity to a domain III region of any one of SEQ ID NOs: 10-41, which are derived from a Cry1C, Cry1D, or Cry1F family insecticidal polypeptide (Response to rejection, pages 15 and 16, last and first paragraph).
Applicant argues as discussed above, domain swapping in Et Cry proteins can often destroy or substantially alter their functional activity, and Et Cry protein structure-function relationships are highly unpredictable (Response to rejection, page 16, paragraph 2).
Applicant argues the disclosure of Kelly does not anticipate claim 40 because Kelly fails to teach or disclose, either expressly or inherently, each and every element of amended claim 40, as required for anticipation under 35 U.S.C. § 102. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from any protein disclosed in Kelly. Applicant argues a person skilled in the art would not have had any reasonable expectation of success in producing the claimed engineered insecticidal polypeptide based on the broad teachings of Kelly. Applicant argues claim 40 and the claims that depend therefrom are also nonobvious over the disclosure of Kelly. Applicant argues the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to rejection, page 16, paragraph 3).
Applicant argues regarding claim 47, Kelly fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues therefore, Kelly does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631. Applicant argues the claimed polypeptide is structurally distinct from the proteins disclosed in Kelly (Response to rejection, page 16, last paragraph).
Applicant argues claim 47, recites specific polypeptide variants having the amino acid sequence of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273 that were found to exhibit insecticidal activity. Applicant argues each of these engineered variants was developed through specific domain swapping and border/linker connections between different Cry proteins (Response to rejection, page 17, first paragraph). Applicant argues Kelly does not provide any teaching or motivation to arrive at any of the specifically claimed polypeptide sequences having insecticidal activity (Response to rejection, page 17, second paragraph).
Applicant argues the disclosure of Kelly does not anticipate claim 47 because Kelly fails to teach or disclose, either expressly or inherently, each and every element of amended claim 47, as required for anticipation under 35 U.S.C. § 102. Applicant argues the claimed polypeptide is structurally distinct from any protein disclosed in Kelly. Applicant argues in addition, a person skilled in the art would not have had any reasonable expectation of success in producing the claimed polypeptide based on the teachings of Kelly. Applicant argues therefore, claim 47 and the claims that depend therefrom are also nonobvious over the disclosure of Kelly. Applicant argue the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to rejection, page 17, paragraph 3).
Applicant argues regarding claim 72, claim 72 is directed to similar subject matter as claim 40. Applicant argues specifically, claim 72 recites a nucleic acid construct that encodes an engineered insecticidal polypeptide as recited in claim 40. Applicant argues as such, Kelly fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues Kelly does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631 (Response to rejection, page 17, last paragraph).
Applicant argues the disclosure of Kelly does not anticipate claim 72 because Kelly fails to teach or disclose, either expressly or inherently, each and every element of amended claim 72, as required for anticipation under 35 U.S.C. § 102. Applicant argues the engineered insecticidal polypeptide encoded by the claimed nucleic acid construct is structurally distinct from any protein disclosed in Kelly. Applicant argues in addition, a person skilled in the art would not have had any reasonable expectation of success in producing the claimed nucleic acid construct based on the teachings of Kelly. Applicant argues therefore, claim 72 and the claims that depend therefrom are also nonobvious over the disclosure of Kelly. Applicant argues the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to rejection, page 18, first paragraph).
Applicant argues regarding claim 18, Bosch fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues Bosch does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from the proteins disclosed in Bosch (Response to rejection, page 18, paragraph 3).
Applicant argues the claimed domain I and domain II amino acid sequences from SEQ ID NO: 1 correspond to the domain I and II regions of the AFG02511.1 sequence, which is a native Bacillus thuringiensis delta-endotoxin Cry89Aa family insecticidal polypeptide (Response to rejection, page 18, second to last paragraph).
Applicant argues in comparison, Bosch does not provide any teaching or suggestion of delta-endotoxin Cry89Aa family insecticidal polypeptides or hybrid proteins containing Cry89Aa domains thereof (Response to rejection, page 18, last paragraph).
Applicant argues instead Bosch merely relates to hybrid Cry protein toxin fragments particularly involving a CrylC domain III together with domains 1/11 from either a CrylE, CrylA, or CrylG protein. See Bosch at col. 1, lines 56-58; and claims 1 and 13-18. Applicant argues Bosch expressly discusses that "It is particularly preferred that the fragment comprises domains I and II of CrylE, CrylB, CrylD, CrylA, or CrylG, or a part thereof or a protein substantially similar to said domains I and II, and domain III of Cry 1 C or a part thereof or a protein substantially similar to said domain III." Applicant argues thus, Bosch provides no teaching or suggestion of the distinct domain I and II sequences recited in claim 18 (Response to rejection, page 19, first paragraph).
Applicant argues Bosch fails to provide any teaching or guidance for connecting a heterologous domain III within 10 amino acids of a border II region positioned between the domain II and the heterologous domain III. Applicant argues nothing in Bosch would teach or motivate a person skilled in the art to arrive at this specific structural configuration and connectivity between the swapped domain regions of its hybrid Cry proteins (Response to rejection, page 19, paragraph 2).
Applicant argues in addition, as discussed above, domain swapping in Bt Cry proteins can often destroy or substantially alter their functional activity, and Bt Cry protein structure-function relationships are highly unpredictable. Applicant argues minor sequence and structural alterations can drastically affect toxicity and pesticidal efficacy. Applicant argues this is supported not only by the data of the instant application, as discussed above (e.g., see SEQ ID NO: 256 and 257 in Table 2), but also the insecticidal activity data of Bosch. Applicant argues for example Table 1 of Bosch shows that the disclosed G27 hybrid Cry toxin was active against both S. exigua and M brassicae insects, while other hybrid Cry toxins such as H7, H8, F59, F71, and F26 were not. See Bosch at Table l; and col. 9, lines 18-47 (Response to rejection, page 19, paragraph 3).
Applicant argues the disclosure of Bosch does not anticipate claim 18 because Bosch fails to teach or disclose, either expressly or inherently, each and every element of amended claim 18, as required for anticipation under 35 U.S.C. § 102. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from any protein disclosed in Bosch. Applicant argues in addition a person skilled in the art would not have had any reasonable expectation of success in producing the claimed engineered insecticidal polypeptide based on the teachings of Bosch. Applicant argues therefore, claim 18 and the claims that depend therefrom are also nonobvious over the disclosure of Bosch. Applicant argues the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to rejection, page 19, paragraph 4).
Applicant argues regarding claim 40, Bosch fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues therefore, Bosch does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from the proteins disclosed in Bosch (Response to Rejection, page 20, second paragraph).
Applicant argues the claimed sequences of SEQ ID NOs: 139 and 145 correspond to the domain I and domain II regions of the AFG02511.1 native Cry89Aa sequence disclosed in SEQ ID NO: 1. See FIG. 1 and Sequence Listing. Applicant argues as discussed above, Bosch does not provide any teaching or suggestion of Cry89Aa polypeptides or hybrid Cry proteins containing Cry89Aa domains thereof. Applicant argues Bosch merely relates to hybrid Cry protein toxin fragments particularly involving a Cry1C domain III together with domains 1/11 from either a Cry1E, Cry1A, or Cry1G protein. See Bosch at col. 1, lines 56-58; and claims 1 and 13-18. Applicant argues thus, Bosch provides no teaching or suggestion for using the distinct domain I and II sequences recited in claim 40, let alone combining these distinct domains I and II sequences from a Cry89Aa protein with a heterologous domain III having at least 90% sequence identity to a domain III region of any one of SEQ ID NOs: 10-41 of the instant application (Response to Rejection, page 20, paragraph 3).
Applicant argues as discussed above and demonstrated by Bosch, domain swapping in Bt Cry proteins can often destroy or substantially alter their functional activity, and Et Cry protein structure-function relationships are highly unpredictable (Response to Rejection, page 20, second to last paragraph).
Applicant argues the disclosure of Bosch does not anticipate claim 40 because Bosch fails to teach or disclose, either expressly or inherently, each and every element of amended claim 40, as required for anticipation under 35 U.S.C. § 102. Applicant argues the claimed engineered insecticidal polypeptide is structurally distinct from any protein disclosed in Bosch. Applicant argues in addition, a person skilled in the art would not have had any reasonable expectation of success in producing the claimed engineered insecticidal polypeptide based on the teachings of Bosch. Applicant argues claim 40 and the claims that depend therefrom are also nonobvious over the disclosure of Bosch. Applicant argues the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to Rejection, pages 20 and 21, last and first paragraph).
Applicant argues regarding claim 47, Bosch fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues Bosch does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631. Applicant argues the claimed polypeptide is structurally distinct from the proteins disclosed in Bosch (Response to Rejection, page 21, paragraph 3).
Applicant argues claim 47 recites specific polypeptide variants having the amino acid sequence of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273 that were found to exhibit insecticidal activity. Applicant argues each of these engineered variants was developed through specific domain swapping and border/linker connections between different Cry proteins (Response to Rejection, page 21, paragraph 4).
Applicant argues Bosch does not provide any teaching or motivation to arrive at any of the specifically claimed polypeptide sequences having insecticidal activity (Response to Rejection, page 21, second to last paragraph).
Applicant argues the disclosure of Bosch et al. does not anticipate claim 47 because Bosch fails to teach or disclose, either expressly or inherently, each and every element of amended claim 47, as required for anticipation under 35 U.S.C. § 102. Applicant argues the claimed polypeptide is structurally distinct from any protein disclosed in Bosch. Applicant argues in addition, a person skilled in the art would not have had any reasonable expectation of success in producing the claimed polypeptide based on the teachings of Bosch. Applicant argues therefore claim 47 and the claims that depend therefrom are also non obvious over the disclosure of Bosch. Applicant argues the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to Rejection, pages 21 and 22, last and first paragraphs).
Applicant argues regarding claim 72, claim 72 is directed to similar subject matter as claim 40. Applicant argues specifically claim 72 recites a nucleic acid construct that encodes an engineered insecticidal polypeptide as recited in claim 40. Applicant argues Bosch fails to disclose each and every element of the claim, as arranged in the claim with no express or inherent disclosure that would make up this gap. Applicant argues therefore, Bosch does not disclose this structure. In re Gleave, 560 F.3d 1331 (Fed. Cir. 2009). Applicant argues anticipation requires that a single prior art reference disclose each and every element of the claimed invention, arranged as in the claim. Verdegaal Bros., 814 F .2d at 631 (Response to Rejection, page 22, paragraph 3).
Applicant argues the disclosure of Bosch does not anticipate claim 72 because Bosch fails to teach or disclose, either expressly or inherently, each and every element of amended claim 72, as required for anticipation under 35 U.S.C. § 102. Applicant argues the engineered insecticidal polypeptide encoded by the claimed nucleic acid construct is structurally distinct from any protein disclosed in Bosch. Applicant argues in addition, a person skilled in the art would not have had any reasonable expectation of success in producing the claimed nucleic acid construct based on the teachings of Bosch (Response to Rejection, page 22, paragraph 4). Applicant argues therefore, claim 72 and the claims that depend therefrom are also nonobvious over the disclosure of Bosch. Applicant argues the dependent claims may contain additional patentable subject matter not explicitly discussed herein (Response to Rejection, page 22, paragraph 4).
Applicant argues neither Kelly nor Bosch discloses any polypeptide having the claimed domain I/II regions that are connected to a heterologous domain III derived from a CrylC/D/F insecticidal polypeptide. Applicant argues the claimed requirement that domain III be connected within 10 amino acids of the border II region is a specific structural constraint absent from the cited references. Applicant argues this prevents the cited references from anticipating the amended claims (Response to Rejection, pages 22 and 23, last and first paragraphs).
Applicant argues claims are also nonobvious. Applicant argues broad statements regarding "domain III swapping" in Kelly or Bosch are speculative and do not suggest the specific combination recited in the claims. See In Touch Techs., Inc. v. VGO Commc 'ns, Inc., 751 F.3d 1327, 1347 (Fed. Cir. 2014). Applicant argues Bosch focuses on hybrids of CrylA/E/G and CrylC, without any teaching regarding Cry89Aa domains (Response to Rejection, page 23, second to last paragraph).
Applicant argues it is well known in the art that Cry toxins are structurally complex; small changes often abolish activity. Applicant argues given this, domain swapping is both complicated and unpredictable. See In re Kubin, 561 F.3d 1351; AbbVie Deutsch/and GmbH v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014). Applicant argues the specification demonstrates this unpredictability: engineered variants 0640A (SEQ ID NO: 256) and 0641A (SEQ ID NO: 257) failed to exhibit activity despite minor sequence changes. See Specification at Table 2. Applicant argues a skilled artisan would not have reasonably expected success in producing the claimed Cry89Aa/CrylC/D/F hybrids (Response to Rejection, page 24, last and first paragraphs).
Applicant argues Bosch at Table 1 shows most domain swaps result in inactive proteins (e.g., H7, H8, F59, F71, F26). See Bosch at Table l; and col. 9, lines 18-47. Applicant argues this teaches away from arbitrary substitutions and reinforces the unpredictability of Cry domain swapping and engineering. See In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994); WL. Gore & Assocs. v. Garlock, Inc., 721 F.2d 1540 (Fed. Cir. 1983) (Response to Rejection, page 24, second paragraph).
Applicant argues neither reference guidance regarding border II or linker length. Applicant argues the claimed connectivity element is therefore nonobvious. See In re Cyclobenzaprine, 676 F.3d at 1071-72 (Response to Rejection, page 24, paragraph 3).
Applicant argues the specification demonstrates unexpected activity retention showing unexpected results. Applicant argues this is because the variants with engineered domain III connections retain activity, while many closely related hybrids (including 0640A and 0641A) are inactive. Applicant argues this comparative data shows the claimed sequences exhibit improved functional properties not predicted by the prior art. See Specification at Tables 1-4. Applicant argues this unpredictability in the structure-function relationship of Bt Cry toxins would have discouraged a person of ordinary skill in the art from performing arbitrary domain substitutions, thereby supporting the nonobviousness of the claimed inventions. See In re Applied Materials, Inc., 692 F.3d 1289, 1297-98 (Fed. Cir. 2012) (Response to Rejection, page 24, second to last paragraph).
Applicant argues in conclusion the claims are nonobvious because there was no specific motivation to combine Cry89Aa domains with a CrylC/D/F domain III, the art is unpredictable and does not provide a reasonable expectation of success, Bosch teaches away by demonstrating that most domain swaps fail, the claimed border II connectivity is not suggested, and the comparative data shows unexpected retention of insecticidal activity.
Applicant's arguments have been fully considered but they are not persuasive since:
Regarding argument Kelly does not provide any teaching or motivation to combine domains I and II from its disclosed polypeptide sequence of SEQ ID NO: 12 was not found persuasive since the statement on paragraph 46 is clear any Cry toxins of domain III can be swapped to their disclosed insecticidal polypeptide to improve toxicity. Furthermore, Bosch et al. teaches swapping Cry1C, Cry1D and Cry1F domain III improve toxicity for some insects. Furthermore, SEQ ID NO:12 comprise the border reason within 10 amino acids, see analysis above.
Regarding argument of requirement of specific structure for insecticidal activity was not found persuasive since other than claims 40, 47 and 72 other claims does not require specific structure other than domain I, II and border II of SEQ ID NO:12 and any of the Cry1C, Cry1D and Cry1F which is expressly taught by Kelly et al. and Bosch et al.
Regarding argument on Kelly et al. and Bosch et al. does not anticipate the amended claims, it was found persuasive therefore the anticipation rejection has been analyzed as obviousness rejection over Kelly et al. and in view of Bosch et al., see above.
Summary
No claim is allowed.
Claims 40-43, 45-51, 53-54, 72-75 and 77-79 are free of prior art. The close prior art is Kelly et al. which teaches SEQ ID NO:12 wherein alignment of SEQ ID NO: 139 (domain I) , 145 (domain II), and 161 (border II) showed that the regions have 100% identity to SEQ ID NO:12 of Kelly et al. (see alignment above). Therefore, the polypeptide of SEQ ID NO:12 comprises domain I, domain II, border II. The inventive distinction is the presence of heterologous domain III having a domain III region of any one of SEQ ID NOs: 10-41 (claims 40 and 72) and insecticidal polypeptide having an amino acid sequence of any one of SEQ ID NOs: 10-41, 43-45, 235-255, or 258-273 (claim 47).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SANTOSH SHARMA/Examiner, Art Unit 1663
/DAVID H KRUSE/Primary Examiner, Art Unit 1663
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