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 .
Applicant’s amendment, filed on 3/25/2026, is acknowledged.
Claims 1-101 are cancelled.
Claims 102-122 are currently pending.
Claims 102 and 115 are independent claims.
Election/Restrictions
Applicants’ election with traverse of the Species of: i) Cry1F; ii) A and B molecules selected from antibody libraries; and iii) a VHH fragment, filed on 3/25/2026, is acknowledged. The traversal is on the grounds that there is no prior art provided to support the conclusion that the inventive group does not have a special technical feature, and the Cry proteins share a common structure. This is not found persuasive because the species differ in structures and mechanisms of action which in turn address different therapeutic endpoints for the same reasons discussed in the Restriction Requirement mailed on 1/28/2026.
The requirement is still deemed proper and is therefore made FINAL.
Claims 102-114 are directed to methods of making affinity constructure comprising fusing affinity molecules A and B, wherein the affinity molecules A and B were raised against an insect gut membrane protein and an insecticidal protein, respectively. The claims are not directed to the A and B affinity molecules selected from antibody libraries, and are therefore drawn to an unelected species of invention.
Claims 102-114 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected Species.
Claims 115-122 are under examination as reading on the elected species of method of making an affinity construct comprising fusing affinity constructs A and B.
Priority
Applicant’s claim for the benefit of a prior-filed U.S. Provisional Application 63/133,386, filed January 3, 2021, and 63/241,896 filed September 8, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 9/13/2023, 3/26/2024, 3/03/2026, and 3/27/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency 1 – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Amino acid sequences are disclosed in Figures 7, 11, 12, and 17 without a corresponding sequence identified either in the Figure or in the “Brief Description of the Drawings” section of the instant specification.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency 2 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Amino acid sequences are disclosed in ¶[000294], [00296], [00300], and [00463] without the corresponding sequence identifiers.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code are disclosed in ¶[0007], [0074], [00145], [00159], [00211], [00217], [00222], [00436], and [00485]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms:
Nanobody™ (¶[0071], [0084]-[0086], [0096], [00118], [00121], [00123], [00129], [00133], [00142], [00233], [00253], [00304], [00451], [00452], [00454], [00457]-[00459], [00487]-[00490], [00496]-[00511], [00513], [00514], [00521]-[00523], [00526]-[00533], [00535], [00536], [00539], [00541]-[00543], Sequences Table);
Blast2GO™ (¶[00485]); and
Superdex™ ([00494]);
which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 122 recites the acronym “Cry”. This is not a readily recognized acronym in the art, such as “DNA” for 5’-deoxyribonucleic acid. Please define the acronym “Cry” when these are first used in the claims. Please note that since instant claims 102-114 are currently withdrawn as directed to unelected species of invention, claim 122 is the first elected and examined claim that currently recites the acronym “Cry”.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 115-122 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claims 115-122 recite methods of making affinity constructs comprising a broad genus of affinity molecules A with no recited structure and the function of “binding to a first antigen comprising extracellular domain of an insect midgut membrane protein” (claims 115-117 and 122), or binds a Bt toxin receptor protein or Na-dependent transporter with an amino acid sequence that is at least 80% identical with SEQ ID NO: 30 or 31 (claims 118-121); as well as a broad genus of affinity molecules B with no recited structure and the function of “binding to an insecticidal protein” (claims 115-121), or a Cry1F protein (claim 122). The “affinity construct” includes any structure that can bind to an antigen, including antibodies, protein ligands, DNA/RNA aptamers, single-domain antibodies, carbohydrates, and more all with the recited functions.
However, the specification fails to provide adequate written description support for a genus of affinity molecules A with no recited structure and the function of “binding to a first antigen comprising extracellular domain of an insect midgut membrane protein” (claims 115-117 and 122), or binds a Bt toxin receptor protein or Na-dependent transporter with an amino acid sequence that is at least 80% identical with SEQ ID NO: 30 or 31 (claims 118-121); OR a genus of affinity molecules B with no recited structure and the function of “binding to an insecticidal protein” (claims 115-121), or a Cry1F protein (claim 122).
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"A sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The specification the generation of novel affinity constructs that have two binding moieties A and B, wherein binding moiety A binds to a specific insect gut membrane protein, and wherein binding moiety B binds to an insecticidal protein (Example 1, Fig. 5). This construct targets the insecticidal protein bound by B to the gut of insects that express the protein bound by A, which could possibly enhance the efficacy of the insecticidal protein (¶[00107]).
The types of insect midgut membrane proteins that can be targeted include natural insect Cry receptors and specific insect cadherin protein structures isolated from S. frugiperda, H. virescens, H. armigera, and D. virgifera (Example 1, ¶[00445], SEQ ID NO: 2, 6, and 8). Other candidate midgut membrane proteins include chitin synthases from S. frugiperda, H. virescens, H. armigera, and D. virgifera (Example 1, ¶[00446], SEQ ID NO: 10 and 12), and the Na-dependent nutrient amino acid transporter 1-like (NAAT) protein (¶[00487]).
The types of insecticidal proteins that act as insect toxins that are bound by the disclosed binding moiety B in the disclosed affinity constructs include the Bt-toxin based Crystal (Cry) proteins (Example 1), including Cry1Ac, Cry3Ab, VIP3Aa, or Cry1F (¶[00444]). These Cry proteins function to produce pores in the membranes of insect midguts, leading to impairment of insect performance and insecticide (¶[00459]).
The specification discloses identification and isolation of single-domain antibodies that specifically bind to the Cry1F toxin, cadherin protein from S. frugiperda, or the NAAT protein (Examples 11 and 12). Llamas were subcutaneously injected with the Cry1F insecticide protein antigen, the cadherin midgut antigen, or NAAT antigen; subsequently VHH antibody libraries were constructed from the immunized animals (¶[00497]).
Regarding the broadly claimed genus of affinity molecules A with no recited structure and the function of “binding to a first antigen comprising extracellular domain of an insect midgut membrane protein” (claims 115-117 and 122), or binds a Bt toxin receptor protein or Na-dependent transporter with an amino acid sequence that is at least 80% identical with SEQ ID NO: 30 or 31 (claims 118-121), 5 specific VHH structures were identified and disclosed that specifically bind to S. frugiperda Cadherin, which are S. frugiperda Cadherin nanobodies #2, #43, $46, #48, and #50 (¶[00502], SEQ ID NO: 86, 88, 90, 92, and 94, respectively). 6 specific VHH structures were identified and disclosed that specifically bind to NAAT, which are NAAT nanobodies #1, #2, #5, #6, #10, and #29 (¶[00504], SEQ ID NO: 74, 76, 78, 80, 82, and 84, respectively).
Regarding the broadly claimed genus of affinity molecules B with no recited structure and the function of “binding to an insecticidal protein” (claims 115-121), or a Cry1F protein (claim 122), 3 specific VHH structures were identified and disclosed that specifically bind to the Cry1F insecticidal protein, which are the Cry1F nanobodies #5, #7, and #51 (Example 18, ¶[00510], and SEQ ID NO: 72, 70, and 72, respectively). Note that Cry1F nanobodies #5 and #51 have identical protein sequences of SEQ ID NO: 72 (¶[00510]).
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
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. 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 Abb Vie 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.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Claims 115-122 encompass a genus of affinity constructs comprising affinity molecules A that binds to “extracellular domain of insect midgut membrane protein”, “NAAT”, or SEQ ID NO: 30 or 31 with up to 20% variation; and affinity molecules B that bind to “an insecticidal protein” or “Cry1F” that are to be used to increase the efficacy of insecticides such as Bt toxin in controlling insect pests. The USPTO has released a Memo on the Clarification of Written Description Guidance for Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following:
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope of “extracellular domain of insect midgut membrane protein”, “NAAT”, SEQ ID NO: 30 or 31, “an insecticidal protein”, or “Cry1F” in providing a fully characterized antigen/specific epitope as well as claiming structural elements of the antigen, and functional attributes (i.e., for increasing insecticidal efficacy), there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed affinity molecules to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies. Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may or may not bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
However, the affinity constructs are required to practice the invention. The specification fails to provide any specific structural or physical information so as to define a genus of affinity constructs having the desired insecticidal properties. Applicant is merely relying on the identification of “extracellular domain of insect midgut membrane protein”, “NAAT”, SEQ ID NO: 30 or 31, “an insecticidal protein”, or “Cry1F” as the antigen and the well-known structure of antibodies, including single-domain antibodies, in general. However, the claims do not recite a general antibody, but an affinity construct comprising two binding arms, each comprising single-domain antibodies (A and B) that have a specific and distinct desired activity. The Federal Circuit provided clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genus of affinity molecules A with no recited structure and the function of “binding to a first antigen comprising extracellular domain of an insect midgut membrane protein” (claims 115-117 and 122), or binds a Bt toxin receptor protein or Na-dependent transporter with an amino acid sequence that is at least 80% identical with SEQ ID NO: 30 or 31 (claims 118-121) AND a genus of affinity molecules B with no recited structure and the function of “binding to an insecticidal protein” (claims 115-121), or a Cry1F protein (claim 122). However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
In the instant case, the application is claiming not only antibodies acting as affinity molecules in the case of A and B, but a broader genus that includes non-antibody structures with the recited functional characteristics such as DNA/RNA aptamers, carbohydrates, non-antibody protein structures, and more. However, the instant specification only discloses single domain antibody structures, defined by their amino acid sequences especially in the VHH CDR regions critical for binding, as affinity molecules with the recited functions.
The instant specification discloses 11 different examples of affinity molecules A with the recited functions “binding to a first antigen comprising extracellular domain of an insect midgut membrane protein” (claims 115-117 and 122), or binds a Bt toxin receptor protein or Na-dependent transporter with an amino acid sequence that is at least 80% identical with SEQ ID NO: 30 or 31 (claims 118-121). All of these are VHH structures defined by their amino acid sequences, and the affinity molecules either bind to NAAT or to S. frugiperda Cadherin. Additionally, the instant specification discloses 3 examples of affinity molecules B with the recited function of “binding to an insecticidal protein” (claims 115-121), or a Cry1F protein (claim 122). All of these are also VHH structures, and the affinity molecules all bind to Cry1F. These limited species of VHH structures do not sufficiently represent the broadly claimed genera of affinity molecules A and/or B with no recited structure and with the broadly defined functional characteristics in the claims.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed affinity molecules A and/or B to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed class of affinity molecules, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed classes of affinity molecules A and/or B, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
The specification at best describes plan for making VHH structures (and other structures that the affinity molecules A and B comprise) that have the disclosed functions of “binds to NAAT”, “binds to S. frugiperda Cadherin”, OR “binds to Cry1F”, and then identifying those VHH structures that satisfy the claim limitations, but a mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
The specification discloses 5 specific VHH structures with the function of “binds to S. frugiperda Cadherin”, 6 specific VHH structures with the function of “binds to NAAT”, and 3 specific VHH structures with the function of “binds to Cry1F”. It is unlikely that single domain antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the VHH region fused to framework sequences have the required binding functions. The specification provides no direction or guidance regarding how to produce other affinity molecules with these functions, let alone the more broadly claimed genera of affinity molecules A with no recited structure and the recited functions “binding to a first antigen comprising extracellular domain of an insect midgut membrane protein” (claims 115-117 and 122), or binds a Bt toxin receptor protein or Na-dependent transporter with an amino acid sequence that is at least 80% identical with SEQ ID NO: 30 or 31 (claims 118-121); OR affinity molecules B with no recited structure and the recited function of “binding to an insecticidal protein” (claims 115-121), or a Cry1F protein (claim 122).
Moreover, the claimed antigen sequences of NAAT with up to 20% variation in the amino acid sequence that the claimed genera of affinity molecules A bind to (SEQ ID NO: 30 and 31) comprise significant sequence variation. For example, SEQ ID NO: 30 is 57 amino acid residues in length. The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula:
N
!
*
19
A
N
-
A
!
A
!
Where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. For SEQ ID NO: 30 that is 57 residues in length with 11 (0.2*57) allowed substitutions, there would be
57
!
*
19
(
11
)
57
-
11
!
11
!
Which is approximately 6.14x1028 variants.
Claim 122 additionally recites “…wherein the insecticidal protein or fragment thereof comprises a three-domain Cry protein…a variant thereof…”, which encompasses any peptide variant of any sequence and size, and thus the claim encompasses affinity molecules B with no recited structure that can bind to these Cry protein variants as well.
Colman et al in Research in Immunology (145(1):33-36, 1994) teach single amino acid changes in an antigen can effectively abolish antibody antigen binding. Abaza et al in Journal of Protein Chemistry (11(5):433-444, 1992) teach that single amino acid substitutions outside the antigenic site on a protein effect antibody binding. Further, Lederman et al in Molecular Immunology (28:1171-1181, 1991) disclose that a single amino acid substitution in a common allele ablates binding of a monoclonal antibody (see entire document). Additionally, Li et al in PNAS (77:3211-3214, 1980) disclose that dissociation of immunoreactivity from other biological activities when constructing analogs (see entire document). Neither the prior art not applicant’s disclosure defines sufficient representative antibodies and/or sufficient structure/function relationship information between a single domain antibody’s 3 CDRs and/or VHH sequences and the function of “binding to NAAT1 that comprises an amino acid sequence having at least 80% or greater identity to the amino acid sequence of” SEQ ID NO: 30 or 31 given this unpredictability in binding based on small changes in antigen sequence.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of affinity molecules A or B falling within the scope of the genera or of a recitation of structural features common to members of the genera, which features constitute a substantial portion of the genera. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 115-122 do not meet the requirements of 35 U.S.C. 112(a) for written description.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
To overcome this rejection, it is recommended to amend the claims to recite the specific VHH structures disclosed for each of the affinity molecules A and B, as well as the specific antigen/epitope that each VHH structure binds.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 122 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The recitation "derived from" in claim 122 is indefinite because it is unclear what changes or how many changes could have occurred to result in a derivative. Derivation only describes the source and not the result.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 115 and 117 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (PNAS USA 2007 Aug 28;104(35):13901-6. doi: 10.1073/pnas.0706011104) in view of Petell et al. (U.S. Pat No. 5,665,595) and Wang et al. (Antibodies 2019 Nov 4;8(4):53. doi: 10.3390/antib8040053).
Instant claim 112 recites a method of making an affinity construct comprising fusion of two affinity molecules A and B, wherein A binds to an insect midgut extracellular domain, and the other
Chen et al. teaches the Bt toxin Cry1A can be used as an insecticide against the tobacco hornworm Manduca sexta (Abstract). Chen et al. additionally teaches that the Bt-R1 cadherin is expressed in the midgut of M. sexta, and the CR12-MPED extracellular domain fragment of this cadherin acts as a synergist for the Cry1A toxin (Abstract, Introduction): “[t] The cadherin Bt-R1 is a binding protein for Bt Cry1A toxins in midgut epithelia of tobacco hornworm (Manduca sexta). We previously identified the Bt-R1 region most proximal to the cell membrane (CR12-MPED) as the essential binding region required for Cry1Ab-mediated cytotoxicity. Here, we report that a peptide containing this region expressed in Escherichia coli functions as a synergist of Cry1A toxicity against lepidopteran larvae.”
Chen et al. teaches that CR12-MPED and Cry1A dual administration enhanced the efficacy of the insecticide action of Cry1A (Results and Fig. 2): “[b]ecause the CR12-MPED peptide contained the critical Cry1Ab binding region, we predicted that this peptide would reduce the potency of Cry1Ab against M. sexta larvae. However, we observed a significant enhancement of Cry1Ab toxicity to M. sexta larvae when including CR12-MPED in our bioassays…”
Chen et al. does not teach methods of making affinity molecules comprising the CR12-MPED region fused to an affinity molecule that targets an insect midgut membrane protein (i.e., the limitations of instant claim 115).
Petell et al., in the same field of endeavor, teaches the development of monoclonal antibodies that bind to the midgut of Lepidoptera species (Abstract). Monoclonal antibodies were developed via hybridoma technology, and two selected monoclonal antibodies were found to bind the midgut of M. sexta, one of which binds the extracellular (apical) portion (Table 1, “THW” column).
Wang et al., in the same field of endeavor, teaches methods of conjugating a peptide to an antibody using a (G4S)3 peptide (Fig. 1A, cropped below; “m336 scFv-pep”):
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Wang et al. further teaches methods of making such fusion constructs (Sections 2.1 and 2.2).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the teachings of Chen et al. in view of Petell et al. and Wang et al. to have fused the CR12-MPED peptide of Chen et al. to the midgut-targeting monoclonal antibody taught by Petell et al. with a reasonable expectation of success, as Wang et al. teaches methods of fusing a peptide to an antibody via a peptide linker that one with ordinary skill in the art could easily apply to other antibodies and peptides, such as the CR12-MPED peptide of Chen et al. and the midgut targeting monoclonal antibody of Petell et al. One would have been motivated to make this change for the purposes of targeting the CR12-MPED peptide to the midgut of M. sexta, where the peptide functions to increase the efficacy of the insecticide.
Thus, the combined teachings of Chen et al., Petell et al., and Wang et al. teach a method of fusing CR12-MPED (which has been “selected to bind to” a Cry insecticidal protein) to an M. sexta midgut-targeting monoclonal antibody (which has been “selected to bind to” a M. sexta apical/extracellular midgut protein) via a peptide linker that comprises more than 1 amino acid residue, which are the limitations of instant claims 115 and 117.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 115-122 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,011,000 (Pat ‘000). Although the claims at issue are not identical, they are not patentably distinct from each other.
Pat’000 claims recombinant nucleic acid molecules comprising a polynucleotide sequence encoding a first sdAb (claim 1), as well as nucleic acids comprising polynucleotides comprising a first sdAb operably connected to a second sdAb operably with an amino acid or peptide linker (claim 14). Pat ‘000 claims the first sdAb comprises the CDR1-3 of SEQ ID NO: 138, 139, and 141, and the second sdAb comprises the CDR1-3 of SEQ ID NO: 148, 149, and 150 (claim 14).
To fully define the limitations of claim 14 of Pat ‘000 in the determination of a case of obviousness, the instant disclosure is relied upon.
Table 4 of Pat ‘000 defines an affinity construct with a first sdAb comprising the CDR1-3 of SEQ ID NO: 148-150 respectively is a VHH selected from a library (i.e., “an antibody library”) that targets the Cry1F toxin; and the second sdAb comprising the CDR1-3 of SEQ ID NO: 138, 139, and 141 respectively is a VHH selected from a library (i.e., “an antibody library”, the limitations of instant claim 116) that targets the NAAT sodium-dependent nutrient amino acid transporter. Example 11 of Pat ‘000 defines the NAAT epitope that was used to generate the nanobodies was S. frugiperda NAAT comprising SEQ ID NO: 31 with the antigenic sequence comprising SEQ ID NO: 30.
SEQ ID NO: 30 of Pat ‘000 is 100% identical to instant SEQ ID NO: 30:
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And SEQ ID NO: 31 of Pat ‘000 is 100% identical to instant SEQ ID NO: 31:
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Therefore, claim 14 of Pat ‘000 claims an affinity construct comprising a first sdAb that specifically binds to Cry1F operably linked to a second sdAb that specifically binds to NAAT comprising SEQ ID NO: 31 with the antigenic extracellular region comprising SEQ ID NO: 30 via a peptide linker. Pat ‘000 additionally claims the polynucleotides comprising a promoter (claim 2) and cells comprising the polynucleotide (claim 3).
It would have been obvious to one with ordinary skill in the art to have used the invention claimed by Pat ‘000 to fuse the first and second claimed sdAbs together via a linker (i.e., “a method of making an affinity construct comprising fusing an affinity molecule A” to “an affinity molecule B”) with a reasonable expectation of success, as one with ordinary skill in the art would appreciate that synthesizing a polynucleotide encoding such an affinity construct is, in fact, a method of making such an affinity construct once such a construct is expressed in a cell. One would have been motivated to make this change for the purposes of producing the affinity construct claimed by Pat ‘000 in claim 14.
This method would make an affinity construct comprising a VHH selected to bind to Cry1F linked to a VHH selected to bind to NAAT comprising SEQ ID NO: 30 and 31 via a peptide linker (i.e., the limitations of instant claims 115 and 118-122).
Regarding claim 116, the claimed VHH domains were selected from library screens (i.e. “an antibody library”, discussed supra), meeting the claim limitations.
Regarding claim 117, Pat ‘000 claims the linker can comprise Gly and Ser residues (claim 9), which is “at least one amino acid”, meeting the claim limitations.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘000, especially in absence of evidence to the contrary.
Claims 115-118 and 122 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 135-148 of copending Application No. 18/637,092 (App ‘092). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘092 claims recombinant nucleic acid molecules comprising a polynucleotide sequence encoding a first sdAb (claim 135), as well as nucleic acids comprising polynucleotides comprising a first sdAb operably connected to a second sdAb operably with an amino acid or peptide linker (claim 143). App ‘092 claims the first sdAb comprises the CDR1-3 of SEQ ID NO: 154, 155, and 157, and the second sdAb comprises the CDR1-3 of SEQ ID NO: 148, 149, and 150 (claim 143).
To fully define the limitations of claim 143 of App ‘092 in the determination of a case of obviousness, the instant disclosure is relied upon.
Table 4 of App ‘092 defines an affinity construct with a first sdAb comprising the CDR1-3 of SEQ ID NO: 154, 155, and 157 respectively is a VHH selected from a library (i.e., “an antibody library”) that targets the Cadherin31 midgut membrane protein; and the second sdAb comprising the CDR1-3 of SEQ ID NO: 148-150 respectively is a VHH selected from a library (i.e., “an antibody library”, the limitations of instant claim 116) that targets the Cry1F toxin.
Therefore, claim 143 of App ‘092 claims an affinity construct comprising a first sdAb that specifically binds to Cry1F operably linked to a second sdAb that specifically binds to Cadherin31 midgut membrane protein. App ‘092 additionally claims the polynucleotides comprising a promoter (claim 136) and cells comprising the polynucleotide (claim 144).
It would have been obvious to one with ordinary skill in the art to have used the invention claimed by App ‘092 to fuse the first and second claimed sdAbs together via a linker (i.e., “a method of making an affinity construct comprising fusing an affinity molecule A” to “an affinity molecule B”) with a reasonable expectation of success, as one with ordinary skill in the art would appreciate that synthesizing a polynucleotide encoding such an affinity construct is, in fact, a method of making such an affinity construct once such a construct is expressed in a cell. One would have been motivated to make this change for the purposes of producing the affinity construct claimed by App ‘092 in claim 143.
This method would make an affinity construct comprising a VHH selected to bind to Cry1F linked to a VHH selected to bind to Cadherin31 via a peptide linker (i.e., the limitations of instant claims 115, 118, and 122).
Regarding claim 116, the claimed VHH domains were selected from library screens (i.e. “an antibody library”, discussed supra), meeting the claim limitations.
Regarding claim 117, App ‘091 claims the linker can comprise 1 to 100 amino acid residues (claim 137), meeting the claim limitations.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘091, especially in absence of evidence to the contrary. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEC JON PETERS whose telephone number is (703)756-5794. The examiner can normally be reached Monday-Friday 8:30am - 6:00pm EST.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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