Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/18/2026 has been entered.
Application Status
Claims 1-5, 12-17, and 19-26 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
All previous objections of claims 12, 19, and 26 have been withdrawn in view of claim amendments.
Drawings
The drawings are objected to because the brief description of the drawings in the specification is inadequate, please see MPEP § 608.01(f): When there are drawings, there shall be a brief description of the several views of the drawings and the detailed description of the invention shall refer to the different views by specifying the numbers of the figures, and to the different parts by use of reference letters or numerals (preferably the latter).
Specification
Content of Specification
(a) TITLE OF THE INVENTION: See 37 CFR 1.72(a) and MPEP § 606. The title of the invention should be placed at the top of the first page of the specification unless the title is provided in an application data sheet. The title of the invention should be brief but technically accurate and descriptive, preferably from two to seven words. It may not contain more than 500 characters.
(b) CROSS-REFERENCES TO RELATED APPLICATIONS: See 37 CFR 1.78 and MPEP § 211 et seq.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT: See MPEP § 310.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT. See 37 CFR 1.71(g).
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM: The specification is required to include an incorporation-by-reference of electronic documents that are to become part of the permanent United States Patent and Trademark Office records in the file of a patent application. See 37 CFR 1.77(b)(5) and MPEP § 608.05. See also the Legal Framework for Patent Electronic System posted on the USPTO website (https://www.uspto.gov/sites/default/files/documents/2019LegalFrameworkPES.pdf) and MPEP § 502.05
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR. See 35 U.S.C. 102(b) and 37 CFR 1.77.
(g) BACKGROUND OF THE INVENTION: See MPEP § 608.01(c). The specification should set forth the Background of the Invention in two parts:
(1) Field of the Invention: A statement of the field of art to which the invention pertains. This statement may include a paraphrasing of the applicable U.S. patent classification definitions of the subject matter of the claimed invention. This item may also be titled “Technical Field.”
(2) Description of the Related Art including information disclosed under 37 CFR 1.97 and 37 CFR 1.98: A description of the related art known to the applicant and including, if applicable, references to specific related art and problems involved in the prior art which are solved by the applicant’s invention. This item may also be titled “Background Art.”
(h) BRIEF SUMMARY OF THE INVENTION: See MPEP § 608.01(d). A brief summary or general statement of the invention as set forth in 37 CFR 1.73. The summary is separate and distinct from the abstract and is directed toward the invention rather than the disclosure as a whole. The summary may point out the advantages of the invention or how it solves problems previously existent in the prior art (and preferably indicated in the Background of the Invention). In chemical cases it should point out in general terms the utility of the invention. If possible, the nature and gist of the invention or the inventive concept should be set forth. Objects of the invention should be treated briefly and only to the extent that they contribute to an understanding of the invention.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S): See MPEP § 608.01(f). A reference to and brief description of the drawing(s) as set forth in 37 CFR 1.74.
(j) DETAILED DESCRIPTION OF THE INVENTION: See MPEP § 608.01(g). A description of the preferred embodiment(s) of the invention as required in 37 CFR 1.71. The description should be as short and specific as is necessary to describe the invention adequately and accurately. Where elements or groups of elements, compounds, and processes, which are conventional and generally widely known in the field of the invention described, and their exact nature or type is not necessary for an understanding and use of the invention by a person skilled in the art, they should not be described in detail. However, where particularly complicated subject matter is involved or where the elements, compounds, or processes may not be commonly or widely known in the field, the specification should refer to another patent or readily available publication which adequately describes the subject matter.
(k) CLAIM OR CLAIMS: See 37 CFR 1.75 and MPEP § 608.01(m). The claim or claims must commence on a separate sheet or electronic page (37 CFR 1.52(b)(3)). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation. There may be plural indentations to further segregate subcombinations or related steps. See 37 CFR 1.75 and MPEP 608.01(i) - (p).
(l) ABSTRACT OF THE DISCLOSURE: See 37 CFR 1.72 (b) and MPEP § 608.01(b). The abstract is a brief narrative of the disclosure as a whole, as concise as the disclosure permits, in a single paragraph preferably not exceeding 150 words, commencing on a separate sheet following the claims. In an international application which has entered the national stage (37 CFR 1.491(b)), the applicant need not submit an abstract commencing on a separate sheet if an abstract was published with the international application under PCT Article 21. The abstract that appears on the cover page of the pamphlet published by the International Bureau (IB) of the World Intellectual Property Organization (WIPO) is the abstract that will be used by the USPTO. See MPEP § 1893.03(e).
(m) SEQUENCE LISTING: See 37 CFR 1.821 - 1.825 and MPEP §§ 2421 - 2431. The requirement for a sequence listing applies to all sequences disclosed in a given application, whether the sequences are claimed or not. See MPEP § 2422.01.
Applicant is required to correct the instant specification to include a brief description of the drawings with an adequate description of each figure.
Applicant is requested to number the tables in the specification for clarity, as well as to make matters of the record easier to refer to and locate.
Claim Rejections - 35 USC § 103
Rejection Maintained
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 12, 14-17, and 19-24 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Pieczykolan (WO 2013/080147 A2; IDS entered 02/15/2023) and Olombrada (Biol. Chem., 2017, 398(1): 135-142; IDS entered 02/15/2023) as evidenced by Uniprot database A0A014PJJ6 (IDS entered 02/15/2023).
Regarding claim 1, Pieczykolan teaches a fusion protein comprising domain a) which is a functional fragment of the TRAIL protein and domain b) which is an effector peptide inhibiting protein synthesis (claim 1), in which the effector peptide has ribonuclease activity and is selected from the protein toxins hirsutellin… (claims 11-12). Pieczykolan further teaches the exemplary sequence of hirsutellin is SEQ ID NO: 72 which has 66.8% sequence identity to the instant claimed SEQ ID NO: 48. Hirsutellin is a homologue of anisoplin.
Regarding claim 2, Pieczykolan teaches to achieve high specificity toxins can be fused to antibodies (page 3, lines 26-31).
Regarding claims 3 and 21-23, Pieczykolan teaches which additionally comprises a flexible steric linker between domains (a), (b) (claim 25), steric linker may be a combination of glycine and serine residues, such as for example Gly Gly Gly Gly Ser/GGGGS or any fragment thereof acting as steric linker (page 25, lines 18-20).
Regarding claims 4, 14, and 23, Pieczykolan teaches which between domain (a) and domain (b) containing protease cleavage site (claim 20). Pieczykolan further teaches that the invention also provides the use of the fusion protein of the invention as defined above for treating cancer diseases in mammals (page 36, lines 19-20) and comprising the sequence of a cleavage site between domains a) and b) recognized by proteases present in the cell environment, especially in the tumor cell environment, e.g. such as metalloprotease, urokinase or furin (page 21, lines 33-34-page 22, lines 1-2). Therefore the protease cleavage site would be specific to an enzyme expressed by a mammalian cell and localized to the cell surface, which are not expressed in plants.
Regarding claims 12, 15, and 24, Pieczykolan teaches heterologous expression systems based on various well-known host cells may be used including plant cell lines (page 32, lines 8-12). Expression in a plant cell line would naturally include plant specific glycosylation.
Regarding claim 16, Pieczykolan teaches a pharmaceutical composition comprising as an active ingredient the fusion protein as defined in any one of claims 1 to 30, in combination with a pharmaceutically acceptable carrier (claim 37).
Regarding claim 17, Pieczykolan teaches concomitant therapeutic interventions (page 39, line 9).
Regarding claim 19, Pieczykolan teaches the fusion protein as defined in any one of claims 1 to 30 for use in the treatment of neoplastic diseases in mammals, including humans (claim 39) and a method of treating cancer diseases in mammal, including human, which comprises administration to a subject in a need thereof an anti-neoplastic- effective amount of the fusion protein as defined in claims 1 to 30, or the pharmaceutical composition as defined in claims 37 or 38 (claim 40).
Pieczykolan does not teach the toxin having a sequence according SEQ ID 48 or 49, an active fragment thereof or a homologue with 80% sequence identity therewith.
Regarding claims 1 and 20, Olombrada teaches that a well-known family of toxic proteins secreted by fungi are ribotoxins, specific ribonucleases (RNases) against the large rRNA in the ribosome with lethal consequences for the target cell and that recent studies focused on their antitumor properties conjugated as immunotoxins (page 136, col 1, para 2). Olombrada further teaches that anisoplin is structurally similar to hirsutellin A with 70% sequence identity to the mature protein and conserved cysteine and active site residues (page 136, col 1, para 3). Olombrada further teaches that anisoplin shows the ribonucleolytic activity typical of ribotoxins and cytotoxicity against insect cells (abstract). Olombrada expressed anisoplin as a fusion protein with thioredoxin for characterization (page 136, col 2, para 2) finding that anisoplin has a signal sequence of 19 amino acid residues similar to hirsutellin as well as similar activity (Fig 1A).
As evidenced by the UniProt ID A0A014PJJ6, which is the sequence of anispolin ARSEF23 tested by Olombrada and named Hirsutellin A ribotoxin like protein, the UniProt sequence has 100% sequence identity to the SEQ ID NO: 48 and 98.6% sequence identity to SEQ ID NO: 49 with the first 19 amino acid residue signal sequence removed as taught by Olombrada, as seen in the alignments below.
PNG
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339
731
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Greyscale
SEQ ID NO: 48 to A0A014PJJ6
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252
598
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Greyscale
SEQ ID NO:49 to A0A014PJJ6
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242
600
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Greyscale
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute anisoplin for hirsutellin as taught by Olombrada into the binder-toxin fusion protein as taught by Pieczykolan. The ordinary artisan would have been motivated to do so because this is a simple substitution of the same element in the fusion protein. Olombrada teaches that anisoplin is structurally similar to hirsutellin A and shows the ribonucleolytic activity typical of ribotoxins and cytotoxicity and that these ribotoxins are useful for their antitumor properties conjugated as immunotoxins. Therefore the ordinary artisan has a reasonable expectation of success to use anisoplin in the binder-toxin fusion protein.
Claims 5 and 25-26 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Pieczykolan (WO 2013/080147 A2; IDS entered 02/15/2023) and Olombrada (Biol. Chem., 2017, 398(1): 135-142; IDS entered 02/15/2023) as evidenced by Uniprot database A0A014PJJ6 (IDS entered 02/15/2023) as applied to claims 1-4, 12, 14-17, and 19-24 above, and further in view of Gelsen (WO 2017/053290 A1; IDS entered 02/15/2023) and Pfeifer (Leukemia 29, 1578–1586 (2015); cited in OA 03/18/2026).
The teachings of Pieczykolan and Olombrada as evidenced by UniProt regarding claims 1-4, 12, 14-17, and 19-24 are detailed above.
Pieczykolan and Olombrada as evidenced by UniProt do not teach wherein the binder toxin fusion protein binds to CD20 or CD79b; or the structure of the binder fusion toxin protein.
Regarding claim 5, Gelsen teaches fusion proteins comprising modified ribotoxin (ex. sarcin) molecules and targeting molecules (para 0010), wherein the targeting molecule is an antibody or antigen-binding fragment thereof (claim 6). Gelsen further teaches the targeting molecule may be directed to a particular tumor surface antigen including CD20 (para 00206) or CD79b (para 00182).
Regarding claims 25-26, Gelsen teaches wherein the modified ribotoxin is fused or linked to the antibody or antigen-binding fragment thereof via a linker (claim 7). Gelsen further teaches scFv-linker-sarcin fusion (figure 1A), wherein the targeting molecule comprises at least one functional FcRn binding site (para 00366) and wherein the fusion protein comprises a modified ribotoxin dimer (para 00171) wherein the ribotoxin fusion protein comprises a cleavable linker linking the modified sarcin molecule to the targeting molecule (para 00384), wherein the cleavable linker can be cleaved in the cytosol (para 00385). This results in a scFv-Fc-cleavable linker-ribotoxin dimer.
Regarding claim 5, Pfeifer teaches that novel therapeutic approach is the use of antibody drug conjugates (ADCs) in which cytotoxic drugs are attached to antibodies that are directed against antigens expressed on tumor cells and that this strategy has already demonstrated high response rates in lymphoma patients (page 1578, col 2, para 2). Pfeifer further teaches that CD79b is physiologically expressed in the vast majority of B cells and therefore represents a promising target for ADC (page 1578, col 2, para 3) which was validated using anti CD79b-MMAE in both in vitro lymphoma cell line testing and phase I clinical testing for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients (page 1584, col 2, para 3). Pfeifer further teaches that anti-CD79b had no toxicity alone (page 1585, col 1, para 2) and was rapidly internalized by cells (Fig 2C).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the antibody binder portion of the binder-toxin fusion protein as taught by Pieczykolan and Olombrada with an antibody targeting CD79b in a scFv-Fc-Toxin dimer as taught by Gelsen and Pfeifer. This results in a CD79b antibody-linker-anispolin construct. The ordinary artisan would have been motivated to do so because Gelsen teaches that CD79b is a known tumor surface antigen in binder fusion protein constructs and this would be a simple substitution of known elements with a reasonable expectation of success. Further, Pfeifer teaches that CD7b antibody internalizes and has been validated in an antibody drug conjugate in vitro and in vivo. Therefore the ordinary artisan has a reasonable expectation of success to generate a CD79b antibody-linker-anisoplin binder fusion toxin protein.
Claim 13 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Pieczykolan (WO 2013/080147 A2; IDS entered 02/15/2023) and Olombrada (Biol. Chem., 2017, 398(1): 135-142; IDS entered 02/15/2023) as evidenced by Uniprot database A0A014PJJ6 (IDS entered 02/15/2023) as applied to claims 1-4, 12, 14-17, and 19-24 above, and further in view of Zoolkefli (Malaysian Journal Of Science (2020): 1-26; cited in OA 11/17/2025).
The teachings of Pieczykolan and Olombrada as evidenced by UniProt regarding claims 1-4, 12, 14-17, and 19-24 are detailed above.
Pieczykolan and Olombrada as evidenced by UniProt do not teach expression of the binder-toxin fusion protein in Nicotania plant cells.
Zoolkefli teaches that different host systems for expression have advantages and disadvantages and that most clinically available therapies are produced from mammalian cells, microbes or yeast but this comes with high cost, inefficient production, and safety concerns. Zoolkefli further teaches that plant host systems for production of therapeutic proteins offers lower production cost and lower risk of contamination compared to mammalian cells, as well as incorporation of post translational modifications that ensure proteins are correctly folded with structural and functional integrity and that numerous functional mammalian proteins have been reported to be produced in plants (page 3, col 1, para 2). Zoolkefli further teaches production of recombinant scFv in Nicotiana tabacum in an economical way without the need for downstream laborious processes (page 20, col 1, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to produce the binder-toxin fusion protein as taught by Pieczykolan and Olombrada in Nicotiana as taught by Zoolkefli. The ordinary artisan would have been motivated to do so because as Zoolkefli teaches plant host systems for production of therapeutic proteins offers lower production cost and lower risk of contamination, as well as incorporation of post translational modifications that ensure proteins are correctly folded with structural and functional integrity with demonstrated success and Pieczykolan also teaches expression of the fusion protein in a plant system would be known to the ordinary artisan. The ordinary artisan has a reasonable expectation of success to express the binder-toxin protein in the Nicotania plant to take advantage of lower cost process.
Response to Arguments
Applicant's arguments filed 06/18/2026 have been fully considered but they are not persuasive.
Applicant submits: Applicant respectfully asserts that a person of ordinary skill in the art (POSA) would not have had a motivation to combine Pieczykolan and Olombrada as evidenced by Uniprot Consortium to arrive at the binder-toxin fusion protein comprising a toxin having the amino acid sequence according to SEQ ID NOs: 48 or 49, or an active fragment thereof; or a homologue having at least 80% sequence identity therewith, as claimed in pending claim 1.
The Examiner further alleges that "the ordinary artisan would have been motivated to do so because . . .. Olombrada teaches that anisoplin is structurally similar to hirsutellin A and shows the ribonucleolytic activity typical of ribotoxins and cytotoxicity and that these ribotoxins are useful for their antitumor properties conjugated as immunotoxins." Id. That rationale is legally and factually deficient.
Under KSR Int'l Co. v. Teleflex Inc. (550 U.S. 398, 418 (2007)), the obviousness inquiry requires an apparent reason to combine the known elements in the way the claim requires, and that analysis must be made explicit; it is not enough to identify isolated similarities at a high level of abstraction and then assert, with hindsight, that the claimed selection would have been routine. KSR also recognizes that the question is not whether elements can be described generally as belonging to the same field, but whether the prior art would have supplied a reason for a skilled artisan to make the particular modification leading to the claimed invention. Here, the Office has not identified a teaching in the cited art that would have directed a skilled artisan to select anisoplin specifically for use in the anticancer binder-toxin fusion protein of Pieczykolan.
Applicant also respectfully asserts that contrary to the Examiner's assertion, the Office fails to establish that a POSA would have had a reasonable expectation of success in arriving at the claimed invention. In the pharmaceutical and biological arts, obviousness requires more than a possibility that a modification might work; it requires a reasonable expectation that the proposed combination will succeed for the claimed purpose. Sanofi-Aventis Deutschland GmbH v. Glenmark Pharmaceuticals Inc. (748 F.3d 1354 (Fed. Cir. 2014)) is directly on point in rejecting an overbroad "obvious to try" theory where the art did not point to the claimed combination and its success was not predictable. As reflected in the Federal Circuit's opinion, Sanofi explains that "obvious to try" applies when there are a finite number of identified, predictable solutions leading to anticipated success, and it further recognizes that in the medical arts "potential solutions are less likely to be genuinely predictable." Here, the cited record does not show that anisoplin had been identified in the prior art as a known toxin for anticancer immunotoxin constructs, much less that its use in the claimed fusion format was a predictable solution with anticipated success. To the contrary, Pieczykolan uses hirsutellin, while Olombrada and UniProt disclose anisoplin and its sequence, but not its use as the toxin payload in an anticancer binder-toxin fusion protein of the type now claimed. Structural similarity and ribonucleolytic activity are not, by themselves, a substitute for evidence that anisoplin would have been expected to function successfully in the claimed targeted fusion- protein context.
In Response: The independent claim is drawn to a binder toxin protein having an amino acid according to SEQ ID NO: 48 or 49 or a homologue with 80% sequence identity. There is no limitation as to function or field of application in claims 1-5, 12-17, or 20-26. Further the specific binder is not defined except for in claim 5 which allows any type of binder protein linked to the toxin for any purpose. The claims are instead drawn to the specific structure and manufacturing process of the binder toxin protein. Claim 19 is the only claim wherein a specific utility is claimed.
The motivation to generate new binder toxin proteins is continuous and understood by one of ordinary skill in the art. The ordinary artisan would have known that there is an ongoing effort to develop new and effective ADCs that have the desired cytotoxicity, low immunogenicity, size, stability and ability to be modified (see Fig 5; Nejadmoghaddam et al; Med Biotechnol. 2019 Jan-Mar;11(1):3-23; PTO-892). Therefore the teachings of Olumbrada that disclose that ribotoxins are known a well-known family of toxic proteins that are already being studied for their anti-tumor properties and used as immunotoxins in fusion molecules and further that anisoplin is structurally similar and has similar activity to hirsutellin makes it prima facie obvious to develop an ADC with this ribotoxin.
Further Maestro-Lopez (Arch Biochem Biophys. 2017 Apr 1;619:45-53; IDS entered 0215/2023) teaches that anisoplin and hirsutellin are smaller than other known ribotoxins and that these smaller versions of ribotoxins represent an optimum compromise among conformational freedom, stability, specificity, and active-site plasticity which allow these toxic proteins to accommodate the characteristic abilities of ribotoxins into a shorter amino acid sequence and more stable structure of intermediate size between that of other nontoxic fungal RNases and previously known larger ribotoxins (abstract).
That there are only two smaller ribotoxins identified in the prior art with similar structure and activity renders the substitution of anisoplin for hirsutellin “obvious to try” in view of Sanofi-Aventis Deutschland GmbH v. Glenmark Pharmaceuticals Inc. (748 F.3d 1354 (Fed. Cir. 2014)). Further the structural similarity combined with the knowledge of one of ordinary skill in the art regarding ADCs yields a reasonable expectation of success.
Applicant submits: Orthopedic Equipment Co. v. United States (702 F.2d 1005, 1012 (Fed. Cir. 1983)) explains that the relevant art is informed by "the nature of the problem confronting the inventor." ("Care must be taken to avoid hindsight reconstruction by using the patent in suit as a guide through the maze of prior art references, combining the right references in the right way so as to achieve the result of the claims in suit."). The problem addressed in Pieczykolan is the design of an anticancer fusion protein for treatment of cancer. Throughout Pieczykolan, the treatment of cancer is discussed using the disclosed fusion protein. In contrast, Olombrada describes anisoplin's potential "as a biological tool in agricultural pest and disease-vector control" and suggests a function during insect infection, not as identifying anisoplin as a toxin for anticancer immunotoxins. On this record, the cited references are not even addressing the same problem in the same therapeutic context. The rejection therefore impermissibly skips the required analytical step - why a person of ordinary skill in the art, starting from the anticancer fusion proteins of Pieczykolan, would have been led to select anisoplin from Olombrada for that very different purpose. The Office's statement that this was merely a "simple substitution" does not cure that defect because it does not explain why anisoplin, rather than any other toxin, would have been chosen for the claimed anticancer binder-toxin fusion construct.
In Response: Orthopedic Equipment Co. v. United States (702 F.2d 1005, 1012 (Fed. Cir. 1983)) is not a precedential case and therefore the decision and statements therein are only applicable to the specific facts of that application.
The claims in that case were drawn to an electrical system for controlled operation of a business and the programming contained therein. The prior art considered was individual patents that disclose one or more, but less than all, of the separate Wolf claim elements. Their combined teachings disclose all of the Wolf claim elements. Several of these patents each show how to combine two or more of the Wolf claim elements. They demonstrate the facility with which the various means identified in the Wolf claims can be made to interface with each other in order to form the desired information processing devices. One of skill in the art of designing information processing systems hardware at the time of the Wolf filing date would have been familiar with telephone line-switching technology.
Claims may be obvious in view of a combination of references, even if the features of one reference cannot be substituted physically into the structure of the other reference. In re Andersen, 391 F.2d 953, 958, 157 USPQ 277, 281, 55 CCPA 1014 (Cust. & Pat.App.1968). What matters in the Sec. 103 nonobviousness determination is whether a person of ordinary skill in the art, having all of the teachings of the references before him, is able to produce the structure defined by the claim. In re Twomey, 218 F.2d 593, 104 USPQ 273, 275, 42 Cust. & Pat.App. 742 (Cust. & Pat.App.1955). Rather, he raises only the point that it was not likely that the Andrews-Vibbard apparatus would be integrated into the Nelson-Robinson apparatus by one of ordinary skill in the art. This may be so for reasons of economic feasibility, but not for any want of technological feasibility. The combination of these two inventions does not make good economic sense, but there is no mismatch between their technologies.
This same reasoning can be applied in the instant case to the prior art, although anisoplin had not been previously tested as a cancer therapeutic Olumbrada teaches that ribotoxins are known a well-known family of toxic proteins that are already being studied for their anti-tumor properties and used as immunotoxins in fusion molecules and further that anisoplin is structurally similar and has similar activity to hirsutellin makes it prima facie obvious to develop an ADC with this ribotoxin. So while not explicitly stating that anisoplin could be used as an immunotoxin the concept of ribotoxins used for cancer treatment fused to a binding protein is disclosed in Olumbrada and the arts can be considered analogous.
Applicant submits: Applicant further respectfully asserts that the present application shows that the binder-toxin fusion protein comprising a toxin having the amino acid sequence according to SEQ ID NOs: 48 or 49, or an active fragment thereof; or a homologue having at least 80% sequence identity therewith surprisingly demonstrated superiority over Polatuzumab, a marketed antibody drug conjugate.
The specification as filed of the present application expresses that "Anisoplin has so far not been described in the context of antitumor treatments, nor as a toxin component in a binder-toxin fusion protein. The inventors have for the first [time] explored the potential of anisoplin in these contexts and have surprisingly found that the toxin has excellent characteristics rendering it suitable for these applications." Specification as filed at page 3, paragraph 5 (emphasis added).
In Response: Page 3 paragraph 5 as numbered in the instant specification, clean copy dated 02/17/2026 recites: According to one embodiment, a binder-toxin fusion protein comprising anisoplin or an active fragment thereof is provided. Preferably, the binder-toxin fusion protein comprises a toxin sequence according to SEQ ID NO 48 or 49, or a homologue thereof having at least 66 % sequence identity with SEQ ID NO 48 or 49.
When indicating surprising results the figure with the surprising results needs to be indicated, it would also be beneficial to clearly indicate where the surprising results are disclosed in the instant specification. The instant specification teaches that the purified binder-toxin demonstrated superiority over Polatuzumab which targets the same antigen but is linked to MMAE see #425 and #507 (page 28, first para). Construct #507 is in Fig 20 with an IC50= 0.02582nM and is listed in the table as CD79b (full IgG)- Liop-anispolin (pages 30-35). Construct #425 cannot be found in any of the figures or described elsewhere in the instant specification. Based on the remarks it is assumed that the construct in the specification is a typographical error and should read 452 as presented in the arguments, instead of 425. Construct 452 is also listed in the table (pages 30-35) as CD79b-G4S-anisoplin. Therefore no results for polatuzumab have been presented for direct comparison and an argument of surprising results is not supported.
The comparison between hirsutellin and anispolin constructs can be seen in the summary of experiments on pages 30-35 of the instant specification which can be considered a viable prior art construct for comparison. In this table it is disclosed that Fig 9 and 10 demonstrate in vitro cytotoxicity of constructs CD79b-G4S-hirsutellin and CD79b-G4S-anisoplin with IC50 of 107nM and 1032nM which does not make the results for anisoplin surprising.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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