DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
Claims 1, 2, 4, 6, 26, 27, 30, 31, 39, 40, 42, 44, 48, 49, 51, 52, 54, 56, 60, and 63 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1, 2, 4, 6, 26, 27, 30, and 31, drawn to a broad-spectrum neutralizing composition, in the reply filed on 15 April 2026 is acknowledged. The traversal is on the ground(s) that the invention of Group I is basically the same as Group II and Group III and any prior art searched for one group is applicable to the other group. Applicant also states that there would not be a serious search and/or examination burden.
This is not found persuasive. As discussed in-depth in the Restriction requirement of 17 February 2026, Groups I-III lack unity of invention because the technical feature of a neutralizing receptor decoy antibody (RDA) comprising a fusion protein comprising a fragment of a Fc region; and a fragment of a chondroitin sulfate proteoglycan 4 (CSPG4) receptor tandemly attached to the Fc region, is not a special technical feature as it does not make a contribution over the prior art in view of Gillies et al. (U.S. Patent 7,067,110), as evidenced by Jordaan et al. (Biomed 5: 37, 2017). Gillies et al. teach a fusion protein comprising Fc and a fragment of MCSP (melanoma-specific chondroitin sulfate proteoglycan), termed “Fc-MCSP” (columns 28-29, Example 9). It is noted that MCSP is also known in the prior art as chondroitin sulfate proteoglycan 4 (CSPG4), as evidenced by Jordaan et al. (bottom of page 1).
The requirement is still deemed proper and is therefore made FINAL.
Claims 39, 40, 42, 44, 48, 49, 51, 52, 54, 56, 60, and 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 15 April 2026.
Claim 1, 2, 4, 6, 26, 27, 30, and 31 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 30 December 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Oath/Declaration
As a reminder, it is noted to Applicant that as stated in the Communication of 25 October 2023, a properly executed inventor’s oath or declaration has not been received for the inventors of the instant application. Although no time period for reply is set forth in the instant Office Action, Applicant must submit the inventor's oath or declaration no later than the expiration of the time period set forth in the “Notice of Allowability” to avoid abandonment (see 37 CFR 1.495(c)). Applicant must file the oath or declaration in compliance with 37 CFR 1.63, or a substitute statement in compliance with 37 CFR 1.64, executed by or with respect to each actual inventor.
Drawings
1. The drawings are objected to because:
(a) In Figures 3C, 4E, 7A, 7B, 14A, the text and numbers are blurry and/or too faint, making the information illegible and difficult for the Examiner to interpret the data presented therein (see 37 CFR 1.84(p)).
(b) In Figures 18A-18D, the amino acid letters are blurry, making it difficult to tell the difference between many amino acids. Also, it is suggested to remove the gray shading.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
2. The disclosure is objected to because of the following informalities:
2a. The tables listed in the specification are not in consecutive order. For example, the first table in the specification is titled, “Table 7” (see page 12). The second table is titled, “Table 8” (pages 22-23). The third table is labeled “Table 1” (pages 26-30), etc. This is confusing and the Tables should be renumbered in consecutive order.
2b. At page 5, paragraph [0023] states “FIG. 4B and 2C shows an open-book…”. The “2C” limitation in this sentence appears to be a typographical error that should be amended to recite “4C”.
2c. The Brief Description of the Drawings at page 5, [0024] does not refer to Figure 5E.
2d. At page 7, [0031] (lines 5-6 from the top of the page), the specification states “FIG. 12C, 12D, and 12D show the WT (n=5) and…”. The second recitation of “12D” is a typographical error and should be deleted or amended to reflect the appropriate Figure.
2e. At page 7, [0032], the specification states “FIG. 13B, 4C, and 4D shows the harvested cecum was processes…”. Also, five lines below this sentence, the specification recites “C. difficile to CSPG4-/- n = 3) (FIG.4D)”. The “4C” and “4D” limitations appear to be typographical errors and that should be amended to recite “13C” and “13D”.
2f. At page 7, [0033], the specification states “FIG. 14B, 5C, and 5D shows the indicated TcdB mutants or the control…”. The “5C” and “5D” limitations appear to be typographical errors and that should be amended to recite “14C” and “14D”.
2g. At page 5, [0023] and page 8, [0034], the Brief Description of the Drawings for Figures 4C and 15A refers to different colors (i.e., green, blue, and purple). However, no color drawings have been submitted. It cannot be determined from the black and white drawings what elements the Brief Descriptions are referring to. It is suggested that Applicant amend the specification or submit color drawings. Applicant is reminded that photographs and color drawings are not accepted unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), three sets of color drawings or color photographs, as appropriate, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37CFR 1.84(b)(2). Note that the requirement for three sets of color drawings under 37 CFR 1.84(a)(2)(ii) is not applicable to color drawings submitted via EFS-Web. Therefore, only one set of such color drawings is necessary when filing via EFS-Web. Appropriate correction is required.
Appropriate correction is required.
Claim Objections
3. Claims 6, 30, and 31 are objected to because of the following informalities:
3a. Claim 6 recites the acronym “VHH” without first defining what it represents. While the claim can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym and/or in each independent claim.
3b. In claim 30, line 2, the phrase “RDA is able to block” should be amended to simply recite “RDA blocks”.
3c. In claim 31, line 2, the phrase “RDA is able to neutralize” should be amended to simply recite “RDA neutralizes”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
4. Claim 31 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 31 recites the composition of claim 1, wherein the RDA is able to neutralize a toxin of C. difficile.
However, claim 1, already recites a broad-spectrum neutralizing composition comprising a neutralizing receptor decoy antibody (RDA) that neutralizes a toxin of Clostridium difficile (C. difficile) in various strains of C. difficile, the RDA comprising: a fusion protein comprising a fragment of a Fc region; and a fragment of chondroitin sulfate proteoglycan 4 (CSPG4) receptor tandemly attached to the Fc region (emphasis added by the Examiner).
Therefore, since claim 31 recites the same limitation of a RDA that neutralizes a toxin of C. difficile, as recited in claim 1, claim 31 fails to further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
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.
5. Claims 1, 2, 4, 6, 26, 27, 30, and 31 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.
Claim 1 recites a broad-spectrum neutralizing composition comprising a neutralizing receptor decoy antibody (RDA) that neutralizes a toxin of Clostridium difficile (C. difficile) in various strains of C. difficile, the RDA comprising: a fusion protein comprising a fragment of a Fc region; and a fragment of chondroitin sulfate proteoglycan 4 (CSPG4) receptor tandemly attached to the Fc region.
Claim 2 recites that the composition further comprises a fragment of a frizzled protein (FZD) receptor, wherein the fragment of the FZD receptor comprises a cysteine rich domain (CRD).
Claim 6 recites that the composition of claim 2 further comprises a VHH nanobody, wherein the VHH nanobody is tandemly attached to the CSPG4 receptor fragment, the Fc region, or the FZD receptor fragment.
The specification of the instant application teaches that is it an object of the invention to provide for a neutralizing receptor decoy antibody (RDA) composition that allows for treatment or prevention of Clostridium difficile infection caused by a protein toxin produced by C. difficile (e.g., TcdB) (page 2, [0009]; page 3, [0012]). The specification states that the present invention was able to determine the 3-dimensional structure of the TcdB1 binding to the CSPG4 receptor and precisely determine the exact fragment of CSPG4 that sufficiently binds to TcdB1 (page 3, [0017]). The specification continues to disclose that using the structural data, a recombinant, highly expressed, stable small fragment of CSPG4 (amino acids 410-551 of CSPG4) as a receptor decoy that prevents TcdB1 from binding to full-length CSPG4 was generated and named “Repeat1” (pages 3-4, [0017]). The specification teaches the generation of “Repeat1-Fc” and that such receptor decoy is a broad spectrum TcdB inhibitor (page 37, [00105]; page 49, [00141]; page 53, [00153-00154]; Figures 17A-17F).
The instant specification also discloses the generation of a receptor decoy antibody, “RDA1” comprising the amino acid sequence of SEQ ID NO: 46 (page 23). RDA1 is a fusion protein comprising a fragment of CSPG4 (“Repeat1”), a fragment of a Fc region, and a fragment of a frizzled protein receptor (CRD1 of FZD1, SEQ ID NO: 4) (page 23, [0055]; page 23). The specification also teaches “RDA1” fused to a VHH nanobody named, “h5D” (SEQ ID NO: 47; page 23; “h5D” is SEQ ID NO: 8, page 30, page 33, [0081]).
The specification also teaches that the CSPG4 fragment is a fragment that includes residues 30-551 (SEQ ID NO: 3) or residues 410-551 (“Repeat1”, SEQ ID NO: 2) (page 31). The specification indicates that the CSPG4 fragment is as small as about 10-25 amino acids in length (page 31, [0075]). The specification states that the CSPG4 portion may comprise a peptide that is at least 80%, 85%, 90%, 95%, or 99% identical to the CSPG4 protein or a fragment thereof (page 32, [0076]).
The specification teaches that a fragment Fc may refer to the tail region of an antibody that interacts with cell surface receptors and includes a peptide that is at least 80%, 85%, 90%, 95%, or 99% identical to an Fc region or fragment thereof (pages 32-33, [0079]).
The frizzled protein portion of the “RDA” composition comprises a peptide that is at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to a FZD protein or a fragment thereof (page 30, [0071-0072]). The fragment of a FZD receptor may also comprise a cysteine rich domain (CRD) that is at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to a FZD protein or a fragment thereof (page 30, [0072]).
Lastly, the specification discloses that the “VHH nanobody” refers to the antigen binding fragment of heavy chain only antibodies (page 33, [0081]). The specification indicates that the VHH may be a 5D antibody or a peptide that is at least 80%, 85%, 90%, 95%, or 99% identical to a humanized 5D antibody or a fragment thereof (page 33, [0081-0082]).
Therefore, in view of the teachings of the instant specification, the “fragment of a CSPG4 receptor”, “fragment of a Fc region”, “fragment of a FZD receptor”, and “VHH nanobody” limitations are broadly interpreted by the Examiner has reading upon any CSPG4 receptor fragment, any Fc protein fragment, any FZD receptor fragment, and any VHH nanobody. However, the specification does not teach all possible fragments of a CSPG4 receptor, Fc region, and FZD receptor. The specification also does not disclose all possible VHH nanobodies. In turn, the specification does not teach all possible neutralizing receptor decoy antibody fusions that comprises such fragments.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the factors present in the claims for the claimed fusion protein composition are (1) structural characteristics of a fragment of a CSPG4 receptor, a fragment of a Fc region, a fragment of a FZD receptor, and a VHH nanobody and (2) functional characteristics of neutralizing a toxin of C. difficile and blocking a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both. There is no identification of any particular sequence or structure of the fragment of a CSPG4 receptor, the fragment of a Fc region, the fragment of a FZD receptor, and a VHH nanobody that must be conserved in order to provide the required functions of neutralizing a toxin of C. difficile and blocking a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both. Thus, the claims are drawn to a genus of CSPG4 receptor fragments, Fc region fragments, FZD receptor fragments, and VHH nanobodies. The claims are also drawn to a genus of decoy antibody fusions that comprises such fragments.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of CSPG4 receptor fragments, Fc region fragments, FZD receptor fragments, and VHH nanobodies and the functions of neutralizing a toxin of C. difficile and blocking a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both. In other words, the specification does not teach the structure which results in a decoy antibody fusion protein composition with the claimed required characteristics. The descriptions of (i) a CSPG4 fragment comprising residues 30-551 (SEQ ID NO: 3) or residues 410-551 (“Repeat1”, SEQ ID NO: 2) (page 31, [0074]; page 23, Table 8); (ii) an Fc region fragment comprising amino acids 164-385 of the RDA1 fusion of SEQ ID NO: 46 (page 23, Table 8); (iii) an FDZ1 fragment comprising amino acids 96-253 from FZD1 (SEQ ID NO: 4) (page 28; page 23, Table 8); (iv) a VHH nanobody comprising the amino acid sequence of SEQ ID NO: 8 (page 30), and (v) RDA1/RDA1-h5D (entire fusion proteins) comprising the amino acid sequences of SEQ ID NOs: 46 and 47 (page 23, Table 8), are not adequate written description of an entire genus of CSPG4 receptor fragments, Fc region fragments, FZD receptor fragments, and VHH nanobodies, respectively.
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability.
Applicant is reminded that generally, 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 (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, clearly states 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). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). 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). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the genus of CSPG4 receptor fragments, Fc region fragments, FZD receptor fragments, and VHH nanobodies (and the neutralizing receptor decoy antibody fusions that comprises such fragments), and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The specific protein fragments are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only a receptor decoy antibody that comprises:
(I) the amino acid sequence of SEQ ID NO: 46 or 47; or
(II) a fusion protein comprising
(a) a CSPG4 fragment comprising the amino acid sequence of SEQ ID NO: 2 (CSPG4 “Repeat1”, residues 410-551) or SEQ ID NO: 3 (CSPG4 residues 30-551);
(b) an Fc region fragment comprising amino acids 164-385 of the RDA1 fusion of SEQ ID NO: 46;
(c) an FDZ1 fragment comprising the amino acid sequence of SEQ ID NO: 4 (amino acids 96-253 from FZD1); and optionally,
(d) a VHH nanobody comprising the amino acid sequence of SEQ ID NO: 8,
but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
6. Claims 1, 2, 4, 6, 26, 27, 30, and 31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a composition comprising a neutralizing receptor decoy antibody (RDA) that comprises:
(I) the amino acid sequence of SEQ ID NO: 46 or 47; or
(II) a fusion protein comprising (a) a CSPG4 fragment comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3;
(b) an Fc region fragment comprising amino acids 164-385 of SEQ ID NO: 46;
(c) an FDZ1 fragment comprising the amino acid sequence of SEQ ID NO: 4; and optionally,
(d) a VHH nanobody comprising the amino acid sequence of SEQ ID NO: 8,
does not reasonably provide enablement for a composition comprising a neutralizing receptor decoy antibody (RDA) that neutralizes a toxin of Clostridium difficile (C. difficile) in various strains of C. difficile, the RDA comprising: a fusion protein comprising a fragment of a Fc region; and a fragment of chondroitin sulfate proteoglycan 4 (CSPG4) receptor tandemly attached to the Fc region. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 1 of the instant application recites a broad-spectrum neutralizing composition comprising a neutralizing receptor decoy antibody (RDA) that neutralizes a toxin of Clostridium difficile (C. difficile) in various strains of C. difficile, the RDA comprising: a fusion protein comprising a fragment of a Fc region; and a fragment of chondroitin sulfate proteoglycan 4 (CSPG4) receptor tandemly attached to the Fc region.
Claim 2 recites that the composition further comprises a fragment of a frizzled protein (FZD) receptor, wherein the fragment of the FZD receptor comprises a cysteine rich domain (CRD).
Claim 6 recites that the composition of claim 2 further comprises a VHH nanobody, wherein the VHH nanobody is tandemly attached to the CSPG4 receptor fragment, the Fc region, or the FZD receptor fragment.
The specification of the instant application teaches that is it an object of the invention to provide for a neutralizing receptor decoy antibody (RDA) composition that allows for treatment or prevention of Clostridium difficile infection caused by a protein toxin produced by C. difficile (e.g., TcdB) (page 2, [0009]; page 3, [0012]). The specification states that the present invention was able to determine the 3-dimensional structure of the TcdB1 binding to the CSPG4 receptor and precisely determine the exact fragment of CSPG4 that sufficiently binds to TcdB1 (page 3, [0017]). The specification continues to disclose that using the structural data, a recombinant, highly expressed, stable small fragment of CSPG4 (amino acids 410-551 of CSPG4) as a receptor decoy that prevents TcdB1 from binding to full-length CSPG4 was generated and named “Repeat1” (pages 3-4, [0017]). The specification teaches the generation of “Repeat1-Fc” and that such receptor decoy is a broad spectrum TcdB inhibitor (page 37, [00105]; page 49, [00141]; page 53, [00153-00154]; Figures 17A-17F).
The instant specification also discloses the generation of a receptor decoy antibody, “RDA1” comprising the amino acid sequence of SEQ ID NO: 46 (page 23). RDA1 is a fusion protein comprising a fragment of CSPG4 (“Repeat1”), a fragment of a Fc region, and a fragment of a frizzled protein receptor (CRD1 of FZD1, SEQ ID NO: 4) (page 23, [0055]; page 23). The specification also teaches “RDA1” fused to a VHH nanobody named, “h5D” (SEQ ID NO: 47; page 23; “h5D” is SEQ ID NO: 8, page 30, page 33, [0081]).
The specification also teaches that the CSPG4 fragment is a fragment that includes residues 30-551 (SEQ ID NO: 3) or residues 410-551 (“Repeat1”, SEQ ID NO: 2) (page 31). The specification indicates that the CSPG4 fragment is as small as about 10-25 amino acids in length (page 31, [0075]). The specification states that the CSPG4 portion may comprise a peptide that is at least 80%, 85%, 90%, 95%, or 99% identical to the CSPG4 protein or a fragment thereof (page 32, [0076]).
The specification teaches that a fragment Fc may refer to the tail region of an antibody that interacts with cell surface receptors and includes a peptide that is at least 80%, 85%, 90%, 95%, or 99% identical to an Fc region or fragment thereof (pages 32-33, [0079]).
The frizzled protein portion of the “RDA” composition comprises a peptide that is at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to a FZD protein or a fragment thereof (page 30, [0071-0072]). The fragment of a FZD receptor may also comprise a cysteine rich domain (CRD) that is at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to a FZD protein or a fragment thereof (page 30, [0072]).
Lastly, the specification discloses that the “VHH nanobody” refers to the antigen binding fragment of heavy chain only antibodies (page 33, [0081]). The specification indicates that the VHH may be a 5D antibody or a peptide that is at least 80%, 85%, 90%, 95%, or 99% identical to a humanized 5D antibody or a fragment thereof (page 33, [0081-0082]).
Therefore, in view of the teachings of the instant specification, the “fragment of a CSPG4 receptor”, “fragment of a Fc region”, “fragment of a FZD receptor”, and “VHH nanobody” limitations are broadly interpreted by the Examiner has reading upon any CSPG4 receptor fragment, any Fc protein fragment, any FZD receptor fragment, and any VHH nanobody. However, the specification does not teach all possible fragments of a CSPG4 receptor, Fc region, and FZD receptor. The specification also does not disclose all possible VHH nanobodies. In turn, the specification does not teach all possible neutralizing receptor decoy antibody fusions that comprises such fragments.
There are no methods or working examples in the specification that indicate all possible fragments of a CSPG4 receptor, Fc region, and FZD receptor or all possible VHH nanobodies neutralize a toxin of C. difficile and block a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both. A large quantity of experimentation would be required of the skilled artisan to generate all possible CSPG4 receptor fragments, Fc region fragments, FZD receptor fragments, and VHH nanobodies (and the neutralizing receptor decoy antibody fusions that comprises such fragments), and then screen such for neutralizing a toxin of C. difficile and blocking a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both. Such experimentation is considered undue. Additionally, one skilled in the art would not be able to predict that all possible CSPG4 receptor fragments, Fc region fragments, FZD receptor fragments, and VHH nanobodies would have the desired functional activity of neutralizing a toxin of C. difficile and blocking a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both. For example, the instant specification even teaches that regarding CSPG4, the first repeat (“Repeat1”, amino acids 410-551), is mainly responsible for TcdB binding while the rest of SPG4 is pointing away from the toxin (page 47, [00137]). A person of skill in the art would not know which amino acid residues are considered essential and which are non-essential. Without detailed direction as to which amino acids are essential to the function of the fragments and VHH nanobodies, the skilled artisan would not be able to determine without undue experimentation which fragment sequences and VHH nanobodies encompassed by the instant claims would exhibit the desired functional characteristics of neutralizing a toxin of C. difficile and blocking a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both.
The problem of predicting protein and DNA structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein and DNA is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495). However, Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the proteins which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427).
See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph).
Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract).
Due to the large quantity of experimentation necessary to generate all possible CSPG4 receptor fragments, Fc region fragments, FZD receptor fragments, and VHH nanobodies (and the neutralizing receptor decoy antibody fusions that comprises such fragments) and screen such for the desired functional activities of neutralizing a toxin of C. difficile and blocking a C. difficile toxin from binding a CSPG4 receptor, a FZD receptor, or both; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
7. Claims 1, 27, 30, and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gillies et al. (U.S. Patent 7,067,110), as evidenced by Jordaan et al. (Biomed 5: 37, 2017; cited on the PTO-892 of 17 February 2026).
Gillies et al. teach a fusion protein comprising Fc and a fragment of MCSP (melanoma-specific chondroitin sulfate proteoglycan), termed “Fc-MCSP”, meeting the limitations of instant claim 1 (columns 28-29, Example 9; Figure 13). It is noted that MCSP is also known in the prior art as chondroitin sulfate proteoglycan 4 (CSPG4), as evidenced by Jordaan et al. (bottom of page 1).
Although instant claims 1, 27, 30, and 31 recite the additional limitations of neutralizing a toxin of C. difficile, mimicking a CSPG4 receptor, and blocking C. difficile toxin from binding a CSPG4 receptor, these activities would inherently occur in the prior art of Gillies et al., absent evidence to the contrary (see Ex parte Novitski, 26 USPQ2d 1389 (BPAI 1993); see also Integra LifeSciences I Ltd. V. Merck KGaA, (DC SCalif) 50 USPQ2d 1846; In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)). See MPEP §2112.01(I)(II). Applicant is also reminded that the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004); Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)). MPEP §2112(I).
Conclusion
No claims are allowable.
The art made of record and not relied upon is considered pertinent to applicant's disclosure:
TcdB binds FZDs and inhibits Wnt signaling
Chen et al. Science 360: 664-669, 2018
Chen et al. FEBS J 286: 874-881, 2019
Review of Clostridium difficile (and its receptors)
Aktories et al. Ann Rev Microbiol 71: 281-307, 2017
Chen et al. Nature Struct Mol Biol 26: 712-719, 2019
Chen et al. Nature Comm 12: 3748, 2021
Pan et al. PLoS Pathogens 17(1): e1009197, 2021
Tao et al. Nature 538: 350-355, 2016
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BEB
Art Unit 1647
11 June 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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