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
The amendment of 23 December 2025 has been entered in full. Claims 24, 28-30 are amended. Claims 1-23, 25-27, and 31 are cancelled. Claims 36-39 are added.
Claims 24, 28-30, and 32-39 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 24-31, drawn to a fusion protein comprising IL-1Ra and an extracellular matrix binding protein, in the reply filed on 23 December 2025 is acknowledged. The traversal is on the ground(s) that the claims in each of Groups I-IV relate to a single general inventive concept because they share the special technical feature of a fusion protein comprising IL-1Ra and an ECM binding peptide comprising a specific peptide sequence from amphiregulin (SEQ ID NO: 2). In view of the amended claims and review of the prior art, Applicant’s argument is found to be persuasive.
The restriction requirement among inventions I-IV as set forth in the Office Action mailed on 05 November 2025 is hereby withdrawn and claims 32-35 are rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 24, 28-30, and 32-39 are under consideration in the instant application.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09 January 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
1. The drawings are objected to because the instant drawings do not comply with 37 C.F.R. § 1.84(U)(1), which states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter. Figure 31 of the instant application, for example, is presented on 2 separate sheets. The two total sheets of drawings for Figure 31 should be renumbered ''Figures 31A-31B”.
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.
Applicant is reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1 1.84(U)(1), Applicant is required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
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.
2. Specific deficiencies and the required response to this Office Action are as follows:
2a. Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825. Specifically, sequences are present in the drawings and specification that are not in the sequence listing or not identified by sequence identifiers.
The sequence disclosures are located in Figure 1A and the following locations in the specification:
Page 17, lines 28-29
Page 35, line 34
Page 26, lines 2, 5, and 8
Page 77, lines 1-2
2b. Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
3. The disclosure is objected to because of the following informalities:
3a. At pages 13-14, the Brief Description of the Drawings does not refer to Figure 16I.
Appropriate correction is required.
Claim Objections
4. Claims 30, 32, and 35-39 are objected to because of the following informalities:
4a. In claim 32, lines 1-4, it is suggested to insert semi-colons or subparts (i.e., “(i)”, “(ii)”, “(a)”, “(b)”, etc.) in between each recitation. For example:
A nucleic acid molecule encoding the fusion protein of claim 24; ; or a cell or a non-human organism transformed or transfected with a nucleic acid molecule encoding the fusion protein of claim 24 or with a vector comprising a nucleic acid molecule encoding the fusion protein of claim 24.
4b. In claim 35, line 3, it is suggested to insert semi-colons in between each recitation. For example:
The method of claim 33 in which the condition in which IL-1Ra administration is beneficial or in which IL-1R1 signalling needs to be dampened is a wound, burn or muscle condition or injury; or a cartilage, tendon or bone disorder or injury, particularly a diabetic wound.
4c. In claims 38 and 39, the ECM binding peptide sequence is an amino acid sequence, not a sequence identifier (SEQ ID NO:). Thus, for clarity, the claims should be amended to recite, for example, "wherein the ECM binding peptide comprises the amino acid sequence of SEQ ID NO: 2” and “wherein the ECM binding peptide consists of the amino acid sequence of SEQ ID NO: 2”.
4d. Claims 36 and 37 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
4e. Claim 30 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 36. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
5. Claims 33-35 are 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.
5a. Regarding claims 33-35, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). See claim 33, line 4; claim 34, line 3; and claim 35, line 3.
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.
Written Description
6. Claims 24, 28, 29, 32-35 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 24 is directed to a fusion protein comprising interleukin-1 receptor antagonist (IL-1Ra) and an extracellular matrix (ECM) binding peptide which specifically binds to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate, wherein the ECM binding peptide comprises a peptide from amphiregulin (AREG) comprising the amino acid sequence provided as SEQ ID NO: 2 or conservative variations thereof.
The specification of the instant application teaches that an embodiment of the present invention seeks to provide a controlled release form of IL-1Ra capable of being retained at the desired site of action (page 2, lines 1-2). The specification discloses that a first aspect provides a fusion protein comprising interleukin-1 receptor antagonist (IL-1Ra) and an extracellular matrix (ECM) binding peptide which specifically binds to one or more or all extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate, wherein the ECM binding peptide comprises a peptide from amphiregulin (AREG) comprising the amino acid sequence of SEQ ID NO: 2 or conservative variations thereof (page 2, lines 8-11, 16-19). The specification teaches that functional homologs or variants may be derived by insertion, deletion, or substitution of amino acids in, or chemical modification of, the native carboxy-terminal sequence (page 23, lines 26-28). The specification states that substitutions can be made with conservative amino acids (page 23, lines 35-36). The specification discloses that a conservative substitution is where one amino acid residue is substituted by another with similar biochemical properties, e.g. charge, hydrophobicity, and size (page 24, lines 1-2). The specification lists examples of conservative substitutions at page 24, lines 3-9. The specification also indicates that the ECM binding peptide may comprise one, two, three, four, or five insertions, deletions, or substitutions compared with the natural ECM binding peptide (page 24, lines 10-13). The specification teaches that variants of the ECM binding peptide may have at least 80%, 81%., 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence similarity to SEQ ID NO: 2 (page 24, lines 20-26).
Therefore, the “conservative variations” of the amino acid sequence of SEQ ID NO: 2 limitation recited in the instant claims is broadly interpreted by the Examiner as reading upon any peptide variant of the amino acid sequence of SEQ ID NO: 2 that binds to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate. However, the specification does not teach any peptide variants (conservative or otherwise) of the amphiregulin (AREG) amino acid sequence of SEQ ID NO: 2.
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 only factors present in the claims are a structural characteristic of a conservative variation of an AREG peptide comprising the amino acid sequence of SEQ ID NO: 2 and a functional characteristic of binding to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate. There is no identification of any particular sequence or structure of the AREG peptide comprising the amino acid sequence of SEQ ID NO: 2 that must be conserved in order to provide the required function of binding to one or more extracellular matrix proteins. Thus, the claims are drawn to a genus of fusion proteins comprising a genus of peptide variants of the AREG amino acid sequence of SEQ ID NO: 2.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of peptide variants of the AREG amino acid sequence of SEQ ID NO: 2 and the function of binding to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate. In other words, the specification does not teach the structure which results in a peptide variant of the AREG amino acid sequence of SEQ ID NO: 2 with the required characteristics. The description of the AREG amino acid sequence of SEQ ID NO: 2 is not adequate written description of an entire genus of variants of the amino acid sequence of SEQ ID NO: 2 that bind to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate. There is little guidance in the specification indicating which amino acids are considered essential for the required biological activity of the AREG peptide amino acid sequence of SEQ ID NO: 2 of the instant claims.
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. 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).
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, 19USPQ2d 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 peptide variants of the AREG amino acid sequence of SEQ ID NO: 2 that are biologically active of the encompassed claims, 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 or variant thereof is 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 peptide from AREG comprising the amino acid sequence of SEQ ID NO: 2, 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).
Scope of Enablement
7. Claims 24, 28, 29, 32-35 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 fusion protein comprising Il-1Ra and an ECM binding peptide which specifically binds to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate, wherein the ECM binding peptide comprises a peptide from amphiregulin (AREG) comprising the amino acid sequence provided as SEQ ID NO: 2, does not reasonably provide enablement for a fusion protein comprising Il-1Ra and an ECM binding peptide which specifically binds to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate, wherein the ECM binding peptide comprises a peptide from amphiregulin (AREG) comprising the amino acid sequence provided as SEQ ID NO: 2 or conservative variations thereof. 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 24 is directed to a fusion protein comprising interleukin-1 receptor antagonist (IL-1Ra) and an extracellular matrix (ECM) binding peptide which specifically binds to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate, wherein the ECM binding peptide comprises a peptide from amphiregulin (AREG) comprising the amino acid sequence provided as SEQ ID NO: 2 or conservative variations thereof.
The specification of the instant application teaches that an embodiment of the present invention seeks to provide a controlled release form of IL-1Ra capable of being retained at the desired site of action (page 2, lines 1-2). The specification discloses that a first aspect provides a fusion protein comprising interleukin-1 receptor antagonist (IL-1Ra) and an extracellular matrix (ECM) binding peptide which specifically binds to one or more or all extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate, wherein the ECM binding peptide comprises a peptide from amphiregulin (AREG) comprising the amino acid sequence of SEQ ID NO: 2 or conservative variations thereof (page 2, lines 8-11, 16-19). The specification teaches that functional homologs or variants may be derived by insertion, deletion, or substitution of amino acids in, or chemical modification of, the native carboxy-terminal sequence (page 23, lines 26-28). The specification states that substitutions can be made with conservative amino acids (page 23, lines 35-36). The specification discloses that a conservative substitution is where one amino acid residue is substituted by another with similar biochemical properties, e.g. charge, hydrophobicity, and size (page 24, lines 1-2). The specification lists examples of conservative substitutions at page 24, lines 3-9. The specification also indicates that the ECM binding peptide may comprise one, two, three, four, or five insertions, deletions, or substitutions compared with the natural ECM binding peptide (page 24, lines 10-13). The specification teaches that variants of the ECM binding peptide may have at least 80%, 81%., 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence similarity to SEQ ID NO: 2 (page 24, lines 20-26).
Therefore, the “conservative variations” of the amino acid sequence of SEQ ID NO: 2 limitation recited in the instant claims is broadly interpreted by the Examiner as reading upon any peptide variant of the amino acid sequence of SEQ ID NO: 2 that binds to one or more extracellular matrix proteins selected from the group consisting of fibrinogen, fibronectin, vitronectin, tenascin C, and heparan sulfate. However, the specification does not teach any peptide variants (conservative or otherwise) of the amphiregulin (AREG) amino acid sequence of SEQ ID NO: 2.
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 to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the AREG amino acid sequence of SEQ ID NO: 2 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). There is little to no guidance in the specification indicating which amino acids are considered essential for the AREG amino acid sequence of SEQ ID NO: 2 of the instant claims.
The amount of experimentation required to generate fusion proteins comprising peptide variants of the AREG amino acid sequence of SEQ ID NO: 2 would not have been routine, much less could one of ordinary skill in the art predict that any combination of all the variants encompassed by the instant claims would result would result in a functional peptide (and overall functional fusion protein). Because of this lack of guidance in the instant specification, the extended experimentation that would be required to determine which amino acid sequences and modifications would be acceptable to retain occluding structural and functional activity, and the fact that the relationship between the sequence of a protein/peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable, it would require an undue amount of experimentation for one of skill in the art to arrive at the large number of peptide variants of the AREG amino acid sequence of SEQ ID NO: 2 of the encompassed claims. Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the genus of peptide variants of the AREG amino acid sequence of SEQ ID NO: 2 in the claims in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970).
Due to the large quantity of experimentation necessary to generate peptide variants of the AREG amino acid sequence of SEQ ID NO: 2 and screen such for the desired functional activity; 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.
Conclusion
Claims 30 and 36-39 are objected. Claims 24, 28, 29, and 32-35 are rejected.
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BEB
Art Unit 1647
21 January 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647