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 .
Response to Amendment
Applicant’s amendment filed 26 February 2026 has been received and entered. Claims 1 and 4-5 have been amended and claims 14-18 and 22 have been previously canceled. Claims 1-13, 19-21 and 23-26 are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-5 in the reply filed on 26 February 2026 is acknowledged.
Claims 6-13, 19-21 and 23-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 26 February 2026.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statements (IDS) submitted on 08 December 2023, 15 January 2025 and 26 February 2026 have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Specifically, page 9 of the specification, lines 20-22, contains several amino acid sequences which are not accompanied by a Sequence identifier.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Claim Rejections - 35 USC § 112
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5 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 is directed to a method for obtaining soluble calprotectin by expressing calprotectin from a vector comprising two polynucleotide chains each encoding a polypeptide comprising a chain with at least 80% sequence identity to SEQ ID NO:1 and 2, respectively and a linker linking the first and second chain, whiner the linker is a peptide linker comprising a protease recognition sequence. However, the claims are broader than the instant disclosure with regard to 80% identity for the respective protein chains.
The specification at pages 7-8 defines soluble calprotectin as a protein “obtained by the methods of the invention which is structurally essentially identically to native calprotectin and is therefore capable of binding monoclonal antibodies that are specific for S100A8/S100A9 heterodimers, in particular monoclonal antibody mAb27E10”. The specification also teaches that human S100A8 has the amino acid sequence of SEQ ID NO:1 but also has 4 known isoforms (having 93, 101, 116 or 117 amino acids). Human S100A9 has the amino acid sequence of SEQ ID NO:2. The specification does not indicate various isoforms, but contemplates lengths of 90, 100 or 110 amino acids. S100A8/S100A9 heterodimers oligomerize in the presence of metal ions thus forming calprotectin heterodimers. The specification at page 10 indicates that the polypeptide according to the invention is capable of being recognized by binding reagents which recognize S100A8 monomer, S100A9 monomer, S100A8/S100A9 dimer and/or oligomers thereof.
The instant specification discloses the amino acid sequence for S100A8 (SEQ ID NO:1) and the amino acid sequence for S100A9 (SEQ ID NO:20) and while the specification states that various isoforms are known with different amino acid lengths, the specification fails to indicate what those isoforms are and if they have any amino acid sequence variation from the disclosed amino acid sequences of SEQ ID NO:1 and 2. The claim is directed to obtaining soluble calprotectin, which based on the disclosure means that the protein must be capable of binding monoclonal antibodies that are specific for S100A8/S100A9 heterodimers.
The instant specification does not disclose variants of S100A8 and S100A9 with as much as 20% variation in the amino acid sequence wherein the heterodimer (e.g. soluble calprotectin) is capable of binding monoclonal antibodies that are specific for S100A8/S100A9. Claim 2 requires that the soluble calprotectin is capable of binding monoclonal antibody mAb27E10, however, the specification fails to disclose which amino acids in calprotectin are involved in binding, therefore, there is no guidance as to which amino acids must not be modified such that the antibody can still bind. The instant specification does not appear to provide an adequate written description of any variants, let alone an adequate written description of proteins that have 80% amino acid sequence identity to SEQ ID NO:1 and 2 which would function in a manner consistent with soluble calprotectin (which would be required for the protein to be considered “soluble calprotectin”).
The instant specification lacks an adequate written description for polypeptides comprising at least 80% sequence identity to SEQ ID NO:1 and 2, where in the two polypeptides form a heterodimer and bind to antibodies which bind to each monomer and to the heterodimer. No variants were ever made and there is no disclosure of what structures are needed for antibody binding such that the antibodies which bind native calprotectin and its monomers will also bind to “soluble calprotectin”.
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 disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the claim is a partial structure in the form of a recitation of percent identity. There is not even identification of any particular portion of the structure that must be conserved. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), 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.) 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).
With the exception of soluble calprotectin which comprises a first polypeptide having the amino acid sequence of SEQ ID NO:1 and a second polypeptide having the amino acid sequence of SEQ ID NO:2, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, 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 compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). 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 soluble calprotectin which comprises a first polypeptide having the amino acid sequence of SEQ ID NO:1 and a second polypeptide having the amino acid sequence of SEQ ID NO:2, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, 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).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 is indefinite as it depends from claim 1 which recites “wherein the linker is a peptide linker” but claim 4 recites that the “linker is between 1 and 20 amino acids long”. The claim is unclear because a “peptide” is understood in the art to be comprised of at least 2 amino acids but claim 4 seems to only require a single amino acid. The claim is indefinite; is the linker a peptide or can it be a single amino acid?
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.
Claim 4 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 4 is broader than the claim from which it depends as it recites “wherein the linker is between 1 and 20 amino acids long”. Claim 4 depends from claim 1 which limits the linker to a “peptide linker”. A peptide is a short chain of two or more amino acids. Therefore, claim 4 does not properly depend from 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 § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Futami et al. (Biochem. Biophys. Reports. 6(2014): 94-100) in view of US 2018/0045724 A1 (Estruch et al.) and Chen et al. (Adv. Drug Deliv. Rev. 2013; 65(10): 1357-1369).
Futami et al. teach the recombinant expression of preferentially heterodimerized recombinant S100A8/A9 in E. coli. Futami et al. teach that heterodimerization from semi-stable homodimers is not a spontaneous process and requires external energy and therefore, coexpression of heterodimerizing S100 proteins is a reasonable strategy to yield stable heterodimer. Futami et al. practice a coexpression strategy utilizing a bicistronic plasmid DNA expression system which produces active heterodimeric S100A8/A9 protein which is then purified using ion-exchange chromatography. Futami et al. teach the construction of plasmid DNA and expression of recombinant S100A8 and S100A9 (see page 95). Futami et al. do not teach expression of calprotectin from a single vector wherein the S100A8 and S100A8 proteins are expressed as a fusion protein with a peptide linker that comprises a protease recognition sequence.
Estruch et al. teach a fusion protein comprising S100A8 and S100A9 linked by an amino acid sequence (see [0143]). Estruch et al. also disclosue a fusion protein comprising S100A8 and S100A9 linked by a linker that can comprise a polyhistidine peptide (see [0198] and claim 23). The linker is an amino acid sequence of 10-30 amino acids (see claim 24). SEQ ID NO:19 of Estruch et al. corresponds to SEQ ID NO:1 of the instant application and SEQ ID NO:20 corresponds to SEQ ID NO:2 of the instant application. The fusion protein of Estruch et al. is utilized as a detection agent for autoantibodies which bind calprotectin, therefore, the fusion protein would necessarily form a heterodimer that binds to the autoantibodies. Estruch et al. do not teach that the linker comprises a protease recognition sequence.
Chen et al. teach fusion protein linkers. Chen et al. teach cleavable linkers (see 3.3) that covalently join functional domains together to act as one molecule. Chen et al. teach that cleavable linkers can be introduced to release free functional domains in vivo. Chen et al. also teach that linkers can improve folding and stability of fusion proteins (see 5.1) as well as improve expression of fusion proteins (see 5.2).
It would have been obvious to one of ordinary skill in the art before the filing date of the instant invention to recombinantly produce calprotectin by expression of S100A8 and S100A9 as a fusion protein comprising a linker because calprotectin is a heterodimer of S100A8 and S100A9 and expression as a fusion protein would provide the two components in a single molecule such that they can associate and form a heterodimer. One would be motivated to express the calprotectin in this manner because Futami et al. teach that it requires extra energy to form a heterodimer from homodimers that need to dissociate and reassociate as the heterodimer. One of ordinary skill in the art would have been motivated to modify the method of Futami et al. which expresses the two subunits separately and express the two subunits as a fusion protein as taught by Estruch et al. Additionally, in light of Chen et al. who teach numerous types of linkers for forming fusion proteins, the use of a cleavable linker with a protease recognition sequence would have been an obvious choice because this type of linker would provide for the association of the two subunits of the heterodimer as well as the means for cleavage of the linker so that the proteins are not constricted by the linker. One would have had a reasonable expectation of success in obtaining a soluble calprotectin protein using a recombinant method and expressing the protein as a fusion protein because recombinant methods of producing proteins is old and well-known in the art. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine J Saoud whose telephone number is (571)272-0891. The examiner can normally be reached M-F, 8am-4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Z 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Christine J Saoud/Primary Examiner, Art Unit 1645
Prosecution Insights