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 .
Election/Restrictions
Applicant's election with traverse of Group 1, claims 1-17, drawn to an isolated peptide in the reply filed on 10/6/2025 is acknowledged. The traversal is on the ground(s) that it would not be unduly burdensome to perform a search on all of the claims together in the present application. This is not found persuasive because the inventions recited in Groups I-III in the Election/Restriction Requirement have separate statuses in the art in view of their different classifications. The inventions have separate statuses in the art due to their divergent subject matter. The inventions require different search queries. These require search of several different inventive concepts. Also, each invention is likely to raise different issues under 35 USC 101 and 112, first paragraph.
Thus, the requirement is still deemed proper and is therefore made FINAL.
Applicant’s election of the species SEQ ID NO: 5 in the reply filed on 10/6/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further search and examination, the species election was broadened to include a first protein moiety comprising residues 113-231 of SEQ ID NO: 2 in addition to the elected species of SEQ ID NO: 5.
Claim Status
Claims 1-20 are pending. Claims 18-20 are hereby withdrawn as non-elected inventions (claims 18-20).
Priority
The instant application is a continuation-in-part of PCT/EP2021/059434, filed 4/12/2021. The priority date of 4/12/2021 is acknowledged.
Information Disclosure Statement
The IDS submitted on 10/12/2022 is under consideration.
Drawings
Figures 1 and 2 should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. See MPEP § 608.02(g). Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. 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.
Further, the drawings are objected to because Figures 4-6, 8-9, and 11-12 depict various types of staining in color but the image is in black and white, making it difficult to interpret. 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.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 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.
The file size must be listed in bytes instead of kilobytes.
Specific deficiency – The "Sequence Listing" has not been entered into the application because the required statement of no new matter is missing. See 37 CFR 1.825(a)(4) or 1.825(b)(5).
Required response – Applicant must provide:
A proper statement of no new matter.
Because the latest CRFE was filed after the initial filing date, a statement of no new matter is required.
Specification
The abstract of the disclosure is objected to because it is more than 150 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Interpretation
Claim 1 recites “An isolated protein comprising (i) a first protein moiety… comprising an amino acid sequence having at least 70% identity to residues 113-231 of SEQ ID NO: 2” (emphasis added). This claim is being interpreted as a peptide comprising residues 113-231 of SEQ ID NO: 2, wherein a peptide or protein encompassing or containing the entirety of residues 113-231 of SEQ ID NO: 2 meets the limitation of the claim. Conversely, smaller fragments encompassed by SEQ ID NO: 1 (i.e., dipeptides) are being interpreted as not meeting the limitations of the claim. This same interpretation is being applied to claims 2 and 3.
Additionally, “an isolated protein”, as recited above in claim 1, is being interpreted as a recombinant protein, comprising a first moiety and a second moiety (fusion protein).
Claim Rejections - 35 USC § 112
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.
Claims 1-8 and 11-17 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.
Claim 1 recites that the isolated protein comprises (ii) a second protein or polypeptide moiety, preferably containing at least 50 amino acid residues. The scope of this claim is indefinite, as it is unclear whether the second protein or polypeptide moiety be any length or must be greater than 50 amino acids. Further, by virtue of their dependency on claim 1, claims 2-8, and 11-17 are also hereby rejected for this same reasoning. For purposes of examination, the claim is being interpreted as the second protein or polypeptide can be of any length.
Claims 7-10 are further rejected for reciting both open and closed language without a clear distinction or cutoff between the protein domains recited.
Claim 1 recites an isolated polypeptide comprising 1) a first protein moiety selected from a group of proteins comprising sequences with at least 70% identity to various Bri2 domains; and 2) a second protein or polypeptide moiety, preferably containing at least 50 amino acids (emphasis added). As stated above, the length limitation of the second protein or polypeptide moiety has been interpreted to be any length. Collectively, these limitations do not place limitations on the length of either the first or the second protein moiety. There are also no limitations regarding where the first moiety ends and the second moiety begins.
Claims 7-10, which all depend from claim 1, subsequently limit the length of either the first protein moiety (claims 7 and 8) or the second one (claims 9 and 10). The scope of these claims are indefinite as there are inconsistencies between the closed limitations (i.e., length limitations) and open limitations (i.e., a moiety comprising) of the claim.
For purposes of examination, claims 7 and 8 have been interpreted as an isolated polypeptide comprising 1) a first protein moiety consisting of a sequence with at least 70% identity to various Bri2 domains that is less than or equal to 200 amino acids (claim 7) or more than or equal to 90 amino acids (claim 8). Claims 9 and 10 have been interpreted as an isolated polypeptide comprising 2) a second protein or polypeptide moiety that is 500-2000 amino acid residues (claim 9) or 5-200kDa (claim 10).
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.
Claim 15 is 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 15 recites that the second protein or polypeptide moiety is selected from the group consisting of “enzymes known to be genetically mutated, and therefore functionally deficient in lysosomal storage diseases (LSDs).” The rejection is based on this limitation, which recites a feature by functional rather than structural language. There is nothing further in the claim to indicate the structural feature(s) required to meet this functional limitation, and describing an invention by function is insufficient to meet the written description requirement.
Per MPEP 2163(II)(3)(a), for some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. As explained by the Federal Circuit, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure." Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006); see also Capon v. Eshhar, 418 F.3d at 1358, 76 USPQ2d at 1084 ("The Board erred in holding that the specifications do not meet the written description requirement because they do not reiterate the structure or formula or chemical name for the nucleotide sequences of the claimed chimeric genes" where the genes were novel combinations of known DNA segments.). However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
Applicants have disclosed lysosomal acid lipase as one enzyme that can serve as the second protein or polypeptide moiety. No others are disclosed within the instant specification, and the claims listed above are written such that they contemplate or include additional compounds that retain the same functional characteristics beyond these limited examples. Thus, the instant specification does not provide adequate written description to possess the broad genus described above.
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.
Claims 16 and 17 are 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 16 recites that the isolated protein is a recombinant fusion protein. Claim 16 depends from claim 1, which recites an isolated protein comprising a fusion protein (a first protein moiety and a second protein or polypeptide moiety) that is not a wild-type Bri2 protein. An isolated protein that necessarily meets these claim limitations must be a recombinant fusion protein, as it would be impossible to isolate such a protein from something naturally-occurring. Thus, claim 16 does not further limit claim 1.
Claim 17 recites that the first protein moiety is chemically linked to said second protein moiety. As stated above, claim 1, from which claim 17 depends, recites a fusion protein. A fusion protein would necessarily require a chemical linkage between the first protein moiety and the second protein moiety to connect them. Thus, claim 17 does not 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 § 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-11, 16, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. (Chen, G., Andrade-Talavera, Y., Tambaro, S. et al. Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro. Commun Biol 3, 32 (2020)., cited on IDS filed 10/12/2022), as evidenced by Kronqvist et al. (Efficient protein production inspired by how spiders make silk. Nat Commun 8, 15504 (2017).) and Promega (Amino Acid Structure, accessed 11/25/2025).
Chen teaches that the BRICHOS domain of recombinant human Bri2 can be used to efficiently inhibit amyloid formation, particularly Aβ42 fibril formation in vitro and in alleviating the related neurotoxicity to hippocampal slice preparations and in Drosophila models (Pg 2, left column, bottom paragraph).
Chen describes generating recombinant human Bri2 BRICHOS fusion proteins comprising the His6-NT* solubility tag (protein tag) chemically linked to Bri2 residues 113-231 (Pg 9, left column, “Rh Bri2 BRICHOS R221E and Bri2 BRICHOS-AU1 preparation”). As evidenced by the instant specification, residues 113-231 of Bri2 are identical to the instant SEQ ID NO: 2, which also encompasses the instant SEQ ID NO: 5 (List of appended sequences, Pg 7-9). Chen also teaches the addition of AU1 tag (DTYRYI, another protein tag) or an mCherry domain (fluorescent protein) to residues 113-231 of Bri2. Thus, Chen anticipates claims 1-4, 11, 16, and 17. Additionally, as evidenced by the instant Sequence Listing, the instant SEQ ID NO: 2 and SEQ ID NO: 5 are both more than 90 but less than 200 amino acids. Thus, by teaching a fusion polypeptide comprising residues 113-231 of Bri2, Chen also anticipates claims 7 and 8.
Chen further teaches that the monomeric form of Bri2 BRICHOS is most desirable as it is the most potent in preventing Aβ42-induced disruption of neuronal network activity and accumulation of oligomers may contribute to Alzheimer’s disease (Pg 2, right column, first and second paragraphs before “Results”). Thus, it is desirable to introduce mutations that can stabilize Bri2 BRICHOS in the monomeric state, such as substituted Arg for Glu at position 221 (Pg 2-3, “R221E mutant forms stable monomers and unstable oligomers”; Pg 9, left column, “Rh Bri2 BRICHOS R221E and Bri2 BRICHOS-AU1 preparation”). Thus, claims 5 and 6 are anticipated.
As evidenced by Kronqvist, the solubility tag NT* ranges from 133-151 amino acids, depending on whether the His6 tag and any additional cleavage sites are included (see Supplementary Figure 2). As evidenced by Promega, the average molecular weight of an amino acid is 110Da. Thus, a second protein or polypeptide motif of 133-151 residues would result in a molecular weight of ~133-151kDa. Thus, claims 9 and 10 are anticipated.
Claim(s) 1-4, 7-11, 16 and 17 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Johansson et al. (US20180273590 A1, published 9/27/2018), as evidenced by Promega (Amino Acid Structure, accessed 11/25/2025).
Johansson teaches fusion proteins comprising a moiety of 100-160 amino acid residues having at least 70% identity with the N-terminal (NT) fragment of a spider silk protein, wherein the NT protein can enhance the solubility of another moiety in the fusion protein (Abstract). Johansson teaches that an object of the invention is to provide a method for improved recombinant protein production ([0013]). Johansson specifically teaches SEQ ID NO: 66 and 67, which comprise N-terminal Hisx6 and either the wild-type or modified *NT protein tag chemically linked to residues 113-231 of Bri2 (the instant SEQ ID NO: 2), which itself comprises the instant SEQ ID NO: 5 (Sequence Listing). Thus, Johansson anticipates claims 1-4, 11, 16, and 17.
Further, both SEQ ID NO: 2 and SEQ ID NO: 5 are greater than 90 but less than 200 residues, per the instant Sequence Listing. Thus, Johansson also anticipates claims 7 and 8.
Johansson teaches that the His6- wild-type or * NT tag of SEQ ID NO: 66 and 67, respectively, consist of 151 amino acid residues . As evidenced by Promega, the average molecular weight of an amino acid is 110Da. Thus, a second protein or polypeptide motif of 151 residues would result in a molecular weight of ~151kDa. Thus, claims 9 and 10 are anticipated.
Claim(s) 1-4, 7-11, 16 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tambaro et al. (Blood-brain and blood-cerebrospinal fluid passage of BRICHOS domains from two molecular chaperones in mice. J Biol Chem. 2019 Feb 22;294(8):2606-2615., cited on the IDS filed 10/12/2022), as evidenced by Kronqvist et al. (Efficient protein production inspired by how spiders make silk. Nat Commun 8, 15504 (2017).) and Promega (Amino Acid Structure, accessed 11/25/2025).
Tambaro teaches that recombinant human Bri2 BRICHOS domains can cross the blood-brain barrier in mice and represent a new therapeutic strategy for managing Alzheimer’s disease (Abstract). The protein comprises an N-terminal His6-NT* protein tag, chemically linked to recombinant human Bri2 BRICHOS domain corresponding to residues 113-231 of the full-length human Bri2, chemically linked to a C-terminal AU1 tag (DTYRYI) (Pg 2612, “Rh Bri2 BRICHOS”). As evidenced by the instant specification, residues 113-231 of Bri2 are identical to the instant SEQ ID NO: 2, which also encompasses the instant SEQ ID NO: 5 (List of appended sequences, Pg 7-9). Thus, Tambaro anticipates claims 1-4, 11, 16, and 17. Additionally, as evidenced by the instant Sequence Listing, the instant SEQ ID NO: 2 and SEQ ID NO: 5 are both more than 90 but less than 200 amino acids. Thus, by teaching a fusion polypeptide comprising residues 113-231 of Bri2, Chen also anticipates claims 7 and 8.
As evidenced by Kronqvist, the solubility tag NT* ranges from 133-151 amino acids, depending on whether the His6 tag is included in addition to any cleavage sites (see Supplementary Figure 2). As evidenced by Promega, the average molecular weight of an amino acid is 110Da. Thus, a second protein or polypeptide motif of 133-151 residues would result in a molecular weight of ~133-151kDa. Thus, claims 9 and 10 are anticipated.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Tambaro et al. (Blood-brain and blood-cerebrospinal fluid passage of BRICHOS domains from two molecular chaperones in mice. J Biol Chem. 2019 Feb 22;294(8):2606-2615.), as evidenced by Kronqvist et al. (Efficient protein production inspired by how spiders make silk. Nat Commun 8, 15504 (2017).) and Promega (Amino Acid Structure, accessed 11/25/2025), in view of Chen et al. (Chen, G., Andrade-Talavera, Y., Tambaro, S. et al. Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro. Commun Biol 3, 32 (2020)., cited on IDS filed 10/12/2022).
The teachings of Tambaro have been set forth above. Tambaro does not teach mutating the residue equivalent to residue 221 in SEQ ID NO: 1 into Glu or Asp.
Chen further teaches that the monomeric form of Bri2 BRICHOS is most desirable as it is the most potent form for preventing Aβ42-induced disruption of neuronal network activity and accumulation of oligomers may contribute to Alzheimer’s disease (Pg 2, right column, first and second paragraphs before “Results”). Thus, it is desirable to introduce mutations that can stabilize Bri2 BRICHOS in the monomeric state, such as substituted Arg for Glu at position 221 (Pg 2-3, “R221E mutant forms stable monomers and unstable oligomers”; Pg 9, left column, “Rh Bri2 BRICHOS R221E and Bri2 BRICHOS-AU1 preparation”).
Thus, regarding claims 5 and 6, Tambaro teaches that recombinant human Bri2 BRICHOS domains can cross the blood-brain barrier in mice and represent a new therapeutic strategy for managing Alzheimer’s disease. Chen teaches that introducing Glu at position 221 of Bri2 BRICHOS stabilizes its monomeric form, which can best prevent Aβ42-induced disruption of neuronal network activity and does not further contribute to the disease manifestation. Therefore, it would be prima facie obvious to introduce a Glu to position 221 of the fusion peptide taught by Tambaro in order to increase the peptide’s potency. One skilled in the art would have a reasonable expectation of success as it was already established that Glu at this position further stabilizes the monomeric, and more potent, form of Bri2 BRICHOS.
Claim(s) 1-4 and 7-17 are rejected under 35 U.S.C. 103 as being unpatentable over Tambaro et al. (Blood-brain and blood-cerebrospinal fluid passage of BRICHOS domains from two molecular chaperones in mice. J Biol Chem. 2019 Feb 22;294(8):2606-2615.), as evidenced by Kronqvist et al. (Efficient protein production inspired by how spiders make silk. Nat Commun 8, 15504 (2017).) and Promega (Amino Acid Structure, accessed 11/25/2025), in view of Wolfe et al. (CA 2799470 A1, published 11/17/2011).
The teachings of Tambaro have been set forth above. Tambaro does not teach that the second protein or polypeptide moiety is an antibody.
Wolfe teaches fusion proteins comprising the bacterial derived C fragment of tetanus toxin (TCC), which can bind neurons and carry reporter proteins or therapeutic proteins useful in the treatment of neurological disorders (Abstract; Pg 4, lines 15-18; Pg 5, lines 26-34; Pg 6, lines 7-8). The therapeutic protein can be an antibody (Pg 6, lines 26 and lines 28-34).
Thus, regarding claim 12, Tambaro teaches fusion proteins comprising the instant SEQ ID NO: 2 and 5 chemically linked to protein tags can cross the blood-brain barrier, thereby representing a potential new avenue to administer therapeutics targeting Alzheimer’s and other neurological disorders. Wolfe teaches similar fusion proteins comprising the peptide TCC that can target therapeutic proteins to neurons useful in the treatment of neurological disorders. Therefore, it would be prima facie obvious to generate a fusion protein comprising the instant SEQ ID NO: 2 or 5 conjugated to a therapeutic such as an antibody in order to more effectively target said antibody to the brain. One skilled in the art would have a reasonable expectation of success as Tambaro had already established that fusion proteins comprising SEQ ID NO: 2 or 5 could effectively transport other proteins to the brain, such as the NT* tag.
Regarding claim 13, Wolfe teaches the therapeutic protein of the fusion protein can be growth factors such as epidermal growth factor, acidic and basic fibroblast growth factor, insulin-like growth factor, brain-derived neurotrophic growth factor, glial-derived neurotrophic factor, neutrophin-3, or platelet-derived growth factor (Pg 7, lines 4-16).
Regarding claims 14, Wolfe teaches the therapeutic protein of the fusion protein can be acidic α-glucosidase, iduronate-2-sulfatase, α-L-iduronidase, N-acetylgalactosamine-4-sulfatase, or α-galactosidase A (Pg 7, lines 24-27).
Regarding claim 15, Wolfe teaches the production and secretion of a fusion protein comprising TCC and the lysosomal enzyme β-D-glucuronidase, which is defective in mucopolysaccharidosis type VII (Pg 2, lines 24-28).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1-4, 7, and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 8,785,391 B2 (US ‘391). Although the claims at issue are not identical, they are not patentably distinct from each other because they contain overlapping subject matter.
Claim 1 of US ‘391 recites a method for therapeutically treating or delaying the progression of a condition selected from the group consisting of Alzheimer's disease, familial Danish dementia and familial British dementia in a mammal in need thereof, the method comprising administering to said mammal a therapeutically effective amount of an isolated protein, wherein the isolated protein decreases or reduces amyloid fibril formation and aggregation of amyloid β peptide, and wherein the isolated protein is selected from the group consisting of proteins comprising an amino acid sequence having at least 70% identity to residues 90-236 of Bri2 from human (SEQ ID NO: 2); and proteins comprising an amino acid sequence having at least 70% identity to any one of the Brichos domains of Bri2 from human (SEQ ID NO: 5), chimpanzee (SEQ ID NO: 6), bovine (SEQ ID NO: 7), pig (SEQ ID NO: 8), mouse (SEQ ID NO: 9) and rat (SEQ ID NO: 10); with the provisos that said protein is not comprising an amino acid sequence having at least 70% identity to residues 1-89 of Bri2 from human (SEQ ID NO: 3); and said protein is not comprising an amino acid sequence having at least 70% identity to human ABri23 (SEQ ID NO: 4). SEQ ID NO: 2 of US ‘391 exhibits 100% sequence identity to the instant SEQ ID NO: 2, and SEQ ID NO: 5 of US ‘391 and the instant SEQ ID NO: 5 are identical. Further, the instant specification states that an object of the invention is to provide a new treatment option for the treatment of Alzheimer’s (Pg 4, lines 24-25).
Dependent claims further include the percent identity (claims 2-4), the size of the isolated protein (claims 5-7), treatment of Alzheimer’s disease (claim 8), treating a human (claim 9), and the identity of the isolated protein (claims 10-13).
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-13, and 20-22 of copending Application No. 17/784,591 (‘591 reference application; claim set filed 9/10/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because they contain overlapping subject matter.
Claim 1 of copending Application No. ‘591 recites an isolated protein comprising a moiety of 90-200 amino acid residues having at least 70% identity to SEQ ID NO: 7, wherein the amino acid residue corresponding to position 221 in SEQ ID NO: 1 is selected from the group consisting of Glu and Asp. SEQ ID NO: 7 of copending Application No. ‘591 and the instant SEQ ID NO: 5 are identical. Claim 7 similarly recites an isolated protein comprising a moiety of 90-200 amino acid residues having at least 70% identity to SEQ ID NO: 7, wherein the amino acid residue corresponding to position 221 in SEQ ID NO: 7 is not Arg, Lys, or His, or a nucleic acid encoding the isolated protein for use as a medicament.
Dependent claims include modification of position 221 (claims 2, 5, 8-11, 13, and 22), the percent identity (claims 3 and 20-21), and the size of the overall isolated protein (claims 4 and 12). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-8, 11, 12, 16 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-8, 13, 14, 16, 20-26, 29, and 30 of copending Application No. 19/120,509 (‘509 reference application; claim set filed 4/11/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because they contain overlapping subject matter.
Claim 1 of copending Application No. ‘509 recites an isolated protein comprising:
(1) a first protein moiety selected from a group of proteins comprising an amino acid sequence having at least 70% identity to residues 113-231 of Bni2 from human (SEQ ID NO: 2); and proteins comprising an amino acid sequence having at least 70% identity to any one of the BRICHOS domains of Bri2 from human (SEQ ID NO: 5), chimpanzee (SEQ ID NO: 6), bovine (SEQ ID NO: 7), pig (SEQ ID NO: 8), mouse (SEQ ID NO: 9) and rat (SEQ ID NO: 10); and
(ii) a second protein or polypeptide moiety, preferably containing at least 50 amino acid residues, wherein the second protein or polypeptide moiety is a monoclonal antibody; wherein said isolated protein is not comprising an amino acid sequence having at least 70% identity to residues 1-89 of Bri2 from human (SEQ ID NO: 3); and wherein said isolated protein is not comprising an amino acid sequence having at least 70% identity to human ABni23 (SEQ ID NO: 4). SEQ ID NO: 2 and 5 of copending Application No. ‘509 are identical to the instant SEQ ID NO: 2 and 5, respectively.
Dependent claims include modification specific species of antibodies (claims 5-8), the isolated protein is a recombinant fusion protein (claims 13, 14), the percent identity (claim 16, 20-22), modification of position 221 (claims 23 and 24), and properties of the first and second protein moieties (claims 25, 26, 29, and 30). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Prior Art Cited but not Referenced
US20130172262A1 (published 7/4/2013) teaches proteins comprising at least 70% identity to SEQ ID NO: 5 or 90-236 residues of Bri2 from human (reads on SEQ ID NO: 2)
US20140030274A1 (published 1/30/2014) teaches a method involving screening candidates for activity in the treatment of a condition associated with formation of amyloid protein fibrils in a mammal comprising determining whether a chaperone protein is decreased in the presence of the candidate, wherein the chaperone protein has at least 70% identity to SEQ ID NO: 5 or residues 90-243 of Bri2 from human (reads on SEQ ID NO: 2)
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658