DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
Claims 1-3, 5, 7, 10, 12, 14-24, 26, 28, 30, 33, 35-37, 39, 41, 43-46, 57-59, 67-69, 72, 75, and 83-85 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-3, 5, 7, 10, 12, 14-24, 26, 28, 30, 33, 35-37, 39, 41, 43, 44, 57-59, 67-69, 72, drawn to a polypeptide comprising (a) a b1 domain of neuropilin; and (b) an immunoglobulin domain, in the reply filed on 29 September 2025 is acknowledged.
Claims 45, 46, 75, and 83-85 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 29 September 2025.
Claims 1-3, 5, 7, 10, 12, 14-24, 26, 28, 30, 33, 35-37, 39, 41, 43, 44, 57-59, 67-69, 72 are under consideration in the instant application.
Drawings
1. The drawings are objected to for the following reasons:
1a. In Figures 1A, 1B, 2A, 2C, 3A, 3C, 13-18, 28-30, and 41, the text and numbers are blurry and/or too small, making the information illegible and difficult for the Examiner to interpret the data presented therein (see 37 CFR 1.84(p)). The text on top of shaded areas is also difficult to read. Applicant is reminded that numbers, letters, and reference characters must measure at least .32 cm. (1/8 inch) in height.
1b. In Figures 8, 9, 13-18, 25-34, 36, and 27-29, the different lines on the graphs cannot be differentiated from one another since they all appear as a gray/black line. It is suggested to change the lines to different patterns or utilize different symbols on the lines.
1c. Figure 41L is missing. There are panels for “41K” and “41M”, as well as a Brief Description for Figure 41L (page 17, [0094]), but the respective line graph is missing.
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.
2. Specific deficiencies and the required response to this Office Action are as follows:
2A. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See Figure 2C. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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.
2B. 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). Please see the following:
Claim 69
Page 7, [0025]
Page 8, [0031]
Page 10, [0038]
Page 11, [0040]
Page 95, [0300]
Page 96, [0302]
Page 99, [0320]
Page 100, [0323]
Pages 185-191, Tables 36-37
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.
2C. 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. Specifically, the incorporation by reference paragraph does not identify the size of the text file in bytes. Rather, the paragraph indicates that the file is 980 KB (kilobytes).
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.
Specification
3. The disclosure is objected to because of the following informalities:
3a. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see page 123, [0473]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
3b. At page 31, in the first sentence of [0157], the second recitation of neuropilin-1 is a typographical error and should be amended to recite neuropilin-2 (see bold/underline below):
Neuropilin, a transmembrane glycoprotein, is divided into two types: neuropilin-1 (NRP1; the human NRP1 amino acid sequence is provided as SEQ ID NO:1) and neuropilin-1 (NRP2; the human NRP2 amino acid sequence is provided as SEQ ID NO:1) (Kolodkin et al. 1997).
Appropriate correction is required.
Claim Objections
4. Claims 17, 23, 36, 41, and 57 are objected to because of the following informalities:.
4a. In claims 17, 23, and 41, the b1 domain, linker, and signal peptide sequences are amino acid sequences, not sequence identifiers (SEQ ID NO:). Thus, for clarity, claim 17 could be amended to recite, for example, “…wherein the b1 domain, or derivative or fragment thereof [comprises the amino acid sequence selected from the group consisting of…”.
Similarly, claim 23 could be amended to recite, for example, “…wherein the linker [is] comprises the amino acid sequence selected from the group consisting of…”.
Claim 41 could be amended to recite, for example, “…wherein the signal peptide comprises the amino acid sequence of SEQ ID NO…”.
4b. In claim 57, line 8, the word “acid” is missing after the phrase “one or more amino”.
4c. In claim 57, line 8, the phrase “selected from groups consisting of” should recite “selected from the group consisting of”.
4d. In claim 57, lines 10-11, the phrase “the one or more one or more substitutions”, recites a duplicate phrase of “one or more” that should be deleted.
4e. Claim 36 is 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.
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 12, 20, 26, 28, 30, 33, 35, 37, 39, and 41 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. Claim 12 is rejected as being indefinite because the claim references specific amino acid mutations as compared to an unmutated neuropilin b1 domain. However, the metes and bounds of the claim cannot be determined because it is not clear what neuropilin b1 domain the claim is referencing. For instance, is it murine, human? From Neuropilin-1 or Neuropilin-2? Without knowing the species or a sequence identifier of the wild-type neuropilin b1 domain, one skilled in the art would not be apprised of the correct locations of the amino acid mutations.
5b. Claim 20 is rejected as being indefinite because the claim references specific amino acid mutations as compared to in an ACE2 domain. However, the metes and bounds of the claim cannot be determined because it is not clear what ACE2 domain the claim is referencing. For instance, is it murine, human, or something else? Without knowing the species or a sequence identifier of the wild-type ACE2 domain, one skilled in the art would not be apprised of the correct locations of the amino acid mutations.
5c. Claims 26, 28, 30 are rejected as being indefinite because the claim refers to a Fc domain while also reciting specific mutations at specific amino acid positions. The metes and bounds of the claims cannot be determined because it is not clear what Fc molecule these mutations are referring to. For instance, are the mutations in IgG1, IgG2, IgG3, IgG4, or IgA? Without knowing the reference Fc molecule, one skilled in the art would not be apprised of the correct locations of the amino acid mutations.
5d. Claim 33 recites the following limitations in lines 3-9:
"IgG1 WT",
“ACE2-1”,
“b1b2”,
“IgG1 (T307A/E380A/N434A)”,
“ACE2-2”,
“G4S*2”,
“IgG1 (N297A)”,
“ACE2-3”,
“IgG1 (L324A/L325A)”,
“ACE2-4”,
“b1(E319A)”,
“IgG1 (N297A/T307A/E380A/N434A)”,
“ACE2-5”,
“b1(K351A)”,
“IgG1 (L324A/L325A/ T307A/E380A/N434A)”, and
“ACE2-6”.
There is insufficient antecedent basis for these limitations in the claim. Claims 1 and 2, from which claim 35 depends, do not recite any of the components recited above. Applicant is also reminded that while claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
5e. Claim 35 recites the limitation "the Fc domain" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claims 18 and 2, from which claim 33 depends, does not recite a Fc domain.
5f. Claim 37 recites the limitation "the Fc domain" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 37 depends, does not recite a Fc domain.
5g. Claim 39 recites the limitation "the Fc domain" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 2, from which claim 39 depends, does not recite a Fc domain.
5h. Claim 41 is rejected as being indefinite because lines 2-3 recite that the polypeptide further comprises a signal peptide and wherein the signal peptide comprises SEQ ID NO: 51. However, the specification (at page 47, Table 4) and the sequence listing identify SEQ ID NO: 51 as a linker domain sequence, and not a signal peptide. Therefore, claim 41 is incomplete because it is not clear what amino acid sequence is encompassed for the signal peptide. The metes and bounds of the claim cannot be determined. It is noted to Applicant that the instant specification discloses one possible signal peptide as comprising the amino acid sequence of SEQ ID NO: 53 (page 47).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claim 23 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 22 recites the polypeptide of claim 2, further comprising a linker between the b1 domain and ACE2 domain.
Claim 23 recites the polypeptide of claim 22, wherein the linker is selected from the group consisting of SEQ ID NOs: 44-50.
However, the amino acid sequences of SEQ ID NOs: 44 and 45 are not linker sequences according to the instant specification. Rather, the amino acid sequences of SEQ ID NOs: 44 and 45 are ACE2 domain sequences (see Table 3 at page 46). Table 4 at pages 46-47 only lists linkers comprising the amino acid sequence of SEQ ID NOs: 46-52. Therefore, claim 23 is of improper dependent form because it fails to further limit the subject matter of claim 22.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
7. Claims 1-3, 5, 10, 12, 14-16, 18-24, 26, 28, 30, 33, 35, 37, 39, 41, 43, 44, 57-59, 67-69, and 72 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 polypeptide comprising: (a) a b1 domain, or a derivative or fragment thereof, of a neuropilin; and (b) an immunoglobulin domain, wherein the b1 domain is capable of binding to a coat protein of a virus.
Instant claim 2 recites that the polypeptide of claim 1 further comprises an ACE2 domain, or a derivative or a fragment thereof, of an angiotensin enzyme 2.
Claim 57 recites a recombinant polypeptide comprising: (a) one or more neuropilin (NRP) b1 domains, NRP b2 domains, or fragments thereof, and (b) an immunoglobulin Fc domain; wherein one or more NRP b1 domains, NRP b2 domains, or fragments thereof are derived from an NRP1 or an NRP2 protein; wherein the one or more mutant NRP b1 domains, NRP b2 domains, or fragments thereof have one or more amino [acid] substitutions selected from groups consisting of: K373E, K351A, E319A, K358E, R513E, K514E, K516E, R513A, K514A, K516A, Y297A, S345A, and Y353A, relative to the wild-type amino acid sequence set forth in SEQ ID NO: 1; and wherein the one or more amino acid substitutions result in reduced binding of the recombinant polypeptide to heparin or heparan sulfate.
Claim 72 recites the recombinant polypeptide of claim 1, comprising an amino acid sequence that is at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201, or a pharmaceutically acceptable salt thereof. The specification of the instant application teaches that the present invention relates to fusion protein compositions, more specifically, polypeptides comprising a combination of neuropilin-1 (NRP1) domain, neuropilin-2 (NRP2) domain, angiotensin converting enzyme 2 (ACE2) domain, and/or an immunoglobulin domain that can be used to specifically bind a coat protein of a virus particle such as a S protein of a COVID-19 virus. The specification discloses that Neuropilin is divided into two types: neuropilin-1 (human NRP1 amino acid sequence is provided as SEQ ID NO:1) and neuropilin-2 (human NRP2 amino acid sequence is provided as SEQ ID NO:1) (page 31, [0157]). The specification indicates that NRP1 and NRP2 show an amino acid sequence homology of about 44%, and share several biological activities and structural aspects, such as extracellular al, a2, bl, b2 and MAM domains and an intracellular PDZ-binding domain (page 31, [0157]). At pages 33-37, the specification provides specific amino acid sequences for full-length NRP1 and NRP2; NRP1 b1; NRP2 b1; NRP1 b1b2; and NRP2 b1b2 (Table 1). The specification also provides NRP1 and NRP2 b1 amino acid sequences with substitutions at E319A; K351A; and Y297A, S346A, and Y353A (Table 1).
Regarding ACE2, the specification discloses that a crystal structure of ACE2 bound to an S protein fragment containing the recognition binding domain (RBD) (residues 306 to 527) shows that ACE2 residues Q24, T27, K31, H34, E37, D38, Y41, Q42, L45, L79, M82, Y83, N90, Q325, E329, N330, K353 and G354 make direct contact with the RBD (page 43, [0187]). The specification states that most key residues involved in S-protein binding are found on the N-terminal back-to-back alpha helices 1 and 2 (page 43, [0187]). At page 43 [0188] and pages 44-46 (Table 3), the specification teaches specific domain sequences for ACE2.
However, the specification does not provide a definition for or example of (i) a neuropilin b1 domain derivative or fragment and (ii) an ACE2 domain derivative or fragment.
In the instant case, the only factors present in the claims are requirements that the polypeptide comprises a neuropilin b1 domain or a derivative or fragment thereof that is capable of binding to a coat protein of a virus; an ACE2 domain derivative or fragment thereof that is capable of binding to a coat protein of a virus (claim 5); and a recombinant polypeptide amino acid sequence that is at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201. There is no identification of any particular structure or component of the neuropilin b1 domain derivative or fragment; ACE2 domain derivative or fragment; or recombinant polypeptide amino acid sequence that must be conserved in order to provide the required function of binding to a coat protein of a virus (see for example, claims 1, 5, and 59). Therefore, the claims are drawn to a genus of neuropilin b1 domain derivatives or fragments; a genus of ACE2 domain derivatives or fragments; and a genus of recombinant polypeptide amino acid sequences that are at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201.
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 (1) structural requirements that the polypeptide comprises a neuropilin b1 domain or a derivative or fragment thereof; an ACE2 domain derivative or fragment thereof; and a recombinant polypeptide amino acid sequence that is at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201; and (2) a functional requirement of binding to a coat protein of a virus. There is no identification of any particular sequence or structure of structure of a neuropilin b1 domain or a derivative or fragment thereof; an ACE2 domain derivative or fragment thereof; and a recombinant polypeptide amino acid sequence that is at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201 that must be conserved in order to provide the required function of binding to a coat protein of a virus. Thus, the claims are drawn to a genus of neuropilin b1 domain derivatives or fragments; a genus of ACE2 domain derivatives or fragments; and a genus of recombinant polypeptide amino acid sequences that are at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of (i) the genus of neuropilin b1 domain derivatives or fragments; (ii) the genus of ACE2 domain derivatives or fragments; (iii) the genus of recombinant polypeptide amino acid sequences that are at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201; and the function of binding to a coat protein of a virus. In other words, the specification does not teach the structure which results in a polypeptide comprising neuropilin and ACE2 domains with the claimed required characteristics. The description in the prior art and the specification of the full-length NRP1 and NRP2 sequences; full length NRP1 and NRP2 b1 and b2 domains; NRP1 and NRP2 b1/b2 domains with specific substitutions (pages 33-37 of instant specification); specific ACE2 domains (pages 43-47 of instant specification); and full length polypeptide amino acid sequences of SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201 are not adequate written description of an entire genus of (i) neuropilin b1 domain derivatives or fragments; (ii) ACE2 domain derivatives or fragments; and (iii) recombinant polypeptide amino acid sequences that are at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201.
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, Herzog et al. (Mol Bio Cell 22: 2766-2776, 2011) teach that mutations in the NRP1 b1 domain (Y297A and D320A) result in complete loss of VEGF binding to NRP1 (abstract; page 2767, entire column 1 through page 2770, top of column 1). Geretti et al. also teach that exchange of electronegative residues in b1b2 NRP2 to neutral ones (E284A, E291A) show a 2-fold reduced affinity for VEGF binding (J Biol Chem 287(35): 25698-25707, 2007; page 25699, top of column 1; abstract; page 25702, column 2; Table 2). Conversely, increasing the electronegative potential in b1b2 NRP2 (R287E, N290S/D) increases affinity for VEGF binding by 8-fold (Geretti et al., page 25699, column 1; page 25702, column 2; Table 2).
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 (i) the genus of neuropilin b1 domain derivatives or fragments; (ii) the genus of ACE2 domain derivatives or fragments; (iii) the genus of recombinant polypeptide amino acid sequences that are at least 90% identical to an amino acid sequence set forth in any one or SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201 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 neuropilin b1 domain, ACE2 domain, and full length polypeptides (of SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201) are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet 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).
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.
8. Claims 1, 7, 16, 17, 24, 26, and 37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Burkart et al. (WO 2020/023918, published 30 January 2020; cited on the PTO-892 of 24 September 2025).
Burkart et al. teach a polypeptide comprising (a) a b1 domain or Neuropilin-2 and (b) an Fc domain, meeting the limitations of instant claims 1 and 37 (page 87; Table N1, SEQ ID NOs: 196-197). Burkart et al. disclose that the Fc domain is derived from a human IgG immunoglobulin, including subclasses IgG1, IgG2, IgG3, and/or IgG4, meeting the limitations of instant claim 24 (page 60, last paragraph; page 53). Burkart et al. teach that the Fc domain comprises a mutation at N297, meeting the limitations of instant claim 26 (page 74, last six lines at the bottom of the page; page 75, 1st full paragraph)
It is noted that amino acids 255-405 of SEQ ID NO: 196 of Burkart et al. comprise the b1 amino acid sequence of SEQ ID NO: 11 of instant claims 7 and 17 (see Burkart et al., page 87). See also sequence alignment, below.
Qy= instant SEQ ID NO: 11
Db= amino acids 255-405 of SEQ ID NO: 196 of Burkart et al.
Query Match 100.0%; Score 807; DB 1; Length 1060;
Best Local Similarity 100.0%;
Matches 151; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CNVPLGMESGRIANEQISASSTYSDGRWTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 255 CNVPLGMESGRIANEQISASSTYSDGRWTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFL 314
Qy 61 TMLTAIA TQGAISRETQNGYYVKSYKLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 315 TMLTAIA TQGAISRETQNGYYVKSYKLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLN 374
Qy 121 KLHAPLLTRFVRIRPQTWHSGIALRLELFGC 151
|||||||||||||||||||||||||||||||
Db 375 KLHAPLLTRFVRIRPQTWHSGIALRLELFGC 405
Additionally, amino acids 133-283 of SEQ ID NO: 197 of Burkart et al. comprise the b1 amino acid sequence of SEQ ID NO: 11 of instant claim 7 (see Burkart et al., page 87). See also sequence alignment, below.
Qy= instant SEQ ID NO: 11
Db= amino acids 133-283 of SEQ ID NO: 197 of Burkart et al.
Query Match 100.0%; Score 807; DB 1; Length 678;
Best Local Similarity 100.0%;
Matches 151; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CNVPLGMESGRIANEQISASSTYSDGRWTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 133 CNVPLGMESGRIANEQISASSTYSDGRWTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFL 192
Qy 61 TMLTAIA TQGAISRETQNGYYVKSYKLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 193 TMLTAIA TQGAISRETQNGYYVKSYKLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLN 252
Qy 121 KLHAPLLTRFVRIRPQTWHSGIALRLELFGC 151
|||||||||||||||||||||||||||||||
Db 253 KLHAPLLTRFVRIRPQTWHSGIALRLELFGC 283
The Neuropilin-2 fusion polypeptides of Burkart et al. also comprise a linker (“RVTDAP”, instant SEQ ID NO: 48) and a b2 domain of Neuropilin-2, meeting the limitations of instant claim 16 (for example, see SEQ ID NO: 197 of Burkart et al reproduced below. Italics=b1 domain of Nrp2; bold=linker; underlined=b2 domain of Nrp2).
GSEDCSKNFTSPNGTIESPGFPEKYPHNLDCTFTILAKPKMEIILQFLIFDLEHDPLQVGEGDCKYDWLDIWDGIPHVGPLIGKYCGTKTPSELRSSTGILSLTFHTDMAVAKDGFSARYYLVHQEPLENFQCNVPLGMESGRIANEQISASSTYSDGRWTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFLTMLTAIA TQGAISRETQNGYYVKSYKLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLNKLHAPLLTRFVRIRPQTWHSGIALRLELFGCRVTDAPCSNMLGMLSGLIADSQISASSTQEYLWSPSAARLVSSRSGWFPRIPQAQPGEEWLQVDLGTPKTVKGVIIQGARGGDSITAVEARAFVRKFKVSYSLNGKDWEYIQDPRTQQPKLFEGNMHYDTPDIRRFDPIPAQYVRVYPERWSPAGIGMRLEVLGCDWTDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
9. Claims 1, 7, 16, 24, 37, 41, 43, 44, and 72 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sapieha et al. (US 2017/0283502).
Sapieha et al. teach a “trap” polypeptide comprising a b1 domain of neuropilin-1 (NRP1) and a human IgG1 Fc domain, meeting the limitations of instant claims 1, 24, and 37 (Figures 19-20; pages 11-12, Table 1; page 13, [0165]; page 24, [0249, 0251]). It is noted that several of the trap polypeptides comprise a NRP1 b2 domain and/or a linker, meeting the limitations of instant claim 16 (see Figure 19; pages 11-12, Table 1; page 13, [0166]). Sapieha et al. indicate that the NRP1 traps initially comprise a signal peptide, which is cleaved upon cell secretion, meeting the limitations of instant claim 41 (page 11, [0157]; Figure 26). Sapieha et al. disclose a method of producing the NRP1-Fc trap polypeptide comprising transfecting a vector encoding the fusion construct into 293T cells, growing the cells, and purifying the expressed trap polypeptide, meeting the limitations of instant claim 43 (page 24, [0250-0253]). Sapieha et al. also teach a sterile formulation of the purified traps for in vivo injection, meeting the limitations of instant claim 44 (page 24, [0254]).
It is noted that amino acids 254-403 of SEQ ID NO: 1 of Sapieha et al., for example, comprise the b1 amino acid sequence of SEQ ID NO: 3 of instant claim 7 (see Sapieha et al., page 11, Table 1). See also sequence alignment, below.
Qy= instant SEQ ID NO: 3
Db= amino acids 254-403 of SEQ ID NO: 1 of Sapieha et al.
RESULT 1
AASEQ2_01152026_182707
Query Match 100.0%; Score 801; DB 1; Length 560;
Best Local Similarity 100.0%;
Matches 150; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CMEALGMESGEIHSDQITASSQYSTNWSAERSRLNYPENGWTPGEDSYREWIQVDLGLLR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 254 CMEALGMESGEIHSDQITASSQYSTNWSAERSRLNYPENGWTPGEDSYREWIQVDLGLLR 313
Qy 61 FVTAVGTQGAISKETKKKYYVKTYKIDVSSNGEDWITIKEGNKPVLFQGNTNPTDVVVAV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 314 FVTAVGTQGAISKETKKKYYVKTYKIDVSSNGEDWITIKEGNKPVLFQGNTNPTDVVVAV 373
Qy 121 FPKPLITRFVRIKPATWETGISMRFEVYGC 150
||||||||||||||||||||||||||||||
Db 374 FPKPLITRFVRIKPATWETGISMRFEVYGC 403
Furthermore, the amino acid sequence of SEQ ID NO: 11 of Sapieha et al. comprises a sequence that is 94.1% identical to the instant amino acid sequence of SEQ ID NO: 113, meeting the limitations of instant claim 72 (see sequence alignment below).
Qy= instant SEQ ID NO: 113
Db= SEQ ID NO: 11 of Sapieha et al.
US-15-507-407-11
Sequence 11, US/15507407
GENERAL INFORMATION
APPLICANT: RSEM, LIMITED PARTNERSHIP
APPLICANT: Sapieha, Przemyslaw
APPLICANT: Beaulieu, Normand
TITLE OF INVENTION: COMPOSITIONS AND METHODS FOR TREATING AND PREVENTING INFLAMMATION
FILE REFERENCE: 7386-98565-01
CURRENT APPLICATION NUMBER: US/15/507,407
CURRENT FILING DATE: 2017-02-28
PRIOR APPLICATION NUMBER: US 62/046,459
PRIOR FILING DATE: 2014-09-05
PRIOR APPLICATION NUMBER: PCT/CA2015/050862
PRIOR FILING DATE: 2015-09-08
NUMBER OF SEQ ID NOS: 128
SEQ ID NO 11
LENGTH: 632
TYPE: PRT
ORGANISM: artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic polypeptide
Query Match 94.1%; Score 2012.5; Length 632;
Best Local Similarity 94.9%;
Matches 376; Conservative 2; Mismatches 5; Indels 13; Gaps 1;
Qy 1 EDFKCMEALGMESGEIHSDQITASSQYSTNWSAERSRLNYPENGWTPGEDSYREWIQVDL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 250 EDFKCMEALGMESGEIHSDQITASSQYSTNWSAERSRLNYPENGWTPGEDSYREWIQVDL 309
Qy 61 GLLRFVTAVGTQGAISKETKKKYYVKTYKIDVSSNGEDWITIKEGNKPVLFQGNTNPTDV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 310 GLLRFVTAVGTQGAISKETKKKYYVKTYKIDVSSNGEDWITIKEGNKPVLFQGNTNPTDV 369
Qy 121 VVAVFPKPLITRFVRIKPATWETGISMRFEVYGCGGGGSGGGGSEPKSCDKTHTCPPCPA 180
|||||||||||||||||||||||||||||||||| |||||||||||
Db 370 VVAVFPKPLITRFVRIKPATWETGISMRFEVYGC-------------RSDKTHTCPPCPA 416
Qy 181 PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 417 PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 476
Qy 241 REEQYNSTYRVVSVLAVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL 300
||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||
Db 477 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL 536
Qy 301 PPSRDELTKNQVSLTCLVKGFYPSDIAVAWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 360
||||:|:||||||||||||||||||||| |||||||||||||||||||||||||||||||
Db 537 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 596
Qy 361 VDKSRWQQGNVFSCSVMHEALHAHYTQKSLSLSPGK 396
|||||||||||||||||||||| |||||||||||||
Db 597 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 632
It is also noted that the amino acid sequences of SEQ ID NOs: 9 and 118 of Sapieha et al. comprises a sequence that is 96.3% identical to the instant amino acid sequence of SEQ ID NO: 122, meeting the limitations of instant claim 72.
Conclusion
No claims are allowable.
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BEB
Art Unit 1647
14 January 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647