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 .
Claims 1-14 are pending.
Applicant’s election without traverse of Group I that read on N51/V343 as the species of amino acid residues in the reply filed on December 17, 2025 is acknowledged.
Claims 6-14 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-5, drawn to a particular stabilized angiotensin-converting enzyme 2 (Ace2) variant that read on N51/V343 as the species of amino acid residues, are being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 4, 2023 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on April 4, 2023 are acceptable.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objection
Claims 1-5 are objected to because of the following informalities: The [ ] should be removed.
Claim 3 is further objected to because of the following informality: “N51/V343” should have been “N51C and V343C”, for example.
Claim 4 is further objected to because of the following informality: “wherein the Ace2-derived protein is a protein derived from an ectodomain of an Ace2 protein” should have been “wherein the Ace2-derived protein is an ectodomain of an Ace2- protein”.
Claim 5 further objected to because of the following informality: “wherein the Ace2-derived protein comprises amino acid residues at positions 1 to 615 of a wild-type Ace2 protein” should have been “wherein the Ace2-derived protein comprises amino acid residues 1 to 615 of a wild-type Ace2 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 3 and 5 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 applicant regards as the invention.
The recitation of “N51/V343…Ace2-derived protein” in claim 3 is indefinite because the claim fails to provide any frame of reference that would allow one of skill in the art to unambiguously identify the positions being referred to in Ace2-derived protein without a sequence identifier or SEQ ID NO. Amending the claim to recite “SEQ ID NO: 1” would obviate this rejection.
The recitation of “wild-type” in claim 5 is indefinite because it is unclear whether “wild-type” is referring to human Ace2 or Wombat Ace2. MPEP 2173.02 states that "if the language of a claim, given its broadest reasonable interpretation, is such that a person of ordinary skill in the relevant art would read it with more than one reasonable interpretation, [a] rejection under 35 U.S.C. 112(b) or 2nd paragraph is appropriate.”
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses any stabilized angiotensin-converting enzyme 2 (Ace2) variant comprising a disulfide bond formed by substituting cysteine for any one or more of the amino acid residue pairs present in any Ace2-derived protein.
Claim 2 encompasses the stabilized Ace2 variant according to claim 1, wherein the distance between the central carbons (C-alphas) in the amino acid residue pairs forming the disulfide bond is from 4.5 to 7.0 A.
Claim 3 encompasses the stabilized Ace2 variant according to claim 1, wherein the amino acid residue pair comprises one or more selected from the group consisting of N51/V343, N53/Q340, I54/K341, H239/V604, 121/E87, M62/S47, A193/V107, V364/V298, T365/T294, H401/H378, T445/T276, S502/R169, N508/S 124 and A348/H378, present in the Ace2-derived protein.
Claim 4 encompasses the stabilized Ace2 variant according to claim 1, wherein the Ace2-derived protein is a protein derived from an ectodomain of an Ace2 protein.
Claim 5 encompasses the stabilized Ace2 variant according to claim 1, wherein the Ace2-derived protein comprises amino acid residues at positions 1 to 615 of a wild-type Ace2 protein.
The specification discloses angiotensin-converting enzyme 2 (Ace2) variant comprises cysteine amino acid substitutions at one or more positions selected from the group consisting of N51C and V343C, N53C and Q340C, I54C and K341C, H239C and V604C, I21C and E87C, M62C and S47C, A193C and V107C, V364C and V298C, T365C and T294C, H401C and H378C, T445 and T276C, S502C and R169C, N508C and S124C, and A348 and H378C, numbering according to a wild-type Ace2 protein of SEQ ID NO: 1. The angiotensin-converting enzyme 2 (Ace2) variant comprising the amino acid sequence selected from the group of SEQ ID NO: 3 to 16, see Table 1. The Ace2 variant having a distance between the central carbons (C-alphas) of the amino acids forming the residue pair is from 4.5 to 7.0A.
However, the specification does not describe the structure-identifying information, e.g., amino acid sequence for any Ace2-derived protein, other than SEQ ID NO:1, having any one or more pairs of amino acids substitution for cysteines (claim 1), such as N51/V343 (claim 3) for preventing or treating any coronavirus infectious disease 19 (COVID-19).
The term “derived” encompasses any substitutions, deletions, additions or a combination thereof.
The specification does not describe where and what amino acid pairs within Ace2 (claim 1) or an ectodomain of Ace2 protein (claim 4) or comprises amino acid residues 1 to 615 of a wild-type Ace2 protein (claim 5) to be substituted, deleted, added or a combination thereof such that the derivative of Ace2 protein further comprises cysteine substitutions at one or more amino acid residues pairs present in said Ace2-derived protein still maintains tertiary structures and binding to which type of coronavirus.
Further, substituting cysteine for one or more amino acid residue pairs in Ace2-derived protein may increase aggregation.
For example, Bailey (US20230183668, PTO 892) teaches that introducing A714C in Angiotensin-converting enzyme-2 (ACE2) resulted in increased aggregation, see Example 14, para. [0329], FIG. 23A, in particular. The cysteine amino acid substitutions S43C and G66C appeared to reduce the amount of aggregated protein that did not enter a native protein gel in the context of an ACE2-Ig protein, see para. [0333]. Applicants have provided insufficient evidence or nexus that would lead the skilled artisan to predict cysteine substitutions at random location within Ace2-derived protein maintains COVID-19 binding and without aggregation.
Regarding number of species, the specification does not describe a representative number of species for the claimed genus. The disclosure does not describe a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed stabilized angiotensin-converting enzyme 2 (Ace2) variant having a disulfide bond formed by substituting cystine for any one or more amino acid pairs present in any Ace2-derived protein themselves. As such, the distance ranging from 4.5 to 7.0 angstrom (claim 2) cannot be correlated between the central carbons (C-alphas) and the undisclosed amino acid pairs having cysteine substitutions.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only (1) a stabilized angiotensin-converting enzyme 2 (Ace2) variant comprising a disulfide bond formed by substituting cysteine for one or more pair of amino acid residue present in an Ace2-derived protein comprising SEQ ID NO: 1, wherein the pair is selected from the group consisting of N51C and V343C, N53C and Q340C, I54C and K341C, H239C and C, 121C and E87C, M62C and S47C, A193C and V107C, V364C and V298C, T365C and T294C, H401C and H378C, T445C and T276C, S502C and R169C, N508C and S124C and A348C and H378C, present in the Ace2-derived protein, (2) Said stabilized angiotensin-converting enzyme 2 (Ace2) variant, wherein the disulfide bond distance between a central carbons (C-alphas) and the amino acid residue pairs ranges from 4.5 to 7.0 Angstrom, (3) Said stabilized angiotensin-converting enzyme 2 (Ace2) variant, wherein the Ace2-derived protein is a protein from an ectodomain of an Ace2 protein, (4) said stabilized angiotensin-converting enzyme 2 (Ace2) variant, wherein the Ace2-derived protein comprises amino acid residues 1 to 615 of a wild-type Ace2 protein, (5) the stabilized angiotensin-converting enzyme 2 (Ace2) variant comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 3 to 16, but not the full breadth of the claims 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).
Claims 1-5 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a stabilized angiotensin-converting enzyme 2 (Ace2) variant comprising a disulfide bond formed by substituting cysteine for one or more pair of amino acid residue present in an Ace2-derived protein comprising SEQ ID NO: 1, wherein the pair is selected from the group consisting of N51C and V343C, N53C and Q340C, I54C and K341C, H239C and C, 121C and E87C, M62C and S47C, A193C and V107C, V364C and V298C, T365C and T294C, H401C and H378C, T445C and T276C, S502C and R169C, N508C and S124C and A348C and H378C, present in the Ace2-derived protein, (2) Said stabilized angiotensin-converting enzyme 2 (Ace2) variant, wherein the disulfide bond distance between a central carbons (C-alphas) and the amino acid residue pairs ranges from 4.5 to 7.0 Angstrom, (3) Said stabilized angiotensin-converting enzyme 2 (Ace2) variant, wherein the Ace2-derived protein is a protein from an ectodomain of an Ace2 protein, (4) said stabilized angiotensin-converting enzyme 2 (Ace2) variant, wherein the Ace2-derived protein comprises amino acid residues 1 to 615 of a wild-type Ace2 protein, (5) the stabilized angiotensin-converting enzyme 2 (Ace2) variant comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 3 to 16, does not reasonably provide enablement for any stabilized angiotensin-converting enzyme 2 (Ace2) variant for preventing or treating any coronavirus infectious disease 19 (COVID-19). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any stabilized angiotensin-converting enzyme 2 (Ace2) variant comprising a disulfide bond formed by substituting cysteine for any one or more of the amino acid residue pairs present in any Ace2-derived protein.
Claim 2 encompasses the stabilized Ace2 variant according to claim 1, wherein the distance between the central carbons (C-alphas) in the amino acid residue pairs forming the disulfide bond is from 4.5 to 7.0 A.
Claim 3 encompasses the stabilized Ace2 variant according to claim 1, wherein the amino acid residue pair comprises one or more selected from the group consisting of N51/V343, N53/Q340, I54/K341, H239/V604, 121/E87, M62/S47, A193/V107, V364/V298, T365/T294, H401/H378, T445/T276, S502/R169, N508/S 124 and A348/H378, present in the Ace2-derived protein.
Claim 4 encompasses the stabilized Ace2 variant according to claim 1, wherein the Ace2-derived protein is a protein derived from an ectodomain of an Ace2 protein.
Claim 5 encompasses the stabilized Ace2 variant according to claim 1, wherein the Ace2-derived protein comprises amino acid residues at positions 1 to 615 of a wild-type Ace2 protein.
Enablement is not commensurate in scope with claims as how to use any angiotensin-converting enzyme 2 (Ace2) variant for preventing any coronavirus infectious disease 19 (COVID-19).
The specification discloses angiotensin-converting enzyme 2 (Ace2) variant comprises cysteine amino acid substitutions at one or more positions selected from the group consisting of N51C and V343C, N53C and Q340C, I54C and K341C, H239C and V604C, I21C and E87C, M62C and S47C, A193C and V107C, V364C and V298C, T365C and T294C, H401C and H378C, T445 and T276C, S502C and R169C, N508C and S124C, and A348 and H378C, numbering according to wild-type Ace2 protein of SEQ ID NO: 1. The angiotensin-converting enzyme 2 (Ace2) variant comprising the amino acid sequence selected from the group of SEQ ID NO: 3 to 16, see Table 1. The Ace2 variant having a distance between the central carbons (C-alphas) of the amino acids forming the residue pair is from 4.5 to 7.0A.
However, the specification does not teach the structure-identifying information, e.g., amino acid sequence for any Ace2-derived protein, other than SEQ ID NO:1, having any one or more pairs of amino acids substitution for cysteines (claim 1), such as N51/V343 (claim 3) for preventing or treating any coronavirus infectious disease 19 (COVID-19). The term “derived” encompasses any substitutions, deletions, additions or a combination thereof. The specification does not teach where and what amino acid pairs within Ace2 (claim 1) or an ectodomain of Ace2 protein (claim 4) or comprises amino acid residues 1 to 615 of a wild-type Ace2 protein (claim 5) to be substituted, deleted, added or a combination thereof such that the derivative of Ace2 protein further comprises cysteine substitutions at one or more pairs present in said Ace2-derived protein still maintains tertiary structures and binding to which coronavirus isotype.
Further, substituting cysteine for one or more amino acid residue pairs in Ace2-derived protein may increase aggregation.
For example, Bailey (US20230183668; PTO 892) teaches that introducing A714C in Angiotensin-converting enzyme-2 (ACE2) resulted in increased aggregation, see Example 14, para. [0329], FIG. 23A, in particular. The cysteine amino acid substitutions S43C and G66C appeared to reduce the amount of aggregated protein that did not enter a native protein gel in the context of an ACE2-Ig protein, see para. [0333]. Applicants have provided insufficient evidence or nexus that would lead the skilled artisan to predict cysteine substitutions at random location within Ace2-derived protein maintains COVID-19 binding and without aggregation.
Further, the specification does not teach a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can make and use the genus of the actual claimed stabilized angiotensin-converting enzyme 2 (Ace2) variant having more than one disulfide bonds formed by substituting cysteine for any one or more amino acid residue pairs present in any Ace2-derived protein themselves without undue experimentation. As such, the distance ranging from 4.5 to 7.0 angstrom (claim 2) cannot be correlated between the central carbons (C-alphas) and the undisclosed amino acid pairs having cysteine substitutions.
Regarding preventing any coronavirus infectious disease 19 (COVID-19), the specification provides no in vivo working examples showing that which undisclosed stabilized angiotensin-converting enzyme 2 (Ace2) variant is effective for treating any and all coronavirus infectious disease 19 (COVID-19), much less preventing all coronavirus infectious disease 19 (COVID-19).
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Bailey and the absence of working examples, undue experimentation would be required to practice the claimed stabilized angiotensin-converting enzyme 2 (Ace2) variant for treatment and prevention of all coronavirus infectious disease 19 (COVID-19) commensurate with the scope of the claims.
Claim Rejections - 35 USC § 102
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)(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 1 is rejected under 35 U.S.C. 102 (a)(2) as being anticipated by Procko et al (BioRxiv: 1-21, May 2020; PTO 892).
Claim 1 encompasses any stabilized angiotensin-converting enzyme 2 (Ace2) variant comprising a disulfide bond formed by substituting cysteine for any one or more of the amino acid residue pairs present in any Ace2-derived protein.
Procko teaches cysteines substitution present in Ace2 protein such as T27C, N33C, E35C and Q42C, N90C, T92C, see p. 2, ACE2 primary structure is on the vertical axis, amino acid substitutions are on the horizontal axis.
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The two cysteines are inherently formed disulfide bond. Thus, the reference teachings anticipate the claimed invention.
Claims 1, 4 and 5 are rejected under 35 U.S.C. 102 (a)(2)as being anticipated by Bailey et al (US20230183668, claimed earliest priority to 63/027,884, filed May 20, 2020; PTO 892).
Claim 1 encompasses any stabilized angiotensin-converting enzyme 2 (Ace2) variant comprising a disulfide bond formed by substituting cysteine for any one or more of the amino acid residue pairs present in any Ace2-derived protein.
Bailey teaches various stabilized cysteine amino acid substitutions optionally form a disulfide bond. In certain embodiments, the ACE2 mutein comprises the substitutions K74C and S106C, and/or S128C and V343C in human ACE2 (SEQ ID NO: 1), see para. [0011], [0062], [0197], [0198], reference claims 3-5, 7-8, 12, 29, 31, in particular. The ACE2 mutein comprises the amino acid substitutions H374C and G405C, H374C and S409C, or H374C and G405C, see [0012].
Regarding claims 4-5, Bailey teaches that the substitutions are located to amino acids 19-615 (aka ectodomain) of wild-type human ACE2, wherein amino acid residues 1-18 is the signal peptide, see para. [0014], [0087].
Thus, the reference teachings anticipate the claimed invention.
Species Restriction Withdrawn
Upon reconsideration in view of the elected species N51/V343 (aka SEQ ID NO: 3) is free of prior art, the search and examination has been extended to include all species in claim 3 (aka SEQ ID NO: 4-16).
Allowable Subject Matter
SEQ ID NO: 3-16 are free of prior art.
Claims 2-3 are free of prior art.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641