DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment of 3/9/26 (which is identical to the amendment of 1/22/26) has been entered in full. Claims 1-6 and 14-18 are canceled. Claims 7-13 are amended. New claims 19-25 are added. Claims 7-13 and 19-25 are pending.
Election/Restrictions
The 12/8/25 Office action required election of a single invention from four Groups (see page 3). The claims as amended now correspond to the following Groups:
Group I, claims 7-11 and 20-24, drawn to a medicament comprising an ACE2 polypeptide that has been enzymatically deglycosylated;
Group II, claims 12-13 and 19, drawn to a method for treating a coronavirus infection in a subject with a medicament of Group I;
Groups III and IV, no pending claims; and
Group V (new), claim 25, drawn to a method for regulating blood pressure, treating PAH or ARDS, or protecting organ(s) with a medicament of Group I.
Applicants' election without traverse of Group I in the reply filed on 3/24/17 is acknowledged. Claims 12-13, 19 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The election without traverse of “contact with beta-N-acetylglucosaminidase” as the species of “means of deglycosylation” in the reply is also acknowledged.
Claims 7-11 and 20-24 are under consideration.
Drawings
Corrected drawings in compliance with 37 CFR 1.121(d) are required because:
(1) The instant drawings do not comply with 37 C.F.R. 1.84(U)(1), which states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter. Figure 5 of the instant application is presented on two sheets, labeled "FIG. 5" and "FIG. 5 (cont.)". These sheets should be relabeled "FIG. 5A" and "FIG. 5B".
(2) The amino acid sequences shown in Figures 5A, 5B, 11 and 14 are not identified by the corresponding SEQ ID NO found in the sequence listing, as required by the sequence rules for amino acid sequences, in either the figure itself or the corresponding brief description of the figure in the specification.
Applicants are advised to employ the services of a competent patent draftsperson outside the Office, as the USPTO no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
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). Applicants are reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1.84(U)(1), Applicants are required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
Claim Objections
Claims 7-11 and 20-24 are objected to because of the following informalities:
In independent claim 7, line 2, the acronym “ACE2” should be accompanied by the full terminology the first time it appears in a series of claims; e.g., “angiotensin converting enzyme 2 (ACE2)”. See page 1 of the specification.
In each of claims 8-11, line 1 of each, the word “of” is missing between “medicament” and “claim 7”; i.e., “medicament of claim 7”.
In each claims 20-22 and 24, there is an extraneous space before the concluding period.
The remaining claim(s) are objected to for depending from an objected claim.
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.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
In claim 9, line 2, the term “preferably” renders the claim indefinite because it is unclear whether the limitations following the term are part of the claimed invention. See MPEP § 2173.05(d). Specifically, it is unclear whether the limitations of the claim require that the soluble ACE2 lacks a transmembrane domain or are met by any soluble ACE2.
Claim Rejections - 35 USC § 112, enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.-The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 7-11 and 20-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling for
A medicament comprising an ACE2 polypeptide lacking at N-linked glycosylation of two or more sugar residues at an amino acid corresponding to Asn53, Asn90, Asn103, Asn322, Asn422, Asn546 and/or Asn690 of SEQ ID NO: 1 or having a truncated N-linked glycosylation at an amino acid corresponding to Asn53, Asn90, Asn103, Asn322, Asn422, Asn546 and/or Asn690 of SEQ ID NO: 1, wherein the truncated N-linked glycosylation is not larger than an -GlcNAc2Man3GlcNAc2 structure, wherein the ACE2 polypeptide is obtained by enzymatic deglycosylation, and wherein the ACE2 polypeptide comprises amino acids corresponding to amino acids 19 to 605 of SEQ ID NO: 1,
does not reasonably provide enablement for
A medicament comprising an ACE2 polypeptide lacking at N-linked glycosylation of two or more sugar residues at an amino acid corresponding to Asn53, Asn90, Asn103, Asn322, Asn422, Asn546 and/or Asn690 of SEQ ID NO: 1 or having a truncated N-linked glycosylation at an amino acid corresponding to Asn53, Asn90, Asn103, Asn322, Asn422, Asn546 and/or Asn690 of SEQ ID NO: 1, wherein the truncated N-linked glycosylation is not larger than an -GlcNAc2Man3GlcNAc2 structure, wherein the ACE2 polypeptide is obtained by enzymatic deglycosylation.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims are product claims that are directed to a medicament comprising an angiotensin converting enzyme 2 (ACE2) polypeptide in which N-glycosylation has been removed or truncated by enzymatic deglycosylation at one of seven specified residues. The specification teaches that the full-length human ACE2 protein is 805 amino acids in length (SEQ ID NO: 2), where “[a]mino acids 1-17 are the signal sequence, amino acids 19-740 form the extracellular domain, amino acids 741-761 are the transmembrane domain and amino acids 762-805 are the cytoplasmic domain” (¶ 44, published application).
The deglycosylated ACE2 of the claimed medicament is not limited to the full-length membrane-bound ACE2 (SEQ ID NO: 2), or even the full 704 amino acids of the soluble protein (SEQ ID NO: 1), but instead broadly encompasses variants in which one or more amino acid residues are mutated by substitution, addition or deletion, without limit. Such encompasses fragments as small as two amino acids in length, and mutated variants in which any number of amino acids are changed, and combinations of the two. Even claims 10 and 11, which in the alternative are directed to variants that are at least 90% identical to residues 19-600 or 18-740, include variants with up to 58 or 72 amino acid mutations, respectively.
The specification points to prior art, U.S. Patent 10,443,049 (cited on the 5/23/24 IDS), teaching smaller fragments of the extracellular domain (ECD), including residues 19-605 and 19-619, that retain ACE2 activity (¶ 51). While this enables use of such fragments, this does not correspond in scope to that which is claimed, which encompasses much smaller fragments, as well as mutations in any combination throughout the protein.
The prior art appreciates that "Mutations … are generally destabilizing, and can reduce protein … fitness" and "In general, more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation" (pg 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604). The prior art published also appreciates that "the range of possible SNV [single nucleotide variation] effects 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" (pg 18 of Bhattacharya et al, 2017. Plos One. 12(3): e0171355, pages 1-22 as printed). Thus, knowledge of the amino acid sequence of the ECD of ACE2 alone is not sufficient for the skilled artisan at the time of the effective filing date to predict which mutations (substitutions, additions and deletions) will result in a truncated ECD that retains functionality.
Beyond the teachings of ‘049 cited above, the specification does not teach a minimal length for the ECD to retain the required functionality; i.e., the ability to bind to a coronavirus. The specification does not demonstrate that any shorter truncations will retain the ability to bind, and does not demonstrate that other mutations that can be made throughout the length of the ECD and allow the retention of binding.
Thus, the limited examples provided by the specification fail to correspond to the scope of the genus encompassed by the claims. The specification fails to provide guidance as to the scope of amino acid changes that can be made to SEQ ID NO: 1 or 2 and still retain the ability to bind to a coronavirus.
Due to the large quantity of experimentation necessary to generate the large number ACE2 variants encompassed by the claims and to screen the same for activity, the lack of direction/guidance presented in the specification regarding which structural features are required in order to provide activity, the absence of working examples directed to same, the complex nature of the invention, the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and use the claimed invention in its full scope.
Note on Prior Art Rejection(s)
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 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.
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)(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.
Claims 7-11 and 20-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shajahan et al, 2021. Glycobiology. 31(4): 410-424; first published October 29 2020. The earliest date to which the instant application claims priority is 12/11/20.
Claim 7 encompasses a medicament comprising an ACE2 polypeptide lacking an N-linked glycosylation of two or more sugar residues at an amino acid corresponding to Asn53, Asn90, Asn103, Asn322, Asn432, Asn546 and/or Asn690 of SEQ ID NO: 1, wherein the ACE2 polypeptide is obtained by enzymatic deglycosylation. The term “medicament” is not provided with a limiting definition in the instant specification. In the absence of any other elements being required, the medicament broadly encompasses the ACE2 polypeptide alone.
Shajahan teaches identification of “glycosylation at all seven potential N-glycosylation sites on hACE2” (page 411). Shajahan teaches that “N-glycans were released” from “hACE2” by treatment with “PNGase F”, producing “de-N-glycosylated hACE2 protein” (page 421). As such, Shajahan teaches an ACE2 polypeptide lacking an N-linked glycosylation of two or more sugars at amino acids corresponding to each of residues Asn53, Asn90, Asn103, Asn322, Asn432, Asn546 and Asn690 of SEQ ID NO: 1, wherein the ACE2 polypeptide is obtained by enzymatic deglycosylation. As such, the teachings of Shajahan anticipate claim 7.
Claim 8 encompasses an ACE2 polypeptide to one that lacks N-linked glycosylation of two or more sugars at Asn90 and Asn322 of SEQ ID NO: 1. In the teachings of Shajahan described above, the protein has had all N-glycosylation released, and therefore lacks N-glycosylation of two or more sugar residues at each of Asn90 and Asn322. As such, the teachings of Shajahan also anticipate claim 8.
Claims 9-11 each encompass an ACE2 polypeptide that is a soluble ACE2 (claim 9), comprises amino acids 19-600 of SEQ ID NO: 1 (claim 10) or comprises amino acids 18-740 of SEQ ID NO: 1 (claim 11). Shajahan further teaches that that ACE2 protein “comprises residues Gln18 to Ser740” (page 421), which constitutes the soluble extracellular domain of ACE2. Residues 18-740 also fully comprises residues 19-600. As such, the teachings of Shajahan also anticipates claims 9-11.
Claims 20 and 21 encompass a medicament of claim 7 wherein the ACE2 polypeptide is obtainable by expressing an ACE2 polypeptide in a mammalian cell, and contacting said ACE2 with a beta-N-acetylglucosaminidase (claim 20) that is PNGase F (claim 21). Shajahan further teaches that the ACE2 polypeptide was expressed in HEK293 cells (page 421), which are mammalian cells, and as described above were de-glycosylated with PNGase F. As such, the teachings of Shajahan also anticipate claims 20 and 21.
Claim 22 encompasses an ACE2 polypeptide to one that lacks N-linked glycosylation of two or more sugars at six of the seven residues recited in parent claim 1 (all except Asn690). In the teachings of Shajahan described above, the protein has had all N-glycosylation released, and therefore lacks N-glycosylation of two or more sugar residues at each of the six residues recited in claim 22. As such, the teachings of Shajahan also anticipate claim 22.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were effectively filed absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned at the time a later invention was effectively filed in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 23 and 24 are rejected under 35 U.S.C. 103(a) as being unpatentable over Shajahan et al, 2021. Glycobiology. 31(4): 410-424; first published October 29 2020, as applied to claim 7 above, and further in view of Niazi, U.S. Patent Application Publication 2021/0284716, published 9/16/21, filed 5/21/20, and claiming priority to 3/11/20.
Claims 23 and 24 encompass a medicament of claim 7 (comprising a deglycosylated ACE2 polypeptide), wherein the ACE2 polypeptide is a fusion protein comprising a heavy chain immunoglobulin domain (claim 23) that is an Fc fragment (claim 24).
The teachings of Shajahan that anticipate parent claim 7 are set forth above. Shajahan does not further teach an ACE2 fusion with an Fc fragment or other heavy chain immunoglobulin domain. Shajahan further teaches that “Evaluation of glycosylation on glycoprotein therapeutics produced from various human and non-human expression systems is critical from the point of view of immunogenicity, stability, as well as therapeutic efficacy” (page 420).
Niazi teaches soluble ACE2-Fc hybrid constructs (¶ 36), including with an ACE2 portion from a human ACE2 protein (¶ 37), for use in treatment and diagnosis of coronaviruses (¶ 3).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the ACE2 polypeptide that has been enzymatically deglycosylated as taught by Shajahan, and substitute the ACE2 polypeptide with an ACE2-Fc fusion polypeptide as taught by Shajahan. The person of ordinary skill in the art would have been motivated to make such a change in order to experimentally verify the presence of N-glycosylation in the ACE2-Fc fusion protein. The person of ordinary skill in the art would have had a reasonable expectation of success because making such a change simply requires producing the ACE2-Fc fusion protein as taught by Niazi and then subjecting it to a de-N-glycosylating enzyme as taught by Shajahan. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Art of Note
The following articles, patents, and published patent applications were found by the Examiner during the art search while not relied upon for a rejection are considered pertinent to the instant application:
Yang et al, WO 2021257512, published 23 December 2021, filed 15 June 2021, and claiming priority to 15 June 2020. Yang teaches “PNGase F digested ACE2-Fc” (page 4, line 7) and “The ACE2-Fc and Spike 1-674-Fc protein were likely to be heavily N-glycosylated since size reduction was observed in SDS-PAGE after PNGase F treatment” (page 31, lines 30-31). The priority claim to 15 June 2020 is based on provisional application U.S. 63/039,228. However, the ‘228 application does not contain either teaching directed to use of PNGase F to remove N-glycosylation from ACE2-Fc, and furthermore does not contain any other teachings directed to N-glycosylation of ACE-Fc. As such, the ‘512 publication only merits priority to the date of its filing, 15 June 2021, which is after the claimed priority date of the instant application.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
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