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 without traverse of claims 1, 3-12, 23-24, 27-28, and 33; and the species of positions 371 and 510 of SEQ ID NO: 1 (claim 1); leucine for 371 and isoleucine for 510 (claim 4); and increase in kcat- in hydrolyzing Angiotensin II (claim 28); in the reply filed on 5/18/2026 is acknowledged.
Claims 29-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 5/18/2026.
In view of the prior art search, the species election is expanded to include position 360 of SEQ ID NO: 1; valine at position 510; and a conservative variant of leucine at position 371.
Priority
This application is a 371 of PCT/US2022/051606 (12/2/2022) which claims benefit of 63/285,592 (12/3/2021).
Information Disclosure Statement
The information disclosure statement (IDS) filed on 2/19/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 4 and 8 are objected to because of the following informalities: claims 4 and 8 recite “or a conservative variant or alanine” in line 5. This should instead read “or a conservative variant of alanine”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-12, 23-24, 27-28, and 33 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.
Regarding written description, 35 U.S.C. 112(a) and the first paragraph of pre-AlA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010). To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention (MPEP § 2163(I)).
MPEP 2163(II)(A)(3)(a)(i and ii) states that 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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or 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 the applicant was in possession of the claimed genus.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., .759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, claim 1 recites a mutant ACE2 protein comprising an amino acid sequence at least 90% identical to positions 18-615 of SEQ ID NO: 1, which has at least one of the claimed substitutions and exhibits activity in hydrolyzing Angiotensin II. Claims 27 and 33 recite that the amino acid sequence is at least 95% identical to positions 18-615 of SEQ ID NO: 1. There is not sufficient written description support for an ACE2 protein with 90 or 95% identity to positions 18-615 of SEQ ID NO: 1 and the claimed activity. This amino acid sequence has 597 residues, meaning that up to ~30-60 residues can be substituted, or that there may be various insertions or deletions, within the scope of 90 or 95% identity. This encompasses a vast number of potential sequences. There is nothing in the specification to indicate which residues or regions are important for activity, i.e. which residues can or cannot be modified while maintaining the claimed function of the protein, other than the specifically claimed substitutions. As there are 10 amino acid residues that can be substituted as recited in claim 1, a sequence having all of the claimed substitutions would have ~98% identity to residues 18-615 of SEQ ID NO: 1. It is not clear which additional residues or regions within the range of 90-95% identity could vary and maintain the claimed activity.
While there is written description support for the specifically disclosed SEQ ID NOs and the specifically disclosed residue mutations, these are not representative of the entire genus of sequences that are 90 or 95% identical to positions 18-615 of SEQ ID NO: 1 with the claimed activity, given the large number of sequences having this percent identity. For these reasons, claim 1 fails to comply with the written description requirement, as it is not clear that the applicant had possession of the full scope of the invention at the time of filing.
Claims 3-12, 23-24, and 28 are included in this rejection because they depend on a rejected claim and do not clarify the issue.
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.
(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.
Claims 1, 3-6, and 27-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bailey et al., WO 2021/236957.
Regarding claims 1 and 3, Bailey teaches Angiotensin-converting enzyme-2 (ACE2) mutant proteins (muteins) having greater stability and/or activity than ACE2 proteins (Bailey p. 1 para. 5). Bailey teaches that the ACE2 protein has a sequence according to SEQ ID NO: 1, which is 100% identical to residues 18-615 of instant SEQ ID NO: 1 (Bailey p. 112; see sequence alignment in OA appendix). Bailey teaches that the ACE2 mutein has a substitution at position M360 (Bailey p. 52 Table 5). Thus, Bailey teaches an unnatural, mutant ACE2 protein comprising an amino acid sequence at least 90% identical to positions 18-615 of SEQ ID NO: 1, with a residue other than methionine at position 360 of SEQ ID NO: 1.
Regarding the limitation “the protein exhibits activity in hydrolyzing Angiotensin II”, this is a functional limitation of the claimed protein. As the protein taught by Bailey has the same structure as the claimed protein (sequence identity and substitution), it is expected that the protein of Bailey exhibits activity in hydrolyzing Angiotensin II.
Regarding claims 4-6, Bailey teaches that the methionine at position 360 of the ACE2 protein is substituted with I, L, H, F, Y, or W (Bailey Table 5). Therefore, Bailey teaches an ACE2 with leucine at position 360 of SEQ ID NO: 1.
Regarding claim 27, Bailey teaches that the ACE2 protein is 100% identical to positions 18-615 of SEQ ID NO: 1 (see sequence alignment in OA Appendix).
Regarding claim 28, the limitation “wherein the protein exhibits an increase in kcat- in hydrolyzing Angiotensin II”, is a functional limitation of the claimed protein. It is expected that any protein having the claimed structure is capable of performing this function, absent any essential unclaimed features. The protein taught by Bailey has a structure as set forth in claim 1, and is therefore considered to have the function as set forth in claim 28.
Claims 1, 3, 11, and 27-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seshagiri et al., WO 2021/203103 A2.
Regarding claims 1, 3, and 11, Seshagiri teaches variants of human ACE2 protein (Seshagiri Abstract). Seshagiri teaches that the ACE2 protein has a sequence according to SEQ ID NO: 1, which is 100% identical to residues 18-615 of instant SEQ ID NO: 1 (see sequence alignment in OA appendix). Seshagiri teaches that the ACE2 protein variant has a substitution at residue Y510 (Y510H), i.e. has a residue other than tyrosine at a position corresponding to position 510 of SEQ ID NO: 1 (Seshagiri p. 18 para. 80).
Regarding the limitation “the protein exhibits activity in hydrolyzing Angiotensin II”, this is a functional limitation of the claimed protein. As the protein taught by Seshagiri has the same structure as the claimed protein (sequence identity and substitution), it is expected that the protein of Seshagiri exhibits activity in hydrolyzing Angiotensin II.
Regarding claim 27, Seshagiri teaches that the ACE2 protein is 100% identical to positions 18-615 of SEQ ID NO: 1 (see sequence alignment in OA Appendix).
Regarding claim 28, the limitation “wherein the protein exhibits an increase in kcat- in hydrolyzing Angiotensin II”, this is a functional limitation of the claimed protein. It is expected that any protein having the claimed structure is capable of performing this function, absent any essential unclaimed features. The protein taught by Seshagiri has a structure as set forth in claim 1, and is therefore considered to have the function as set forth in claim 28.
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.
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 as of the effective filing date of the claimed invention(s) 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 as of the effective filing date of the later invention 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 1, 3-12, 23-24, 27-28, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Towler et al., Journal of Biological Chemistry. 2004 Apr 23;279(17):17996-8007.
Regarding claims 1, 3, and 11, Towler teaches the sequence and structure of the ACE2 protein, as well as the closest homologs, somatic angiotensin-converting enzyme (sACE) and testicular angiotensin-converting enzyme (tACE), which are 42% identical to the catalytic domain of ACE2 (Towler Abstract, p. 17996 para. 1-3; Fig. 1). The sequence of ACE2, GenBank Accession AAF99721, is 100% identical to residues 18-615 of instant SEQ ID NO: 1 (Towler Fig. 1; see sequence alignment in OA appendix).
Towler teaches comparing the sequences of ACE2 with tACE and sACE, and teaches that eight active site ACE2 residues are substituted in tACE, including T371V and Y510V (Towler p. 18002 “Comparison with tACE”). Towler teaches that the changes at the active sites presumably play a significant role in the observed differences in substrate specificity and inhibitor binding profiles for these homologous enzymes (Towler p. 18002-3 “Comparison with tACE”). Towler teaches that Tyr510 in ACE2 accommodates only small and medium sized side chains such as leucyl and prolyl, and that the smaller side chains at the S1 subsite of tACE make this subsite somewhat larger in tACE than observed for ACE2 (Towler p. 18003 first partial para.).
Regarding claim 4-5, Towler teaches that tyrosine at position 510 is substituted for valine in homologous enzyme tACE, and this smaller side chain of valine compared to tyrosine allows for accommodation of larger substrates (Towler p. 18002-3 “Comparison with tACE”). Towler additionally teaches that threonine at position 371 is substituted for valine in the homologous enzymes (Towler p. 18002-3 “Comparison with tACE”; Fig. 1). Valine is a conservative variant of alanine and leucine (see instant specification p. 26).
Regarding claims 6, 23-24, and 33, valine and isoleucine are conservative variants, meaning that these residues are functionally similar to one another (see instant specification p. 26). Towler teaches that tyrosine is substituted for valine at position 510 in the homologous enzymes tACE and sACE. As valine and isoleucine are conservative variants, it would have been obvious for a skilled artisan to substitute isoleucine for tyrosine instead of valine, as these amino acids are functionally similar and it would therefore be expected that isoleucine and valine could be substituted for one another with minimal change to enzyme function. Similarly, Towler teaches that threonine at position 371 is substituted for valine in the homologous enzymes (Towler p. 18002-3 “Comparison with tACE”; Fig. 1). Valine is a conservative variant of leucine (see instant specification p. 26), and it would have been obvious for a skilled artisan to substitute leucine for threonine at position 371 instead of valine.
Regarding claims 7-12, Towler teaches that both residues corresponding to positions 371 and 510 of SEQ ID NO: 1 are substituted in the homologous enzymes tACE and sACE (Towler p. 18002-3 “Comparison with tACE”; Fig. 1).
Regarding claim 27, Towler teaches that the ACE2 protein is 100% identical to positions 18-615 of SEQ ID NO: 1 (see sequence alignment in OA Appendix).
It would have been obvious for a skilled artisan to modify an ACE2 protein with a sequence according to SEQ ID NO: 1 to have a residue other than threonine at position 371 of and/or a residue other than tyrosine at position 510. Towler teaches that ACE2 and tACE structures are very similar, and the substitutions in amino acids in the active site of tACE, including residues 371 and 510, compared to ACE2 contribute to differences in substrate specificity and inhibitor binding (Towler p. 18002 para. 1-3). As the overall structure of these proteins are very similar, and residues corresponding to 371 and 510 are substituted in tACE compared to ACE2, it would have been obvious to substitute these residues in ACE2. It would have further been obvious that positions 371 and/or 510 could be substituted for valine or a conservative variant of valine (leucine or isoleucine) in an ACE2 protein, as the tACE and sACE proteins have a valine in these positions as taught by Towler, and leucine and isoleucine are conservative variants of valine and thus expected to be functionally similar.
A person of ordinary skill in the art would have been motivated to make this substitution because the smaller amino acid residue (valine) in positions 371 and 510 of tACE and sACE accommodates larger side chains and therefore allows for different substrate and inhibitor binding. Making a substitution of threonine at position 371 and/or tyrosine at position 510 for valine would be expected to alter the substrate specificity and inhibitor binding of ACE2, which would be of interest for designing an enzyme with expanded or altered function compared to the wildtype ACE2. As these residues are indicated to be important for conferring differences in substrate specificity between ACE2 and homologous enzymes, a skilled artisan would have been motivated to modify these residues. Additionally, a substitution of leucine at position 371 and/or isoleucine at position 510 would be expected to have similar function as a substitution of valine, as valine, leucine, and isoleucine are conservative variants.
A skilled artisan would have had a reasonable expectation of success in making these substitutions because these residues are substituted in the homologous enzymes which are very similar structurally to ACE2. Therefore, it would be expected that these residues could be successfully substituted in ACE2 with a sequence according to SEQ ID NO: 1. As the homologous enzymes have valine in positions 371 and 510, a skilled artisan could expect success in substituting valine or a conservative variant which is expected to have the same function (leucine or isoleucine) at one or both of these positions.
Regarding claim 28, the limitation “wherein the protein exhibits an increase in kcat- in hydrolyzing Angiotensin II”, this is a functional limitation of the claimed protein. The protein structure as set forth in claim 1 is obvious in view of Towler, and it is expected that any protein having the claimed structure, absent any unclaimed essential features, is capable of performing this function.
Conclusion
Claims 1, 3-12, 23-24, 27-28, and 33 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY F EIX whose telephone number is (571)270-0808. The examiner can normally be reached M-F 8am-5pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMILY F EIX/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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