DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. The Preliminary Amendment filed on 08 August 2023 has been entered in full. Claims 3-5, 7-8, 10-11, 13, 15, 21, 23, 27, 33, 36-37 and 43 have been amended, and claims 6, 9, 12, 14, 16-20, 22, 24-26, 28-32, 35, 38, 40-42 and 44-46 have been cancelled. Therefore, claims 1-5, 7-8, 10-11, 13, 15, 21, 23, 27, 33-34, 36-37, 39 and 43 are pending and the subject of this Office Action.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 13 October 2023 has been considered by the examiner.
Specification
4. The disclosure is objected to because of the following informalities: The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: ACE2-Fc fusions and uses thereof. Appropriate correction is required.
Claim Objections
5. Claim 1 and 3-4 are objected to because of the following informalities: “the amino acid sequences” should recite “amino acid residues”. Appropriate correction is required.
6. Claim 1 is objected to because of the following informalities: While not indefinite, it is suggested that the recitation “T27L or T27Y, H34V, and N90E (LVE or YTE)” be amended to recite “T27L or T27Y, H34V, and N90E (LVE or YTE) relative to SEQ ID NO: 1”.
7. Claim 3 is objected to because of the following informalities: While not indefinite, it is suggested that the recitation “L234S, L235T, and G236R (STR)” be amended to recite “L234S, L235T, and G236R (STR) relative to SEQ ID NO: 6”.
8. Claim 4 is objected to because of the following informalities: While not indefinite, it is suggested that the recitation “M252Y, S254T, and T256E (YTE)” be amended to recite “M252Y, S254T, and T256E (YTE) relative to SEQ ID NO: 6”.
9. Claim 11 is objected to because of the following informalities: “immunoglobin” should recite “immunoglobulin”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
10. 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.
11. Claims 1-5, 7-8, 10-11, 13, 15, 21, 23, 27, 33-34, 36-37, 39 and 43 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.
12. Claim 1 is rejected as being indefinite for reciting the limitations “two Fab arms, wherein at least one of the Fab arms comprises an ACE2 domain”. Since it is not clear if the recitation refers to antibody which has an ACE2 domain attached to one of the arms of the antibody, if it refers to an antibody having one of the Fab arms substituted with an ACE2 domain, or something else, the metes and bounds of the claims cannot be determined.
13. Claim 37 is rejected as being indefinite for reciting the term “effective amount”. Since the claim does not define what is being treated or the desired outcome, the metes and bounds of what is encompassed by the phrase “effective amount ” cannot be determined.
14. Claims 2-5, 7-8, 10-11, 13, 15, 21, 23, 27, 33-34, 36, 39 and 43 are rejected for depending from an indefinite claim
Claim Rejections - 35 USC § 112
15. 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.
16. Claims 33 and 36 and are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In the instant case, claim 33 does not recite any additional elements from the claim from which it depends, and the intended use that is recited in claim 36 does not further limit the composition recited in claim 33. 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 (Written Description)
17. 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.
18. Claims 1-5, 7-8, 10-11, 13, 15, 21, 23, 27, 33-34, 36-37, 39 and 43 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 basis for this rejection is set forth at pp. 7-13 of the previous Office action (mailed 13 February 2025)
19. The claims are drawn quite broadly to a chimeric ACE2-Immunoglobulin antibody, comprising: an immunoglobulin region having an Fe domain; two Fab arms, wherein at least one of the Fab arms comprises an ACE2 domain, the ACE2 domain comprising at least 90% identity with the amino acid sequences 19-45 and 80-100 of SEQ ID NO: 1 and having substitutions T27L or T27Y, H34V, and N90E (LVE or YVE. The claims also recite wherein the Fc domain comprises at least 90% identity with the amino acid sequences 221-251 of SEQ ID NO: 6 and has substitutions L234S, L235T, and G236R (STR), wherein the Fc domain comprises at least 90% identity with the amino acid sequences 237-267 of SEQ ID NO: 6 and has substitutions M252Y, S254T, and T256E (YTE), or wherein the Fc domain has greater than 50% sequence identity to SEQ ID NO: 6. The claims also recite wherein the ACE2 domain has greater than 50% sequence identity to SEQ ID NO: 9. The claims also recite chimeric ACE2-Immunoglobulin antibody of claim 1 having greater than 50% sequence identity to SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5. The claims also recite wherein the ACE2 domain binds to each of two or more SARS CoV-2 variants with a binding affinity indicated by KD less than 10 nM, wherein binding to a SARS-CoV-2 variant comprises binding to one of an S1 subunit, a spike protein trimer, and an RBD; or wherein one of the two or more SARS CoV-2 variants is an Omicron variant, or wherein the it binds to the spike protein trimer of the Omicron variant with a binding affinity indicated by KD less than 0.9 nM (900 pM); or wherein the antibody is capable of neutralizing the binding of SARS CoV-2 to human ACE2, the antibody has a binding affinity for FcRn indicated by KD less than 500 nM, the antibody is capable of binding with decreased Fc effector functions including decreased binding to FcγRs and/or C1q, or a combination of any of the above. The claims also recite pharmaceutical compositions comprising the same, and a method of treatment comprising administering the same. Thus the claims are drawn to an extremely large genus of variant polypeptides that are either defined by a limited structure and a desired functional property.
20. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the claims is a very limited partial structure and a desired function. The language of the claims recite up to 50% variations within the ACE2/Fc fusion. In contrast to the breadth of the claims, the specification provides adequate written description for fusion constructs comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, which comprises an ACE2 domain having the substitutions T27L or T27Y, H34V and N90E relative to SEQ ID NO: 1, fused to an Fc domain having either L234S, L235T and G236R substitutions relative to SEQ ID NO: 6 or M252Y, S254T and T256E substitutions relative to SEQ ID NO: 6.
These constructs are disclosed as having very high binding affinity to multiple SARS-CoV-2 variants as the result of the triple mutation in the ACE2 domain, and having a very long half-life as the result of the mutations in the Fc domain (See Examples 1, 3 and 4 at pp. 49-56) and capable of neutralization of live CoV-2 in human lung organoids (See Examples 12 and 13 at pp. 64-66), it does not provide adequate written description for a commensurate number of the species of variants encompassed by the claims having which also have the claimed activities.
21. A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)(Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.).
22. It is well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. While it is known that many amino acid substitutions are generally possible in any given protein, the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495). However, based on the instant disclosure, there is insufficient guidance based on the reliance of disclosure of a few species of constructs to direct a person of skill in the art to select or to predict particular residues in the claimed ACE2 and Fc domains that are essential for providing the recited activities. The description of a few species of constructs is not adequate written description of an entire genus of functionally equivalent polypeptides, which incorporate all variants that are encompassed by the claims.
23. In the absence of sufficient direction and guidance, the disclosure of 4 species of ACE-2-Fc fusion proteins having very high affinity and neutralizing activity does not provide sufficient written description for the entire genus of chimeric ACE2-Immunoglobulin antibodies encompassed by the claims that also have these activities.
24. For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species, cannot be achieved by disclosing only one or two species within the genus. See, e.g., Eli Lilly. Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, first paragraph.
25. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of TCRs or functional portions thereof, 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 compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
26. 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.
27. Therefore, only ACE2-Fc fusion proteins comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, which comprise an ACE2 domain having the substitutions T27L or T27Y, H34V and N90E relative to SEQ ID NO: 1, fused to an Fc domain having either L234S, L235T and G236R substitutions relative to SEQ ID NO: 6 or M252Y, S254T and T256E substitutions relative to SEQ ID NO: 6, 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).
Claim Rejections - 35 USC § 112 (Scope of Enablement)
28. Claims 37, 39 and 43 are 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 a method of treating SARS-CoV-2 infection in a subject comprising administering an effective amount of an ACE2-Fc fusion proteins comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, does not reasonably provide enablement for methods of “treatment” (See 112(b) rejection supra, or treat antibody-dependent enhancement, or decrease or eliminate post-acute sequelae of 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/or use the invention commensurate in scope with these claims.
29. Factors to be considered in determining whether a disclosure enables one skilled in the art to make and use the claimed invention in its full scope without resorting to undue experimentation include: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance presented; (3) the presence or absence of working examples; (4) the nature or complexity of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. See In re Wands, 8 USPQ2d. 1400 (Fed. Cir. 1988).
30. In the instant case, the claims are broadly drawn to a method of treatment, comprising administering to a subject in need thereof an effective amount of the claimed ACE2-Immunoglobulin antibody (See 112(b) rejections supra), treat antibody-dependent enhancement, or decrease or eliminate post-acute sequelae of COVID-19. Thus the claims encompass complex and unpredictable subject matter, involving the effects of complex biological molecules on diseased physiological states. As was found in Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. This invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology”, Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert, denied, 502 U.S. 856 (1991).
31. The specification provides detailed direction and guidance regarding the effects of ACE2-Fc fusion comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, as having very high binding affinity to multiple SARS-CoV-2 variants as the result of the triple mutation in the ACE2 domain, and having a very long half-life as the result of the mutations in the Fc domain (See Examples 1, 3 and 4 at pp. 49-56). The Specification also discloses that these fusion are capable of neutralization of live CoV-2 in human lung organoids (See Examples 12 and 13 at pp. 64-66). However, the data presented in the Specification does not provide any guidance on the treatment or prophylactic treatment of an undisclosed condition (See 112(b) rejection supra), treatment of antibody-dependent enhancement, or decreasing or eliminating post-acute sequelae of COVID-19 with the claimed fusion proteins. Therefore, while administration of an ACE2-Fc fusion comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5 would be expected to SARS-CoV-2 infection in a subject, one skilled in the art would not predict that administration of the claimed fusion proteins would be sufficient to treat antibody-dependent enhancement, or to decrease or eliminate post-acute sequelae of COVID-19. There are no working examples provided in the instant application which demonstrate that the claimed fusion protein is capable of treating antibody-dependent enhancement, or decreasing or eliminating post-acute sequelae of COVID-19.
32. While the level of skill in the art is high, the amount of guidance provided regarding how to use the recited ACE2-Fc fusions to effectively treat antibody-dependent enhancement, or decrease or eliminate post-acute sequelae of COVID-19. Accordingly, the amount of experimentation required to determine how to use the recited ACE2-Fc fusions in this manner is quite extensive.
33. Due to the large quantity of experimentation necessary to determine how to use the recited ACE2-Fc fusion to treat undisclosed conditions, treat antibody-dependent enhancement, or decrease or eliminate post-acute sequelae of COVID-19, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the unpredictability of the effects of complex biological molecules on diseased physiological systems, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Summary
34. No claim is allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jon M. Lockard whose telephone number is (571) 272-2717. The examiner can normally be reached on Monday through Friday, 8:00 AM to 4:30 PM.
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/JON M LOCKARD/
Examiner, Art Unit 1647
January 10, 2026