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 .
Application Status
The amended claims filed June 4, 2026 with the Response to the non-final Office Action are acknowledged. Claims 1-34 have been canceled. Claims 35-36 are newly added.
Claims 35-56 are pending and under examination herein.
Priority
The present application in a continuation-in-part (CIP) of U.S. Patent Application No. 17/499,012, filed October 12, 2021, and a 371 of PCT/US2022/077889, filed October 11, 2022.
The earliest support for the subject matter recited in claims 35-56, in particular the heavy chain modifications of L234S/L235T/G236R (“STR”) and L234S/L235T/G236R/M252Y/S254T/T256E (“STR/YTE”), is found in the PCT/US2022/077889 application filed October 11, 2022. Accordingly, the filing date of the PCT application will be used for the purposes of applying prior art herein.
WITHDRAWN OBJECTIONS AND REJECTIONS
The prior grounds of objection to the specification with respect to embedded hyperlinks is withdrawn in view of Applicant's amendments to the specification filed June 4, 2026.
All prior grounds of rejection over claims 1-34 are rendered moot by the cancelation of the claims.
MAINTAINED OBJECTIONS AND NEW REJECTIONS NECESSITATED BY
CLAIM AMENDMENT
Specification (Maintained)
The disclosure is objected to for the following informalities:
The description for Figure 5 (page 5) states that human “IGHV2-23*04” was used as the humanization backbone for the heavy chain and that human “IGKV2-39*01” was used as the humanization backbone for the light chain of the antibody construct originally set forth by Du (Supplementary Figure 2). However, the figure itself states that “IGHV3-23*04” was used for the heavy chain and that “IGKV1-39*01” was used for the light chain.
The description for Figure 6 (pages 4-5) recites that the light chain sequence of SEQ ID NO: 76, illustrated in the drawing, comprises residues 21-230, “beginning with DIQ… and ending with …GEC”. However, according to the CRF Sequence Listing and the Drawing, the full sequence is 233 residues and residues 228-230 correspond to “FNR”, not “GEC”.
The descriptions for Figures 7 and 8 (page 5) recite that the heavy chains of SEQ ID NO: 77 and 78 comprise “residues 25-471, beginning with EVQ… and ending with …SPG”. However, according to the CRF Sequence Listing and the Drawings, each of the heavy chains corresponding to SEQ ID NO: 77 and 78 contain 473 amino acid residues, and residues 469-471 in each of these sequences corresponds to “SLS”, not “SPG.”
Appropriate clarification and/or correction is requested.
Response to Arguments
Applicant's arguments filed June 4, 2026 have been fully considered but they are not persuasive.
Regarding the inconsistencies between the Brief Description of the Drawings and Figures 5-8, Applicant states, “In response to the Examiner's objection, and without conceding its correctness, applicant respectfully requests that the Examiner rely on the figures and sequence listing for the purpose of examination.” Remarks at page 10.
In response, it is submitted that clarity and correctness of all parts of Applicant's disclosure, including the specification, are material to the process of examination as a whole and that the submitted amendments to the specification do not remedy the issues described above.
Accordingly, the grounds of objection are maintained.
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.
Claims 35-56 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.
Claims 35 and 38-41 recite the limitation “(with numbering according to the EU Index)” in parentheses. This renders the claims indefinite because it is unclear if the phrase in parentheses is intended to be limiting or merely exemplary of a numbering system that could be used in addition to other numbering systems not set forth. Accordingly, the metes and bounds of the claims cannot be determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth in 35 U.S.C. § 112(b) so as permit the skilled artisan to know or determine infringing subject matter.
Furthermore, the claim scope of claims 35, 38, and 41, is ambiguous because it is recognized in the art that different antibody isotypes have differing sequences in their respective heavy chain Fc regions. By way of example, Shitara (U.S. Patent No. 8,883,981; cited in PTO-892 mailed March 2026) at Figure 1 illustrates an alignment of the constant regions of human IgG1, IgG2, IgG3, and IgG4 according to EU numbering, which shows that at positions 234-236 according to EU numbering, human IgG1 and IgG3 antibodies comprise the residues LLG, human IgG2 antibodies comprise VA-, and human IgG4 antibodies comprise FLG. Accordingly, the intended claim scope cannot be readily determined and the claims are indefinite.
Further regarding claim 35, the claim recites that the sequence identifiers of the heavy chain and light chain CDR amino acid sequences correspond to SEQ ID NOs: 18-23, respectively, in parentheses. However, the amino acid sequences expressly written in the claim (i.e., “GFTFIDYYMN”, “FIRNKANDYTTEYST”, etc.) correspond to SEQ ID NOs: 2-7, respectively, in the Sequence Listing of record (and as previously recited in claim 9, now canceled). Based on these inconsistencies, the intended scope of the claims is indefinite.
For the purpose of compact prosecution and applying prior art under 35 U.S.C. § 102 and 103, the written sequences of the heavy chain and light chain CDR sequences (i.e., “GFTFIDYYMN”, “FIRNKANDYTTEYST”, etc.) will be examined herein.
Claims 36-56, which depend from claim 35 and do not remedy these deficiencies, are similarly rejected.
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.
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.
(1)
Claims 35-41, 44-52, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Yan (CN 114805570 A; cited in PTO-892 mailed March 2026) in view of Hale (WO 2021/234402 A2; cited in PTO-892 mailed March 2026), and as evidenced by Du (Nature Communications (2021) 12: 5000; cited in IDS).
Yan discloses a murine anti-human ACE2 monoclonal antibody, named 11B11, comprising a heavy chain set forth in SEQ ID NO: 11 and a light chain set forth in SEQ ID NO: 12, each comprising the instantly claimed heavy chain and light chain CDR amino acid sequences set forth in claim 35. Said antibody blocks the combination of SARS-CoV-2 RBD and a human ACE2 receptor and inhibits SARS-CoV-2 from infecting a host (e.g., Abstract; ¶ 0007-0018, 0080-0091 of machine translation; Figures 4 and 6). Yan teaches that in the process of humanizing the mouse 11B11, the variable region sequences were fused with human IgG4 Fc regions (e.g., ¶ 0072-0079 of machine translation). The light chain comprising SEQ ID NO: 12 shares 100% sequence identity to residues 21-230 of the light chain set forth in Figure 6 (SEQ ID NO: 76), relevant to claims 42-43. As further evidenced by Du, the 11B11 antibody by virtue of its specific structure inherently possesses the instantly claimed functional properties of (i) specifically binding to the extracellular portion of hACE2, (ii) specifically inhibiting binding of SARS-CoV-2 to the extracellular portion of hACE2, and (iii) not significantly inhibiting the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide (e.g., pages 2-3; page 7, left column; Figures 1a, 1d, and 5), pertinent to claims 35-37.
Relevant to claims 44-45, Yan discloses isolated polynucleotides and expression vectors encoding the anti-hACE2 antibody of the invention (e.g., ¶ 0019-0026 of machine translation). Relevant to claim 46, Yan discloses compositions comprising said anti-hACE2 antibody (e.g., ¶ 0043-0045 of machine translation).
Relevant to claims 47-52 and 54, Yan teaches that the anti-hACE2 antibodies of the invention may be used to prevent and treat viral infection with SARS-CoV-2 and can be dosed based on the patient’s symptoms (e.g., ¶ 0028-0031, 0043-0045, claim 19 of machine translation).
However, Yan does not expressly disclose that the humanized anti-hACE2 antibody comprises heavy chain modification selected from the “STR”, “LS”, “YTE”, and “STR/YTE” modifications set forth in claim 35.
Hale also describes proteins comprising variant IgG Fc regions which exhibit modified effector functions (e.g., Abstract). Hale teaches, “In many situations it is desirable to reduce, or preferably eliminate, the binding of IgG to Fcγ receptors, since the biological effects they mediate are unwanted, and may be harmful … For example, when antibodies are being used to neutralize the activity of an antigen, concomitant activation of cellular responses may be undesirable. However, the Fc region has other useful properties, not least its ability to provide a long half-life by virtue of binding to FcRn. This feature is used in the development of fusion proteins where the Fc region imparts an extended half-life to other bioactive proteins” (page 16).
In one embodiment of the invention, Hale describes an optimized Fc variant comprising the substitutions “L234S/L235T/G236R”, which has reduced binding to FcγR but retains binding to FcRn (e.g., pages 24-27, 35-43, 77-79), relevant to claims 35, 38, and 41. Hale discloses, “Surprisingly, a peptide having only the amino acid substitution G236R was found to have an increased risk of immunogenicity compared with the corresponding wild-type peptide, whereas the addition of additional substitutions at positions 234 and 235 decreased this risk to no more than that of the corresponding wild-type peptide” (pages 30-31). Hale further notes additional amino acid residues involved in FcRn binding include M252, S254, and T256 (e.g., pages 43-44). Hale teaches that the M252Y/S254T/T256E substitution, among others, increases binding to FcRn at acidic pH and increases serum half-life, and can be combined with amino acid substitutions at positions 234-236 (e.g., page 44), relevant to claims 35 and 40-41. Pertinent to claims 35 and 39, Hale further teaches that the mutations of M428L/N434S increase elimination phase half-life and can be.
In view of the teachings above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the humanized anti-ACE2 monoclonal antibody taught by Yan by modifying the heavy chain to incorporate the “STR”, “LS”, “YTE”, or “STR/YTE” modifications. The skilled artisan would have been motivated to substitute the residues “STR” at positions 234-236 because Hale teaches that this modification reduces FcγR binding and improves serum half-life, with or without the “YTE” and “LS” substitutions as these modifications also improve serum half-life and can be combined with the modifications at residues 234-236. There would have been a reasonable expectation of success because the skilled artisan would have recognized that these modifications have suitability for the intended purpose of increasing serum half-life, which is beneficial for antibody-based therapeutics, and it is prima facie obvious to apply a known technique to a known product ready for improvement to yield a predictable result.
(2)
Claims 35 and 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over Yan (CN 114805570 A; cited in PTO-892 mailed March 2026) in view of Hale (WO 2021/234402 A2; cited in PTO-892 mailed March 2026), as evidenced by Du (Nature Communications (2021) 12: 5000; cited in IDS), as applied to claims 35-41, 44-52, and 54 above, further in view of Lazar (US 2015/0071948 A1; cited in PTO-892 mailed March 2026) and Shitara (U.S. Patent No. 8,883,981; cited in PTO-892 mailed March 2026).
The teachings of Yan are discussed in the 35 U.S.C. § 103 rejection above.
However, Yan does not teach an embodiment of the anti-ACE2 monoclonal antibody wherein the heavy chain is an isotypically IgG1 heavy chain comprising an amino acid sequence corresponding to residues 25-471 of SEQ ID NO: 77 (as set forth in claim 42) or residues 25-471 of SEQ ID NO: 78 (as set forth in claim 43).
The teachings of Hale and Du are recited above. Hale additionally teaches that human IgG4 has a tendency to form heterodimers with serum IgG4 (i.e., Fab-arm exchange) and that several modifications can be made to IgG4 to minimize this phenomenon (e.g., S228P, C131X, etc.) (e.g., pages 44-45).
Lazar discloses IgG Fc variants and polypeptides with optimized effector function (e.g., Abstract; ¶ 0011-0017). In aspects of the invention, the variants include isotypic substitutions such as C131S, R133K, and others (e.g., ¶ 0017-0019). Lazar teaches, “The different IgG isotypes offer a variety of unique physical, biological, and therapeutic properties. For example there are significant differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization state among the isotypes IgG1, IgG2, IgG3, and IgG4. These differences must be due to one or more of the isotypic differences between the IgGs shown in FIG. 1. For example, because the binding site for FcγRs resides on the Fc region, it is likely that the IgG differences in Fc, and even more likely the lower hinge and the CH2 domain, are responsible for the differences in their FcγR-mediated effector functions” (¶ 0591). In an embodiment of the invention, Lazar teaches an IgG4 variant comprising the amino acid substitutions of 234S, 235T, and 236R (e.g., ¶ 0069-0071), further relevant to claims 42-43.
Shitara illustrates a sequence alignment of human IgG1, IgG2, IgG3, and IgG4 sequences (Figure 1, reproduced and annotated on page 24 of the non-final Office Action mailed March 26, 2026). Residues annotated with a plain arrow on top (corresponding to residues 131, 133, 137-138, etc. according to EU numbering) are those in which IgG1 comprises a different residue at that position than does IgG4, and that the heavy chain sequences of instant SEQ ID NO: 77 and 78 comprise the IgG1-associated residues in at least these positions. These substitutions are consistent with the isotypic substitutions taught by Lazar. The heavy chain taught by Yan comprises an IgG4 hinge, while instant SEQ ID NO: 77 and 78 comprise an IgG1 hinge sequence.
The locations corresponding to the substitutions of residues 234-236 and 252, 254, and 256 according to EU numbering are annotated with dotted arrows above the alignments.
In view of the further teachings of Lazar and Shitara, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a humanized anti-ACE2 monoclonal antibody having a modified heavy chain comprising an amino acid sequence corresponding to residues 25-471 of instant SEQ ID NO: 77 or 78, and a light chain comprising an amino acid sequence corresponding to residues 21-230 of instant SEQ ID NO: 76. The skilled artisan would have been motivated to use an IgG1 heavy chain in place of an IgG4 heavy chain, or to otherwise incorporate IgG1 isotypic substitutions (as provided by Lazar) into the IgG4 heavy chain used by Yan, because (1) Lazar teaches that the different IgG antibody subtypes have differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization states, which affect their therapeutic properties, and (2) Hale further teaches that IgG4 antibodies are susceptible to Fab-arm exchange. Thus, the skilled artisan would be motivated to optimize for desired qualities either by adding isotypic substitutions into an IgG4 heavy chain and/or substituting between IgG isotypes. There would have been a reasonable expectation of success because it is within the technical skill of those in the art to generate IgG antibodies of differing isotypes and/or introduce mutations thereto, and furthermore, there are a finite number of possible IgG Fc structures.
(3)
Claims 35, 51, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Yan (CN 114805570 A; cited in PTO-892 mailed March 2026) in view of Hale (WO 2021/234402 A2; cited in PTO-892 mailed March 2026), as evidenced by Du (Nature Communications (2021) 12: 5000; cited in IDS), as applied to claims 35-41, 44-52, and 54 above, further in view of Khazaal (Molecules (2022) 27: 2903).
The teachings of Yan are discussed in the 35 U.S.C. § 103 rejection above.
However, Yan does not expressly teach treatment methods for subjects who are infected with SARS-CoV-2 and symptomatic of long COVID.
The teachings of Hale and Du are recited above.
Khazaal reviews the role of the renin-angiotensin system (RAS) in the pathogenesis of acute SARS-CoV-2 infection and long COVID (also known as post-acute sequelae of COVID-19 or PASC). Khazaal teaches that overactivation of the RAS is a critical mediator of COVID-19 symptoms and pathologies, as binding of SARS-CoV-2 virus to ACE2 prevents the cleavage of angiotensin II (Ang II), ultimately leading to vasoconstriction, inflammation, cell damage, and many other negative consequences via excess Ang II binding to angiotensin type-1 receptor (AT1R) and decreased anti-inflammatory activity of the ACE2/Ang-(1-7)/AT2R axis (e.g., Section 2; Figure 1). Khazaal further teaches, “Spike (S) proteins on the SARS-CoV-2 virus attack [ACE2] receptors, facilitating its entry into human cells, gaining control of the cell, and using it for replication. This impairs the enzymatic action of the ACE2 receptors, leading to increased lung symptoms due to RAS impairment” (Section 5). Khazaal discloses that SARS-CoV-2 impacts to ACE2 affect numerous organ systems including the central and peripheral nervous systems, cardiovascular system, respiratory system, and others (e.g., Figure 3; Section 9). Khazaal teaches that based on the significant link of the RAS to long COVID pathophysiology, therapeutic strategies for long COVID that can interplay in the RAS signaling pathway should be explored (e.g., Section 9).
In view of the teachings of Khazaal, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer the anti-hACE2 antibody such as that taught by Yan in a method of treating SARS-CoV-2, wherein the subject is symptomatic for long COVID. The skilled artisan would have been motivated to do so because Khazaal teaches that SARS-CoV-2 binding to ACE2 contributes to negative sequelae and long COVID symptoms, and that mitigating RAS signaling dysregulation is a therapeutic strategy that should be explored for long COVID. Furthermore, one of ordinary skill in the art would recognize that those experiencing long COVID symptoms have a clear need to be treated. There would have been a reasonable expectation of success because ACE2 receptors are expressed in multiple body systems and organs (as shown by Khazaal) and because the anti-hACE2 antibody of Yan binds to ACE2 receptor (and prevents SARS-CoV-2 from doing so) without interfering with its ability to cleave Ang II. As explained by Khazaal, the interference of ACE2 cleaving Ang II impairs the anti-inflammatory effects of the ACE2/Ang-(1-7)/AT2R axis and favors excess activation of the pro-inflammatory ACE/Ang II/AT1R axis.
(4)
Claims 35 and 55-56 are rejected under 35 U.S.C. 103 as being unpatentable over Yan (CN 114805570 A; cited in PTO-892 mailed March 2026) in view of Hale (WO 2021/234402 A2; cited in PTO-892 mailed March 2026), as evidenced by Du (Nature Communications (2021) 12: 5000; cited in IDS), as applied to claims 35-41, 44-52, and 54 above, further in view of Ostrov (WO 2021/207213 A2; cited in IDS).
The teachings of Yan are discussed in the 35 U.S.C. § 103 rejection above.
However, Yan does not expressly describe kits comprising an anti-hACE2 antibody of the invention.
The teachings of Hale and Du are recited above.
Ostrov discloses compounds and pharmaceutical compositions for use in treating coronavirus infection from SARS-CoV-2 (e.g., COVID-19), in particular antibodies and epitope-binding fragments thereof that bind to human ACE2 and inhibit the binding of SARS-CoV-2 to ACE2 (e.g., ¶ 7, 13, 19, 71-72). Ostrov further discloses pharmaceutical compositions comprising antibodies of the invention and pharmaceutically acceptable carriers (e.g., ¶ 80-82). Regarding claims 42-43, Ostrov discloses kits comprising a compound or pharmaceutical composition comprising an antibody of the invention, which can be formulated as a solid formulation (lyophilized) or as a suspension, in combination with a diluent (e.g., ¶ 80, 93-96). Ostrov further discloses treatment methods that comprise administering an anti-ACE2 antibody of the invention to a subject who is suffering from COVID-19, is susceptible to COVID-19, or has had known or suspected exposure to SARS-CoV-2 virus (e.g., ¶ 7-15, 19, 57-58, 128-140; claims 1-3, 19-21).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate kits comprising the humanized anti-hACE2 antibody described by Yan based on the further teachings of Ostrov. The skilled artisan would have been motivated to do so because such a kit would have utility in carrying out methods of treating a SARS-CoV-2 infection (i.e., preventing the virus from binding to host cells) while allowing the host ACE2. There would have been a reasonable expectation of success because it is well within the technical skill and grasp of those in the art to generate kits to facilitate ease of administration of therapeutic antibodies.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(1)
Claims 35-37, 39-40, 44-52, and 54-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13-20, and 30-31 of co-pending Application No. 17/499,012 (reference application; cited in PTO-892 mailed March 2026). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
Regarding claims 35-37 and 39-40, co-pending claims 1-3 recite a humanized monoclonal antibody having the same functional properties and an identical heavy chain and light chain CDR structure (amino acid sequences) as the instantly claimed monoclonal antibody comprising “LS” or “YTE” heavy chain modifications.
Regarding claims 44-45, co-pending claims 13-14 recite an isolated nucleic acid encoding the light chain and/or heavy chain of the monoclonal antibody and a recombinant vector comprising the same. Regarding claim 46, co-pending claim 15 recites a pharmaceutical composition comprising the monoclonal antibody.
Regarding claims 47-52 and 54, co-pending claims 16-20 recite methods with a materially identical step of administering the monoclonal antibody of co-pending claim 1.
Regarding claims 55-56, co-pending claims 30-31 recite kits comprising materially identical components as those instantly claimed.
(2)
Claims 35 and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13-20, and 30-31 of co-pending Application No. 17/499,012 (reference application) as applied to claims 35-37, 39-40, 44-52, and 54-56 above, further in view of Lazar (US 2015/0071948 A1; supra), Hale (WO 2021/234402 A2; supra), and Shitara (U.S. Patent No 8,883,981; supra).
The teachings of the co-pending reference application are discussed in the non-statutory double patenting rejection above.
The co-pending claims do not recite that the monoclonal antibody comprises an isotypically IgG1 heavy chain comprising an amino acid sequence corresponding to residues 25-471 of SEQ ID NO: 77 (as set forth in claim 42) or residues 25-471 of SEQ ID NO: 78 (as set forth in claim 43). The co-pending claims also do not recite that the heavy chain may comprise “STR” or “STR/YTE” modifications.
However, these deficiencies are remedied by the teachings of Lazar, Hale, and Shitara as described in the 35 U.S.C. § 103 rejections above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at an anti-ACE2 monoclonal antibody having a modified heavy chain comprising an amino acid sequence corresponding to residues 25-471 of instant SEQ ID NO: 77 or 78, and a light chain comprising an amino acid sequence corresponding to residues 21-230 of instant SEQ ID NO: 76, through a process of routine optimization. The skilled artisan would have been motivated to use an isotypically IgG1 heavy chain because Lazar teaches that the different IgG antibody subtypes have differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization states. These differences affect their therapeutic properties and can be optimized for desired qualities. There would have been a reasonable expectation of success because it is within the technical skill of those in the art to generate IgG antibodies of differing isotypes and/or introduce mutations thereto, and furthermore, there are a finite number of possible IgG Fc structures.
The skilled artisan would further have been motivated to substitute the residues “STR” at positions 234-236 because Hale teaches that this modification reduces FcγR binding while retaining FcRn binding (which improves serum half-life), as well as the substitutions of M252Y/S254T/T256E, as Hale teaches that these modifications also improve serum half-life. There would have been a reasonable expectation of success because the skilled artisan would have recognized that these modifications have suitability for the intended purpose of increasing serum half-life, which is beneficial for antibody-based therapeutics, and it is prima facie obvious to apply a known technique to a known product ready for improvement to yield a predictable result.
(3)
Claims 35, 51, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13-20, and 30-31 of co-pending Application No. 17/499,012 (reference application) as applied to claims 35-37, 39-40, 44-52, and 54-56 above, further in view of Khazaal (Molecules (2022) 27: 2903; supra).
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
The co-pending reference application does not expressly claim treatment methods for subjects who are infected with SARS-CoV-2 and symptomatic of long COVID.
However, this deficiency is remedied by the teachings of Khazaal as set forth in the 35 U.S.C. § 103 rejection above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer the anti-hACE2 antibody such as that taught by the co-pending claims in a method of treating SARS-CoV-2, wherein the subject is symptomatic for long COVID. The skilled artisan would have been motivated to do so because Khazaal teaches that SARS-CoV-2 binding to ACE2 contributes to negative sequelae and long COVID symptoms, and that mitigating RAS signaling dysregulation is a therapeutic strategy that should be explored for long COVID. Furthermore, one of ordinary skill in the art would recognize that those experiencing long COVID symptoms have a clear need to be treated. There would have been a reasonable expectation of success because ACE2 receptors are expressed in multiple body systems and organs (as shown by Khazaal) and because the anti-hACE2 antibody of the co-pending claims binds to ACE2 receptor (and prevents SARS-CoV-2 from doing so) without interfering with its ability to cleave Ang II. As explained by Khazaal, the interference of ACE2 cleaving Ang II impairs the anti-inflammatory effects of the ACE2/Ang-(1-7)/AT2R axis and favors excess activation of the pro-inflammatory ACE/Ang II/AT1R axis.
(4)
Claims 35-41, 44-52, and 54-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 11-31 of co-pending Application No. 17/996,019 (reference application; cited in PTO-892 mailed March 2026) in view of Yan (CN 114805570 A; supra) and Hale (WO 2021/234402 A2; supra), as evidenced by Du (Nature Communications (2021) 12: 5000; supra).
Co-pending claims 1-3 recite a humanized monoclonal antibody (mAb) with identical functional properties to that of claims 35-37. Co-pending claims 11-12 recite an isolated nucleic acid molecule encoding said antibody and a recombinant vector comprising said nucleic acid molecule, pertinent to claims 44-45. Co-pending claim 14 recites a pharmaceutical composition comprising the claimed antibody, relevant to claim 46.
Co-pending claims 15-16 recite a comparable prophylactic method to that of claims 47-50. Co-pending claims 17-19 recite a comparable treatment method to that of claims 51-52 and 54.
Co-pending claims 20-23 recite recombinant AAV vector comprising a nucleic acid encoding the heavy chain and/or light chain of the claimed antibody, as well as a composition comprising said antibody, further relevant to claims 44-46.
Co-pending claims 29-30 recites comparable kits to those recited in claims 55-56.
The co-pending claims do not expressly recite that the humanized anti-hACE2 monoclonal antibody comprises the combination of heavy chain and light chain CDRs or heavy chain modifications set forth in instant claim 35.
However, these deficiencies are remedied by the teachings of Yan, Du, and Hale as set forth in the 35 U.S.C. § 103 rejections above.
In view of the teachings above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a humanized anti-hACE2 monoclonal antibody such as that taught by Yan, further comprising the heavy chain modifications of “STR”, “LS”, “YTE”, or “STR/YTE”, and to use said antibody in methods of prophylaxis or treatment of SARS-CoV-2 infection. The skilled artisan would have been motivated to use the humanized anti-hACE2 antibody described by Yan/Du because this antibody specifically binds to the extracellular portion of hACE2 and inhibits binding of SARS-CoV-2 to hACE2 without significantly inhibiting the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide, and has utility in the treatment and prophylaxis of COVID-19. There would have been a reasonable expectation of success because one of ordinary skill in the art would recognize that the antibodies recited in the co-pending reference application and by Yan/Du are functional equivalents useful for the same purpose. The skilled artisan would have further been motivated to modify the heavy chain of said humanized antibody to comprise one or more of the “STR”, “LS”, “YTE” mutations because, as taught by Hale, these modifications confer the advantages of reducing FcγR binding and improving serum half-life. There would have been a reasonable expectation of success because the skilled artisan would have recognized that these modifications have suitability for the intended purpose of increasing serum half-life, which is beneficial for antibody-based therapeutics, and it is prima facie obvious to apply a known technique to a known product ready for improvement to yield a predictable result.
(5)
Claims 35 and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 11-31 of co-pending Application No. 17/996,019 (reference application) in view of Yan (CN 114805570 A; supra) and Hale (WO 2021/234402 A2; supra), as evidenced by Du (Nature Communications (2021) 12: 5000; supra), further in view of Lazar (US 2015/0071948 A1; supra) and Shitara (U.S. Patent No 8,883,981; supra).
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
The co-pending claims do not recite that the monoclonal antibody comprises an isotypically IgG1 heavy chain comprising an amino acid sequence corresponding to residues 25-471 of SEQ ID NO: 77 (as set forth in claim 42) or residues 25-471 of SEQ ID NO: 78 (as set forth in claim 43).
However, these deficiencies are remedied by the teachings of Lazar and Shitara as set forth in the 35 U.S.C. § 103 rejections above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at an anti-hACE2 monoclonal antibody having a modified heavy chain comprising an amino acid sequence corresponding to residues 25-471 of instant SEQ ID NO: 77 or 78, and a light chain comprising an amino acid sequence corresponding to residues 21-230 of instant SEQ ID NO: 76, through a process of routine optimization. The skilled artisan would have been motivated to use an isotypically IgG1 heavy chain because Lazar teaches that the different IgG antibody subtypes have differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization states. These differences affect their therapeutic properties and can be optimized for desired qualities. There would have been a reasonable expectation of success because it is within the technical skill of those in the art to generate IgG antibodies of differing isotypes and/or introduce mutations thereto, and furthermore, there are a finite number of possible IgG Fc structures.
(6)
Claims 35, 51, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 11-31 of co-pending Application No. 17/996,019 (reference application) in view of Yan (CN 114805570 A; supra) and Hale (WO 2021/234402 A2; supra), as evidenced by Du (Nature Communications (2021) 12: 5000; supra), further in view of Khazaal (Molecules (2022) 27: 2903; supra).
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
The co-pending reference application does not expressly claim treatment methods for subjects who are infected with SARS-CoV-2 and symptomatic of long COVID.
However, this deficiency is remedied by the teachings of Khazaal as set forth in the 35 U.S.C. § 103 rejection above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer the anti-hACE2 antibody such as that collectively taught by the co-pending claims, Yan, and Hale, in a method of treating SARS-CoV-2, wherein the subject is symptomatic for long COVID. The skilled artisan would have been motivated to do so because Khazaal teaches that SARS-CoV-2 binding to ACE2 contributes to negative sequelae and long COVID symptoms, and that mitigating RAS signaling dysregulation is a therapeutic strategy that should be explored for long COVID. Furthermore, one of ordinary skill in the art would recognize that those experiencing long COVID symptoms have a clear need to be treated. There would have been a reasonable expectation of success because ACE2 receptors are expressed in multiple body systems and organs (as shown by Khazaal) and because the anti-hACE2 antibody of the co-pending claims binds to ACE2 receptor (and prevents SARS-CoV-2 from doing so) without interfering with its ability to cleave Ang II. As explained by Khazaal, the interference of ACE2 cleaving Ang II impairs the anti-inflammatory effects of the ACE2/Ang-(1-7)/AT2R axis and favors excess activation of the pro-inflammatory ACE/Ang II/AT1R axis.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
Prosecution Insights