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 on October 22, 2025 with the Response to the non-final Office Action are acknowledged. Claims 1-7, 13-20, and 30-31 are pending. Claim 1 has been amended. Claims 8-12 have been canceled. Claims 16-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-7, 13-15, and 30-31 are under examination herein.
Priority
The US filing date of the instant application (October 12, 2021) will be considered the priority date for the reasons of record set forth in the non-final Office Action mailed April 24, 2025.
Objections to Specification Withdrawn
The objection to the disclosure for reciting embedded hyperlinks is withdrawn in view of Applicant’s amendments thereto.
Claim Rejections Withdrawn
All prior rejections to claims 8-12 are rendered moot by the cancelation of the claims.
The rejection of claims 1-7, 13-15, and 30-31 under 35 U.S.C. § 112(a) for failing to comply with the written description requirement is withdrawn in view of Applicant's amendments to claim 1.
The rejection of claims 1-7 15, and 30-31 under 35 U.S.C. § 103 as being unpatentable over Ostrov (WO 2021/207213 A1; cited in IDS) in view of Loibner (US 8,241,864 B2; cited in IDS), as evidenced by Du (Nature Communications (2021) 12: 5000; cited in IDS), is withdrawn in view of Applicant's amendments to claim 1.
The rejection of claims 13-14 under 35 U.S.C. § 103 as being unpatentable over Ostrov (WO 2021/207213 A1; cited in IDS) in view of Loibner (US 8,241,864 B2; cited in IDS), as evidenced by Du (Nature Communications (2021) 12: 5000; cited in IDS) and further in view of Verma (Journal of Immunological Methods (1998) 216: 165-181), is withdrawn in view of Applicant's amendments to claim 1.
The provisional non-statutory double patenting rejections of claims 1-7, 13-15, and 30-31 over U.S. Patent Application No. 17/499,030 and U.S. Patent Application No. 17/499,041 are withdrawn in view of the abandonment of said applications.
The prior grounds of rejection in the provisional non-statutory double patenting rejections of claims 1-7, 13-15, and 30-31 over U.S. Patent Application No. 17/996,019 and U.S. Patent Application No. 18/698,856 are withdrawn in view of Applicant's amendments to claim 1.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
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 1-7, 13-15, and 30-31 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. This is a new rejection necessitated by claim amendment.
Claim 1 recites that the monoclonal antibody “comprises a heavy chain modification selected from the group consisting of M252Y/S254T/T256E (YTE) and M428L/N343S (LS)”. However, the claim does not recite a corresponding numbering system against which to compare the intended locations of the amino acid substitutions, rendering the claim scope ambiguous. By way of example, IMGT.org illustrates that the wildtype positions of 252/254/256 and 428/434 in the human IgG1 heavy chain correspond to M/S/T and M/N, respectively, under EU numbering but not under Kabat numbering (See Office Action Appendix). Furthermore, as evidenced by Shitara (US Patent No. 8,883,981) at Figure 1, the corresponding positions of 252/254/256 and 428/434 for human IgG2, IgG3, and IgG4 also correspond to M/S/T and M/N, respectively, under EU numbering but not under Kabat numbering.
The dependent claims do not remedy this deficiency of claim 1 and are similarly rejected.
Claim Rejections - 35 USC § 112(d)
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.
Claim 7 is 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. This is a new rejection necessitated by amendment.
Claim 7 recites that the monoclonal antibody of claim 1, which comprises three heavy chain CDRs comprising the amino acid sequences of SEQ ID NO: 18-20, respectively, and three light chain CDRs comprising the amino acid sequences of SEQ ID NO: 21-23, respectively, binds to an epitope on hACE2 comprising an amino acid residue at Ser19, His34, Glu35, Glu37, Asp38, Tyr41, Gln42, Leu45, Gln325, Glu329, Asn330, Lys353, Gly354, Asp355, or Arg357. However, as set forth by Applicant, “H11B11 binds to hACE2 residues 24, 25, 27, 28, 31, 79, 82, and 83”. See Remarks filed October 22, 2025 at page 11. See also Zhang (bioRxiv, posted August 24, 2022, doi:10.1101/2022.08.24.505169; cited in IDS) at Figure S3G. Based on this fact, claim 7 fails to include all of the limitations of claim 1 from which it depends, because a monoclonal antibody having the combination of heavy chain and light chain CDRs as set forth in claim 1 would not be expected to bind to an epitope on hACE2 at the amino acid residues of Ser19, His34, Glu35, Glu37, Asp38, Tyr41, Gln42, Leu45, Gln325, Glu329, Asn330, Lys353, Gly354, Asp355, or Arg357. Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP § 2112.01.
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 § 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.
Claims 1-7 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Du (Nature Communications (2021) 12: 5000; cited in IDS) in view of Ferrari (WO 2021/234383 A1; filed May 19, 2021), as further evidenced by Zhang (bioRxiv, posted August 24, 2022, doi:10.1101/2022.08.24.505169; cited in IDS) and Applicant’s Remarks filed October 22, 2025. This is a new rejection necessitated by claim amendment.
Du describes the isolation and humanization of an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody, “h11B11”, which has potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages (Abstract). Relevant to claims 1-3, the antibody was generated by immunizing BALB/c mice with hACE2(19-615) soluble antigens in a prime-boost immunization regiment, and the resulting murine h11B11 antibody was humanized through CDR grafting onto human acceptor germline frameworks to minimize immunogenicity, antibody-dependent cellular phagocytosis, and antibody-dependent cell cytotoxicity (Results, page 2). The “11B11” antibody taught by Du, which comprises a combination of heavy chain and light chain CDRs sharing 100% sequence identity to those instantly claimed (e.g., Supplementary Figures 2a and 2b), binds an epitope of hACE2 on the N-terminal helix (NTH), which comprises the extracellular domain (page 7, left column; Figure 5). The h11B11 also blocks binding of the SARS-CoV-2 receptor-binding domain (RBD) to hACE2 (page 2, right column; Figure 1a; page 7, left column; Figure 5) and does not significantly inhibit the ability of hACE2 to cleave angiotensin II (pages 2-3; Figure 1d). Relevant to claims 4-7, as evidenced by Zhang and by Applicant (see Remarks at page 11), the h11B11 antibody binds to hACE2 residues 24, 25, 27, 28, 31, 79, 82, and 83.
Relevant to claim 13, Du discloses sequences of the variable regions of the h11B11 antibody obtained through rapid amplification of cDNA ends amplification (page 2).
Relevant to claim 15, Du discloses the administration of h11B11 as a pharmaceutical composition (5 mg/kg or 25 mg/kg) for treating SARS-CoV-2 infection in mice (e.g., Results, pages 4-5; Methods, pages 9-10).
However, Du does not expressly teach that the h11B11 antibody comprises heavy chain modifications selected from the group consisting of M252Y/S254T/T256E (YTE) and M428L/N434S (LS).
Ferrari discloses polypeptides for blocking SARS-CoV-2 infection, comprising an antigen-binding domain (e.g., scFv, single-domain antibody) that binds specifically to the hACE2 ectodomain and a half-life extending domain (e.g., Abstract; Summary, pages 3-6, 35-43; Figure 2). Further relevant to claim 1, Ferrari teaches embodiments in which said half-life extending moiety is an Fc region, e.g., a variant of a wildtype Fc region that does not interact with selected Fc receptors and displays improved circulation or serum half-life, comprising modifications such as M252Y/S254T/T256E and/or M428L/N434S (e.g., pages 42-43).
Relevant to claims 13-14, Ferrari provides nucleic acids encoding the polypeptides of the invention and expression vectors comprising the same (e.g., page 5). Relevant to claim 15, Ferrari discloses pharmaceutical compositions comprising the polypeptide of the invention and a pharmaceutically acceptable carrier (e.g., page 5).
Based on the teachings of Ferrari, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify h11B11, the humanized anti-hACE2 monoclonal antibody, disclosed by Du by incorporating into the heavy chain Fc the “YTE” or “LS” modifications. The skilled artisan would have been motivated to do so because Ferrari teaches that these modifications reduce binding of the antigen-binding constructs with select Fc receptors and increase serum half-life of the antibody, thereby improving circulation of the antibody after administration. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the suitability of the YTE and LS heavy chain Fc modifications for the intended purpose of increasing serum half-life of the h11B11, anti-hACE2 antibody, disclosed by Du, and such a modification would constitute use of a known technique in the art to improve a similar product (i.e., an anti-hACE2 antibody) in the same way.
Claims 1 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Du (Nature Communications (2021) 12: 5000; cited in IDS) in view of Ferrari (WO 2021/234383 A1; filed May 19, 2021), as further evidenced by Zhang (bioRxiv, posted August 24, 2022, doi:10.1101/2022.08.24.505169; cited in IDS) and Applicant’s Remarks filed October 22, 2025, as applied to claims 1-7 and 13-15 above, further in view of Ostrov (WO 2021/207213 A1; earliest priority date: April 7, 2020; cited in IDS). This is a new rejection necessitated by claim amendment.
The teachings of Du are recited in the 35 U.S.C. § 103 rejection above.
However, Du does not expressly disclose kits comprising the h11B11 antibody.
The teachings of Ferrari are recited in the 35 U.S.C. § 103 rejection above.
Ostrov discloses antibodies and epitope-binding fragments thereof that bind to human ACE2 and inhibit the binding of SARS-CoV-2 to ACE2 (¶ 13, 19, 71-72). Relevant to claims 30-31, 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 liquid suspension, in combination with a diluent (¶ 80, 93-95). Said kits also comprise instructions for use in treating a SARS-related beta-coronavirus infection, alone or in combination with other beta-coronavirus therapies (¶ 93-95).
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 kit comprising an anti-hACE2 antibody, e.g., the humanized h11B11 antibody described by Du, based on the disclosure of Ostrov. The skilled artisan would have been motivated to do so because such a kit would have utility in facilitating ease of use of an anti-hACE2 antibody in a method of treatment for SARS-CoV-2 infection. There would have been a reasonable expectation of success because generating a pharmaceutical kit constitutes applying a known technique to a known product (i.e., an anti-hACE2 antibody) ready for improvement to yield a predictable result.
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.
Claims 1-7, 13-15, and 30-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 12-14, and 29-30 of co-pending Application No. 17/996,019 (reference application; cited in PTO-892 mailed April 24, 2025) in view of Du (Nature Communications (2021) 12: 5000; supra) and Ferrari (WO 2021/234383 A1; supra). This is a new rejection necessitated by claim amendment.
Co-pending claims 1-3 and 9 recite a humanized monoclonal antibody (mAb) with identical functional properties to that of instant claims 1-3.
Co-pending claims 4 and 6 recite identical epitopes to which the co-pending mAb does not bind as instant claims 4 and 6. Co-pending claim 7 recites identical residues as instant claim 7 to which the co-pending mAb specifically binds.
Co-pending claims 12-14 recite identical limitations to instant claims 13-15, respectively.
Co-pending claims 29-30 recites comparable kits to those recited in instant claims 30-31.
However, the co-pending reference application does not recite that the monoclonal antibody comprises the heavy chain and light chain CDRs set forth in instant claim 1, nor that said antibody comprises a heavy chain comprising the YTE or LS modifications.
The teachings of Du and Ferrari are recited in the 35 U.S.C. § 103 rejection 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 a humanized monoclonal antibody that specifically binds to the extracellular portion of hACE2, inhibits binding of SARS-CoV-2 to said extracellular portion, and does not significantly inhibit the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide, which comprises the combination of heavy chain and light chain CDRs comprising SEQ ID NO: 18-20 and 21-23, respectively, and the heavy chain modifications of M252Y/S254T/T256E or M428L/N434S, based on the further teachings of Du and Ferrari. The skilled artisan would have been motivated to do so because (1) Du discloses that an anti-hACE2 antibody comprising said combination of heavy chain and light chain CDRs displays each of the functional properties of specifically binding to the extracellular portion of hACE2, inhibiting binding of SARS-CoV-2 to said extracellular portion, and not significantly inhibiting the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide; and (2) Ferrari teaches that the YTE heavy chain Fc modification increases serum half-life of antibody Fc-containing constructs. There would have been a reasonable expectation of success because chemical compositions and their properties are inseparable, and products of identical composition cannot have mutually exclusive properties. See MPEP § 2112.01.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 13-15, and 30-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-17, and 32-33 of co-pending Application No. 18/698,856 (reference application; cited in PTO-892 mailed April 24, 2025) in view of Ferrari (WO 2021/234383 A1; supra).
Co-pending claims 1-3 and 10 recite a humanized mAb with identical functional properties to that of instant claims 1-3. Co-pending claim 9 recites identical heavy chain and light chain CDRs (including the CDRh3 comprising SEQ ID NO: 20) to those recited in the mAb of instant claim 1.Co-pending claims 4-6 recite identical epitopes to which the co-pending mAb does not bind as those recited in instant claims 4-6.
Co-pending claims 7-8 recite identical amino acid residues (and additionally Ala25) to which the co-pending mAb binds relative to instant claim 7.
Co-pending claims 15-17 recite identical limitations to those of instant claims 13-15, respectively.
Co-pending claims 32-33 recite identical kits to those of instant claims 30-31.
However, the co-pending reference application does not recite that the monoclonal antibody comprises a heavy chain comprising the YTE or LS modifications.
The teachings of Ferrari are recited in the 35 U.S.C. § 103 rejection 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 a humanized monoclonal antibody that specifically binds to the extracellular portion of hACE2, inhibits binding of SARS-CoV-2 to said extracellular portion, and does not significantly inhibit the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide, which comprises the combination of heavy chain and light chain CDRs comprising SEQ ID NO: 18-20 and 21-23, respectively, and the heavy chain modifications of M252Y/S254T/T256E or M428L/N434S, based on the further teachings of Ferrari. The skilled artisan would have been motivated to do so because Ferrari teaches that the YTE heavy chain Fc modification increases serum half-life of antibody Fc-containing constructs. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the suitability of the YTE and LS heavy chain Fc modifications for the intended purpose of increasing serum half-life of the anti-hACE2 antibody, and such a modification would constitute use of a known technique in the art to improve a similar product (i.e., the anti-hACE2 antibody recited in the co-pending reference application) in the same way.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Citation of Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Yan (CN 114805570 A; machine translation attached) discloses an anti-human ACE2 monoclonal antibody, named as h11B11, 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 instant claim 1, as well as polynucleotides encoding the heavy chain and light chain of said antibody and an expression vector comprising said polynucleotide.
Conclusion
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, 9:00am - 5:30pm 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