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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 5, 2026 has been entered.
Application Status
The amended claims filed June 5, 2026 are entered. Claim 1 has been amended. Claims 4-7 are 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 Claims 16-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-3, 13-15, and 30-31 pending and 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.
WITHDRAWN REJECTIONS
All prior rejections of claims 4-7 are rendered moot by the cancelation of the claims.
The prior grounds of rejection over claims 1-3, 13-15, and 30-31 under 35 U.S.C. § 112(b) are withdrawn in view of Applicant's amendments to claim 1.
MAINTAINED REJECTIONS AND 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 1-3, 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.
Claim 1 recites 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.
The dependent claims do not remedy this deficiency of claim 1 and are similarly rejected.
If Applicant is intending to limit the positions to that of the EU numbering system, it is suggested that the rejection could be obviated by amending the claim(s) to recite “according to EU numbering” where needed without any parentheses.
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 1-3 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).. This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
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 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.
Response to Arguments
Applicant's arguments filed June 5, 2026 have been fully considered but they are not persuasive.
Applicant traverses the rejection and maintains that one of ordinary skill in the art would not have arrived at the instantly claimed invention based on the teachings of the cited references. Applicant submits that the claimed antibodies “are advantageous in that, importantly, they comprise a serum half-life-extending heavy chain mutation, and they specifically inhibit binding of SARS-CoV-2 to the extracellular portion of hACE2”. Remarks at page 7. Applicant “stresses that not all heavy chain-modified antibodies specific to the extracellular domain of hACE2 are able to inhibit the binding of SARS-CoV-2 to that extracellular portion”, and that an understanding of which antibodies do requires experimentation. Remarks at page 7. Citing Example 12 of the co-pending 18/698,856 application, Applicant further asserts that the anti-hACE2 antibodies H11B11-hIgG1(STR-YTE) and H11B11-hIgG1(STR) were shown to be potent inhibitors of ACE2 binding to all spike and RBD constructs tested, whereas 3E8-hIgG1 and 3E8-hIgG1_LS were not. Remarks at pages 7-8. Applicant concludes that given the uncertainty of the art and need for experimentation, the cited references without more would not have suggested the solution presented by the claimed invention.
In response, with respect to the purported advantages of the instantly claimed antibodies, it is first noted that at the time of filing of the instantly claimed invention that it was known by those of ordinary skill in the art that the recited “YTE” and “LS” mutations in the heavy chain conferred serum half-life extending properties. It was also known that the functional ability to inhibit binding of a particular antigen to a ligand is conferred primarily by its antigen-binding domain (in particular, the CDRs). In the present case, Du teaches before the filing date of the instantly claimed invention that an antibody having the combination of heavy chain and light chain CDRs presently claimed inhibits the binding of SARS-CoV-2 to hACE2.
With respect to the experimental findings described by the Applicant, it is held that the 3E8 antibody comprises a different combination of heavy chain and light chain CDRs than the presently claimed constructs, which would be expected to contribute to the functional differences (i.e., antigen-binding specificity, inhibition vs. agonism of effect, etc.) observed between the H11B11 antibodies and 3E8 antibodies. As submitted by Applicant, the STR and STR-YTE H11B11 antibodies performed similarly as inhibitors of ACE2 binding. These effects are driven by the combination of CDRs in the antigen-binding domain, which do not differ between the prior art construct described by Du and the presently claimed construct. It is understood in the art that the “YTE” or “LS” mutations in the heavy chain would not be expected to contribute to this effect.
For these reasons, the rejection is maintained.
(2)
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 applied to claims 1-3 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 maintained rejection that has been updated to reflect Applicant's claim amendments.
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.
Response to Arguments
Applicant's arguments filed June 5, 2026 have been fully considered but they are not persuasive.
Applicant maintains that “one of ordinary skill, when presented with the cited references, would not have arrived at the claimed antibody or kits for the reasons above regarding claims 1-3 and 13-15. Ostrov does nothing to cure the shortcomings of Du and Ferrari in this regard.” Remarks at pages 8-9.
In response, it is first noted that the arguments with respect to Du and Ferrari are presented above. With respect to the presently claimed kits, it remains held that it is routine and conventional in the art to generate kits containing antibodies and other drug formulations for ease and convenience in medical treatment or other applications. Accordingly, it would have been obvious to generate a kit for the presently claimed antibody.
For these reasons, the rejection is maintained.
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 1-3, 13-15, and 30-31 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 April 24, 2025) in view of Du (Nature Communications (2021) 12: 5000; supra) and Ferrari (WO 2021/234383 A1; supra). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Co-pending claims 1-3 and 9 recite a humanized monoclonal antibody (mAb) with identical functional properties to that of claims 1-3.
Co-pending claims 12-14 recite identical limitations to claims 13-15, respectively.
Co-pending claims 29-30 recites comparable kits to those recited in 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 claim 1, nor that said antibody comprises a heavy chain comprising the YTE or LS modifications. However, these deficiencies are remedied by Du and Ferrari (supra) as set forth 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.
(2)
Claims 1-3, 13-15, and 30-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-56 of co-pending Application No. 18/698,856 (reference application; cited in PTO-892 mailed April 24, 2025). 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. This is a maintained rejection that has been updated to reflect Applicant's claim amendments in the instant and co-pending applications.
Co-pending claims 35-37 and 39-41 recite a humanized mAb with identical structural and functional properties to that of claims 1-3.
Co-pending claims 43-46 recite identical limitations to those of claims 13-15, respectively.
Co-pending claims 55-56 recite identical kits to those of claims 30-31.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments (Combined)
Applicant's arguments filed June 5, 2026 have been fully considered but they are not persuasive.
Applicant states that they will consider filing a terminal disclaimer once the rejections are no longer provisional.
In response, it is held that the non-statutory double patenting rejections will not be held in abeyance and are maintained.
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, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
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