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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-31 are the original claims filed on 10/28/2022. In the Preliminary Amendment of 10/28/2022, Claim 1 is amended, claims 2-31 are canceled, and claims 32-50 are added. In the Preliminary Amendment of 4/15/2024, Claim 1 is amended. In the Response of 8/30/2024, Claims 1, 35-47 and 50 are amended, claims 32-34 and 48-49 are cancelled, and new Claims 51-55 are added. In the Response After-final of 11/5/2024, Claim 47 is amended. No claims are filed with the RCE of 2/26/2025. No claims are filed with the RCE of 5/23/2025. In the Response of 10/14/2026, claim 1 is amended and claim 38 is canceled.
Claims 1, 35-37, 39-47 and 50-55 are all the claims for this application.
Applicant’s amendment of the claims raises new grounds for objection and rejection. The Office Action is final.
Priority
2. USAN 17/922,230, filed 10/28/2022, and having 2 RCE-type filing therein is a National Stage entry of PCT/CN2021/090794, International Filing Date: 04/29/2021
claims foreign priority to CN 202010365705.9, filed 04/30/2020.
Information Disclosure Statement.
3. As of 1/30/2026, a total of seven (7) IDS are filed for this application: 10/28/2022; 3/5/2024; 8/2/2024; 11/5/2024; 2/26/2025; 5/23/2025; and 11/5/2025. The corresponding initialed and dated 1449 form is considered of record.
Withdrawal of Rejections
Double Patenting
4. The provisional rejection of Claims 1, 35-47 and 50-55 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/593,989 (reference application US 20220143178) in view of Harding et al (WO 2011/084496; published 4/14/2011; IDS 5/23/2025) in view of SHANGHAI JIAOLIAN PHARMACEUTICAL RESEARCH DEVELOPMENT (CN103319599A (Google patent translation); published 2015-02-18; IDS of 5/23/2025; “SHANGHAI”) and further in view of Weisser et al (JP 2017503480 (Google patent translation or WO2015077891A1); published 2017-02-02 (IDS of 5/23/2025)) is moot for canceled claim 38 and withdrawn for the pending claims. AS memorialized in the telephone interview of 10/14/2025, neither the reference assignee nor the reference inventors are identical or overlapping to those corresponding, respectively, to the instant application.
Rejections Maintained
Claim Rejections - 35 USC § 103
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.
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.
5. The rejection of Claim(s)
Claim interpretation
None of the rejected pending claims 1, 35-37, 39-43, 45-47, 51-52 and 54-55 are associated with or required to be reduced in aggregation much less possess any property other than binding to the recited antigen. Accordingly, the instant claimed substitution of residue K30 and/or residue F53 is not predicated on any particular functional outcome to be achieved, but for claims 44, 51 and 53. Claim 47 is a method of treating any HER2 expressing cancer for the genus of cancers recited in claim 47.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
A) Applicants allege Harding does not teach antibody variants of Herceptin comprising a second antibody arm comprising a Fab.
Response to Arguments
Harding teaches per se bispecific formats for the antibodies of the invention at
[0092] Table 19 (19-1 to 19-5) show known mutations in the trastuzumab light chain CDRs found in bispecific antibody phage binding libraries that can be incorporated into the antibodies of the disclosure.
Harding teaches per se heteroconjugate antibodies of the invention as corresponding to bispecific antibodies and antibody fragments such as Fab at
[0107] The present disclosure provides anti-HER2 antibodies. Unless indicated otherwise, the term "antibody" (Ab) refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen, and includes polyclonal, monoclonal, genetically engineered and otherwise modified forms of antibodies, including but not limited to chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bispecific antibodies, diabodies, triabodies, and tetrabodies), and antigen binding fragments of antibodies, including e.g., Fab', F(ab')2, Fab, Fv, rlgG, and scFv fragments.
Harding teaches per se the anti-HER2 antibody as a bispecific at
[0121] The anti-HER2 antibodies of the disclosure can be bispecific antibodies. Bispecific antibodies are monoclonal, often human or humanized, antibodies that have binding specificities for at least two different antigens. In the present disclosure, one of the binding specificities can be directed towards HER2, the other can be for any other antigen, e.g., for a cell-surface protein, receptor, receptor subunit, tissue-specific antigen, virally derived protein, virally encoded envelope protein, bacterially derived protein, or bacterial surface protein, etc.
B) Applicants allege Harding does not disclose K30E nor the combination of K30E + F53Y.
Response to Arguments
Harding provides the motivation to identify improved HER2 antibodies stating:
“there is a need to provide improved monoclonal antibodies that interfere with the HER2 receptor that overcome one or more of these problems, for example, by generating variants with higher affinity than Herceptin.RTM. that can be administered at reduced dosages, or variants with reduced immunogenicity and other side-effects as compared to Herceptin.RTM.. Furthermore, there is a need to provide variants with increased expression in heterologous hosts, with increased solubility, with decreased heterogeneity due to glycosylation and/or with increased stability, e.g., with respect to oxidation, deamidation and/or cyclization of amino acids.”
Cyclization of amino acids, forming cyclic peptides or reducing linear backbone flexibility, significantly impacts peptide and protein aggregation, either by inhibiting amyloid formation through conformational restriction or by promoting self-assembly of short peptides into nanostructures. Accordingly, Harding addresses the need for reduced aggregation.
Harding teaches the substitution of identical residues in the HC and the LC in Figures 5-7 within HER antibodies of the invention.
Figure 5 HC= K30 (W,A) (HCDR1)
Figure 7 HC= K30 (R,V) (HCDR1)
Figure 6 LC= F53 (W,Y) (CDR2)
Harding teaches the hydrophilic substitutions of identical residues in the HC and the LC in Tables 4-6 within HER antibodies of the invention. Harding exemplifies residue substitutions at positions recited in the instant claims at positions 30 and 53 in the VH and VL domains, respectively, of trastuzumab. For example:
K30 in the VH domain (Table 4); F53Y in the VL domain (Table 5); and
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K30 in the VH domain (Table 6).
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C) Applicants allege SHANGHAI does not teach or reasonably suggest conjugating one arm of trastuzumab to a second arm comprising an Fab. Secondly, Shanghai fails to teach a construct comprising F53Y, much less in combination with K30E.
Response to Arguments
SHANGHAI provides the motivation to identify improved HER2 antibodies by the introduction of hydrophilic amino acids into Herceptin at 30 (i.e., K30E) and/or 65 to improve pharmaceutical activity.
SHANGHAI teaches the antibody of the invention may comprise a Fab or Fv fragment:
“the present invention, monoclonal antibody also comprises chimeric antibody and fragment thereof especially, namely the part of the heavy chain of antibody and/or light chain come from certain, certain class or certain subclass, rest part then with another kind of, class or subclass. Antibody fragment comprises the part of antibody, and best is antigen binding domain or variable region. Such as Fab, the part of Fab, the dimeric forms of the part of Fab2 or Fab, or even Fv fragment.”
SHANGHAI teaches the antibody of the invention may comprise a bispecific:
Antibody specifically comprises complete monoclonal antibody in this explanation of getting its broad sense, polyclonal antibody, and bispecific antibody and antibody fragment are as long as they have required biological activity.
SHANGHAI specifically teaches the advantage of a K30E substitution is to lessen the length of the lysine position (K) to increase antigen contact and to improve hydrophilicity:
“Analyze from the crystalline structure (Protein Data Bank numbering 1N8Z) of Herceptin and ErbB2, the heavy chain of Herceptin and the Methionin of variable region of light chain and ErbB2 do not have direct strong interaction, yet because 30 of heavy chains and 65 s' the close ErbB2 of lysine side-chain, and side chain stretches to the ErbB2 direction, on the side chain amino coupled of these 2 Methionins behind the DM1, can form very huge side chain stretching, extension, thereby have influence on the combination of antibody and antigen.The variable region of heavy chain 30 of Herceptin and 65 Methionin, all be in the antibody protein molecular surface, and the non-antibody skeleton construction can't make the skeleton structure of albumen change with the hydrophilic amino acid replacement, and then affects the stable of structure and active to the combination of ErbB2.”
“Main technical schemes of the present invention is: replace the variable region of heavy chain 30 of Herceptin or/and 65 Methionin with hydrophilic amino acid, comprise the arginine that charge property is relatively conservative, the aspartic acid that charge property is opposite and L-glutamic acid, the Histidine of weak charge, glutamine, l-asparagine also comprise uncharged Serine etc.”
D) Applicants allege Weisser teaches the combination of two monospecific antibodies. More importantly, Weisser is silent regarding the specific combination of the K30E and F53Y mutations, which does not remedy the defects of Harding and Shanghai. “As shown in the application as filed, the bispecific antibody of the pending claims outperformed the treatment of a 1:1 combination of trastuzumab with pertuzumab both in killing cancer cell lines, and reducing tumors in mice. See, for example, Examples 8 and 12. This effect could not be reasonably predicted by Weisser, given that they do not teach or reasonably predict the fusion model, nor the specific variations in the pending claims.”
Response to Arguments
The rejection is maintained as regards Weisser because none of the claims recite much less imply a “fusion model”. The specification does not mention any such construct. The specification is silent for the term “fusion”. Applicants comment is not relevant to what is being claimed, therefore the additional comments as regards Weisser are not considered but are placed in the file.
Notably, the figure in the affidavit does not comport to the conventional meaning of a fusion or fusion construct:
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This response is incomplete.
E) As regards the 1.132 affidavit of 10/14/2025, Applicants allege the Inventor Declaration submitted herewith, constructs comprising K30E and F53Y outperformed wild type in reduced aggregation, killing of cancer cell lines, and reducing tumor volumes in mice. These constructs also showed reasonable tolerance and effectiveness in clinical patients who did not respond to other HER2-targeting treatments; and the Inventor Disclosure filed herewith, antibodies comprising an scFv have different aggregation properties than antibodies comprising an Fab alone. Thus, one skilled in the art would not be able to reasonably predict the properties of K30E in antibody aggregation for antibodies comprising scFv.
Response to Arguments
But for claims 44, 51 and 53, none of the rejected pending claims 1, 35-37, 39-43, 45-47, 50, 51-52 and 54-55 are associated with nor are required to be reduced in aggregation much less any property other than binding to an antigen. Accordingly, the instant claimed substitution of residue K30 and/or residue F53 is not predicated on any particular functional outcome to be achieved. Claim 47 is a method of treating any HER2 expressing cancer for the genus of cancers and is without explicit claims to effecting aggregation as a means to achieving a treatment effect.
Note that as regards a POSA reasonably predicting the properties of K30E in aggregation, see the comments above with respect to SHANGHAI.
Finally, in the affidavit of 10/14/2025, the declarant alleges 3 Exhibits are attached:
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No copies of the references for those so named as Exhibits 1-3 in the affidavit are of record in any IDS filed for the application much less with the Response of 10/14/2025. This response is incomplete.
For all of the foregoing 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.
6. The provisional rejection of Claims
The reference claims are not afforded safe harbor protection under 35 USC 121 because the claims do not share continuity or restriction/speciation with the claims of the instant application.
Applicants invocation of a withdrawal of the provisional rejection under MPEP 804(I)(1)(i) is not ripe in view of the outstanding and new grounds for rejection of the claims.
This is a provisional nonstatutory double patenting rejection.
New Grounds for Objection
Claim Objections
7. Claims 1, 35-37, 39-47 and 50-55 are objected to because of the following informalities:
a) Claims 1, 35-37, 39-47 and 50-55 are objected to for redundant and verbose language that does not further limit the claims.
i) Amend claim 1 to recite:
An isolated antibody, comprising a first antigen-binding fragment that is monovalent and specifically binds to ECD4 antigen of HER2 on an HER2- expressing cell, and a second antigen-binding fragment, wherein the first antigen-binding fragment is [an] a scFv and the second antigen-binding fragment is a Fab,
wherein the first antigen-binding fragment comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 comprising the amino acid sequences according to SEQ ID NOs: 43, 28 and 29, respectively, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 comprising the amino acid sequences according to SEQ ID NOs: 30, 31 and 32, respectively.
ii) Amend claim 35 to recite:
The antibody according to claim 1, wherein the first antigen-binding fragment comprising a heavy chain variable region and a light chain variable region comprises the amino acid sequences according to SEQ ID NOs: 35 and 36, respectively; or the first antigen-binding fragment consisting of a heavy chain variable region and a light chain variable region consists of the amino acid sequences according to SEQ ID NOs: 35 and 36, respectively.
iii) Amend claim 50 to recite:
A method for enhancing resistance of an antibody to aggregation,
comprising modifying the antibody comprising a first antigen-binding fragment that is monovalent and specifically binds to ECD4 antigen of HER2 on an HER2- expressing cell, wherein the first antigen-binding fragment is a scFv, wherein the first antigen-binding fragment comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 comprising the amino acid sequences according to SEQ ID NOs: 43, 28 and 29, respectively, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 comprising the amino acid sequences according to SEQ ID NOs: 30, 31 and 32, respectively.
b) Amend Claim 51 to replace “sequences” with “sequence” in both instances.
c) Amend Claim 53 to insert that the second antigen-binding fragment is “a Fab” in order to comport with amended claim 1.
Appropriate correction is required.
New Grounds for Rejection
Claim Rejections - 35 USC § 112
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.
8. Claims 37, 39-41, 44, 51-52 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 37, 39-41, 44, 51-52 are indefinite for reciting in claim 37, “wherein the antibody further comprises a second antigen-binding fragment that is monovalent and specifically binds to ECD2 antigen of HER2 on an HER2-expressing cell.” Amended claim 1 and from which claims 37, 39-41, 44, 51-52 depend, is directed to “a second antigen-binding fragment” and “and the second antigen-binding fragment is a Fab.” The occurrence of another second antigen-binding fragment is confusing and unclear for the rejected claims. The POSA cannot reasonably ascertain the full metes and bounds of the invention.
Conclusion
9. No claims are allowed.
10. 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.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie 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.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643