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
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/30/2026 has been entered.
Status of the Claims
2. 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. In the Response of 7/30/2026, claims 1, 35, 37, 39, 41, 44, 50-53, and 55 are amended and new claims 56-58 are added.
Claims 1, 35-37, 39-47 and 50-58 are all the claims for this application.
Applicants amendment of the claims raises new grounds for rejection.
Priority
3. USAN 17/922,230, filed 10/28/2022, and having 3 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.
4. As of 9/1/2026, a total of ten (10) IDS are filed for this application: 10/28/2022; 3/5/2024; 8/2/2024; 11/5/2024; 2/26/2025; 5/23/2025; 11/5/2025; 2/11/2026; 3/23/2026; and 7/30/2026. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Claim Objections
5. The objections to Claims 1, 35-37, 39-47 and 50-55 because of informalities are withdrawn.
a) Claims 1, 35, and 50 are amended to reduce redundancy and verbose language.
b) Claim 51 is amended to replace “sequences” with “sequence”.
c) Claim 53 is amended to insert the second antigen-binding fragment is “a Fab” to comport with claim 1.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
6. The rejection of Claims 37, 39-41, 44, 51-52 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claims 37, 39-41, 44, 51-52 are amended in claim 37 to correct the dependency for the one and only second antigen binding fragment (Fab) of claim 1.
Double Patenting
7. The provisional rejection of Claims 1, 35-37, 39-47 and 50-55 on the ground of nonstatutory double patenting as being unpatentable over claims 6-8, 10-14 and 19-20 of copending Application No. 18/040498 (reference application US 20230405141; now US 12622977 B2) is withdrawn.
The reference application issued as US 12622977 B2 on 2026-05-12 contains claims drawn to the inventive bispecific anti-HER2 antibody but in the form of a drug conjugate. No terminal disclaimer(s) was filed in the prosecution proceeding for the reference application/patent.
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.
8. The rejection of Claim(s) 1, 35-37, 40-42, 44-46, 50, 52, 54, and 56-57 under 35 U.S.C. 103 as being unpatentable over Harding et al (WO 2011/084496; published 4/14/2011; IDS 5/23/2025 (US 8937159) 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 WO 2015077891A1); published 2017-02-02 (IDS of 5/23/2025)) is maintained.
Claims 56-57 are joined under this rejection.
(A) Claim interpretation/ analysis
Claims 1, 35-37, 40-42, 44-46, 50, 52, 54, and 56-57 are drawn to an isolated antibody, comprising a first antigen-binding fragment that is monovalent and specifically binds to extracellular domain (ECD) 4 of HER2, and a second antigen-binding fragment, wherein the first antigen-binding fragment is an scFv and the second antigen-binding fragment is a Fab, wherein the first antigen-binding fragment comprises a heavy chain CDR (HCDR) 1, an HCDR2, and an HCDR3 comprising SEQ ID NOs: 43, 28 and 29, respectively, and a light chain CDR (LCDR) 1, an LCDR2, and an LCDR3 comprising SEQ ID NOs: 30, 31 and 32, respectively.
But for claim 37, where the second target antigen is identified as ECD2 of HER2, none of the claims identify the antigen to which the Fab binds nor a structure of the Fab for the second antigen-binding fragment for the antibody of claim 1. The statements alleging surprising results shown for specific antibody constructs comprising the mutated trastuzumab (VH K30/ VL53) paired with pertuzimab, under the 37 CFR 1.132 Declaration filed 2/4/2026, are insufficient to overcome the rejection of claims 1, 35-37, 40-42, 44-46, 52, 54, 56-57 based upon the art references as set forth in the last Office action because: the evidence and the Declarant’s statements from the affidavit filed are irrelevant to the scope and subject matter of the instant rejected claims.
(B) Applicants allege based on the significant differences between glutamic acid (E) and the substitutions disclosed in Harding in terms of hydrophobicity and/or electric charge (W, A, R or V), the ordinarily skilled person would have been taught away from the K30E substitution.
Response to Arguments
The amino acid E (glutamic acid or glutamate) is most similar in chemical properties to R (arginine) out of the choices provided, because both are polar and electrically charged at physiological pH.
As regards “teaching away” in arguments against a reference or combination of references see MPEP 2145(X)(D)(1) stating in part:
“the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) (“a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.”) (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)).”
A prior art reference may be considered to teach away when "a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant." See In re Gurley, 31 USPQ2d 1130, 1131 (Fed. Cir. 1994). Here in contrast to Applicant’s assertions of teaching away there is no discouragement or skepticism in any one of the three art references for using an K30 (or F53) mutation in a trastuzumab antigen binding fragment such as scfv.
(C) Applicants allege Shanghai concerns the improvement of trastuzumab-DM1 (Kadcyla®), an antibody-drug conjugate (ADC). Its mutation of K30 (and/or K65) in the heavy chain of trastuzumab is made in a completely different context from Harding. Shanghai mutates the lysine residues in the CDRs of trastuzumab so that they are not conjugated to DM1, whose bulkiness causes steric hindrance to the antibody's binding to HER2. These mutations also are said to improve the ADC preparation's homogeneity to some extent. The only impact of these mutations that is reported by Shanghai is that they "do not change [the antibody variant's] binding affinity to the HER2 receptor".
Response to Arguments
The only functional requirement of the instant claims is the trastuzumab portion of the antibody specifically binds ECD4 of HER2. As excerpted from Applicants comments in the Response it is that “these mutations that is reported by Shanghai is that they "do not change [the antibody variant's] binding affinity to the HER2 receptor". The functional attribute of the instant claimed antibody is specific binding to ECD4 of HER2 by the mutated trastuzumab antigen binding fragment.
(D) Applicants allege the ordinarily skilled person, even if seeking to follow the teachings of Shanghai, would have been drawn to arginine, one of the residues disclosed and tested by Shanghai. Arginine is a hydrophilic and charge-conserving substitution that is disclosed by both Harding and Shanghai. The Examiner's choice of glutamic acid for the present rejection is based on impermissible hindsight.
Response to Arguments
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
(E) Applicants allege the Examiner has not articulated any rationale for the selection of (K30* + F53Y) as a lead compound-where * is W, A, V, or R-out of the 11,360 possibilities, for the skilled person to modify it into (K30E + F53Y).
Response to Arguments
When assessing obviousness of a chemical compound, Federal Circuit caselaw generally follows a two-part inquiry referred to as the “lead compound” analysis. However, in Cytiva BioProcess R&D AB v. JSR Corp., the U.S. Court of Appeals for the Federal Circuit (“Federal Circuit” or “CAFC”) explained the flexibility in the use of lead compound analyses when determining patentability or validity of claimed chemical compounds under 35 U.S.C. § 103. While commonly used, the lead compound analysis is not, as a strict rule, always required. Rather, because the Supreme Court emphasized flexibility over rigid and formalistic rules in considering obviousness in KSR, such flexibility should also be applied to obviousness assessment of new chemical compounds. The lead compound analysis typically involves a two-part inquiry, which includes: step 1) determining whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts; and step 2) determining whether the prior art would have supplied one of ordinary skill with a reason or motivation to modify the lead compound to make the claimed compound with a reasonable expectation of success.
Step 1: Harding teaches variants of trastuzumab or binding fragments (scfv) of trastuzumab similar binding affinity or binding affinity improvements relative to trastuzumab. 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 (Tables 4-6) where R is a potential K30 residue substitution. The amino acid E (glutamic acid or glutamate) is most similar in chemical properties to R (arginine) out of the choices provided in Harding for the K30 mutations, because both are polar and electrically charged at physiological pH. Harding teaches at [0092] “Table 19 (19-1 to 19-5; see column CDR-VL2) show the F53Y mutation in the trastuzumab light chain and in Table 5. SHANGHAI teaches two trastuzumab variants: K30E (Embodiment 4: Trastuzumab mutant (heavy chain K30E) (JL-03)); and K30E and K30S (Embodiment 7: Trastuzumab mutant (heavy chain K30E-K65S) (JL-06)) wherein the amino acid E (glutamic acid or glutamate) of SHANGHAI is most similar in chemical properties to R (arginine) out of the choices provided in Harding for the K30 mutations, because both are polar and electrically charged at physiological pH. In fact, two of the three references teach K30 mutations to trastuzumab specifically, and specifically with respect to binding to ECD4 of HER2 in the context of a bispecific format wherein the amino acid E (glutamic acid or glutamate) of SHANGHAI is most similar in chemical properties to R (arginine) out of the choices provided in Harding for the K30 mutations, because both are polar and electrically charged at physiological pH. Weissner teaches the degree of internalization (improved binding) by specific binding of the anti-HER2 antigen-binding constructs (trastuzumab/pertuzumab) can be further improved by increasing the affinity of one or both antigen-binding polypeptide construct for ECD2 or ECD4 where constructs of equivalent affinity that have a Fab/scFv format are internalized (bind) more efficiently than constructs of equivalent affinity that have a Fab/Fab format.
Step 2: With the claim scope limited to two known antibodies in the art in a bispecific format of scfv and Fab with the sole functional attribute being to specifically bind ECD4 of HER2 in the generic claim 1 and to bind ECD2 of HER2 in dependent claim 37, where only the trastuzumab aspect is required to be mutated in a manner that does not disturb specific binding in the bispecific format but which may increase binding, the motivation and reasonable success in producing the invention is provided by not just one reference but the combined teaching of three references for all the reasons set forth on the record.
The rejection is maintained.
New Grounds for Objection
Claim Objections
9. Claims 35, 43, 52 and 55 are objected to because of the following informalities:
a) Amend claim 35 to insert an inclusive (“and”) or alternative (“or”) coordinating conjunction between the “comprising” and “consisting of” phrases.
b) Amend claim 52 to recite “wherein the first antigen-binding fragment is operably linked to the first Fe polypeptide.”
c) Amend claim 43 to recite “a bivalent, bispecific antibody.”
d) Amend claim 55 to correct numerous grammatical errors.
An isolated antibody, wherein the antibody is a bivalent, bispecific antibody[[,]] comprising: a heavy chain with the amino acid sequence set forth in SEQ ID NO: 11[[,]]; a heavy chain with the amino acid sequence set forth in SEQ ID NO: 13[[,]]; and a light chain with the amino acid sequence set forth in SEQ ID NO: 15.
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.
10. Claims 44 and 57 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.
a) Claim 44 recites the limitation "the heavy chain" and “the light chain”. There is insufficient antecedent basis for this limitation in the claim. Claim 44 depends from claims 1 and 37, and neither of which are drawn to a heavy or light chain, but instead a scfv and a Fab. Clarification is requested whether the limitations refer to the reference antibody or the antibody of claim 1.
b) Claim 57 is indefinite and unclear for the limitation "wherein the Fc is derived from human IgG". Claim 57 depends from claims 1, 37, 40, 52, and 56 where claim 40 recites “an Fc” and claim 52 recites “a first Fc polypeptide and a second Fc polypeptide.” The POSA cannot reasonably ascertain whether the Fc in claim 57 refers to claim 40 or the Fc polypeptides of claim 56.
If claim 57 is intended to depend from claim 40, then its subject matter duplicates claim 41.
If claim 57 is intended to depend from claim 52, then the subject matter is broadening from the first and second Fc polypeptides of claim 52 under 112, 4th paragraph.
Conclusion
11. No claims are allowed.
12. 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.
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, 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 A BRISTOL/Primary Examiner, Art Unit 1643
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