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 .
Claim Status
Claims 2-4, 12-13, 18, and 20 are cancelled. Claims 1, 5-11, 14-17, and 19 as filed on 22 December 2025 are pending. Claim 17 is withdrawn. Claims 1, 5-11, 14-16, and 19 are under examination.
Rejections Withdrawn
Applicant’s arguments, see Remarks 12/22/2025, filed12/22/2025, with respect to rejections over 35 U.S.C. 102 and 103 have been fully considered and are persuasive. The rejections of claims 1-16 and 18-20 has been withdrawn.
The common light chains of SEQ ID NO: 1 with an amino acid residue substitution selected from the group consisting of: (1) F53Y; (2) F53Y, L54R and S56T: (3) N30S and F53Y; and (4) N30S, F53Y, L54R and S56T appear to be free of the art.
Maintained and Clarified
Nucleotide and/or Amino Acid Sequence Disclosures
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834 for the following. The examiner has noted that Applicant has in the specification additional reference to SEQ ID NO: 54, 64, 92 in Table 6. However, this application has 19 sequences listed number 1-19 in total. Appropriate correction is requested. Please be cautious on submitting new matter if the sequence listing is to be amended.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Clarification:
Applicant argues that the sequences are incorporated into the specification from US 20170029529.
Applicant has not correctly incorporated sequences by reference. To use the sequence from the cited publication applicant need to incorporate the document in its entirety. The Examiner has not found an incorporation of the document cited.
Examiner points to MPEP 608.01 (p).
New Rejection Necessitated By Applicant Amendment
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.
Claims 1, 5-11, and 14-16 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 incorrectly incorporates sequences by using “SEQ ID NOs:” and not “SEQ ID NO:”. The lack of incorporation renders the claim indefinite. Claims 5-11 and 14-16 inherit this issue without correction.
The claims were examined as reciting “SEQ ID NO:” at all locations.
New Rejection Necessitated By Applicant Amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5-11, 14-16, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
Claim 1 is to an anti-HER2 bispecific antibody that binds domain II and domain IV of the extracellular domain of HER2 wherein the common light chain is SEQ ID NO: 1 with an amino acid residue substitution selected from the group consisting of: (1) F53Y; (2) F53Y, L54R and S56T: (3) N30S and F53Y; and (4) N30S, F53Y, L54R and S56T; the second heavy chain is set forth in SEQ ID NO: 3 with mutation D102E; and the first heavy chain comprises a HCDR1 of SEQ ID NO: 5, HCDR2 of any one of SEQ ID NO: 6-13, and HCDR3 of any one of SEQ ID NO: 14-19.
Claim 1 allows for mixing and matching of HCDR2 and HCDR3 in the first heavy chain which would result in changes to protein structure and binding activity.
Claims 5-11 and 14-16 do not provide any further limitations on the sequence of the bispecific molecule of the claims.
Claim 19 provides additional limitations on the CDR combinations of the first heavy chain CDRs wherein the first heavy chain comprises one of: a) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 6, and a HCDR3 as shown in SEQ ID NO: 15;b) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 7, and a HCDR3 as shown in SEQ ID NO: 16;c) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 8, and a HCDR3 as shown in SEQ ID NO: 15;d) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 9, and a HCDR3 as shown in SEQ ID NO: 15;e) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 10, and a HCDR3 as shown in SEQ ID NO: 15;f) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 7, and a HCDR3 as shown in SEQ ID NO: 17;Response to Non-Final Office Action g) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 11, and a HCDR3 as shown in SEQ ID NO: 17;h) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 12, and a HCDR3 as shown in SEQ ID NO: 17;i) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 13, and a HCDR3 as shown in SEQ ID NO: 17;j) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 7, and a HCDR3 as shown in SEQ ID NO: 18; or k) a HCDR1 as shown in SEQ ID NO: 5, a HCDR2 as shown in SEQ ID NO: 7, and a HCDR3 as shown in SEQ ID NO: 19.
Summary of Species Disclosed in the original specification:
Applicant recites functional bispecific molecules with known binding activity of KJ1015A, KJ1015B, KJ1015C, and KJ1015D. The table below shows the known sequences of the bispecific antibodies with binding activity shown in Figures 3-5.
From Tables 5 & 6
Common Light
2nd Heavy Chain
1st Heavy Chain
HCDR1
HCDR2
HCDR3
SEQ ID NO:
SEQ ID NO:
SEQ ID NO:
KJ015 A
SEQ ID NO: 1 F53Y
SEQ ID NO: 3
5
6
15
KJ 015 B
SEQ ID NO: 1 F53Y
SEQ ID NO: 3
5
7
16
KJ015C
SEQ ID NO: 1 F53Y & N30S
SEQ ID NO: 3 D102E
5
6
15
KJ015D
SEQ ID NO: 1 F53Y & N30S
SEQ ID NO: 3 D102E
5
7
16
All heavy chain 2 CDR combinations are shown as binding in Table 5 but these are not with the mixing and matching of first heavy and the common light chain.
State of the Relevant Art:
Human Epidermal Growth Factor Receptor 2 (HER2) is highly expressed in breast cancer, ovarian cancer, and gastric cancer. It is a known target for treatment of these cancers including by binding with antibodies (Tai et. al. Journal of Controlled Release. 146:264-275. (2010) (Of Record) (abstract). The extracellular domain of HER2 is approximately 600 residues which is divided into four subdomain. It is known in the art that pertuzumab binds domain II while trastuzumab binds domain IV ( page 265 in col 2 in par 3 and Figure 1). HER2 is important to all stages of healthy cell development while its overexpression could directly lead to tumorigenesis and metastasis (page 266 in col 2 in par 3). The antibodies that target the extracellular domain of HER2 in cancer therapy generally suppress HER2 dimerization and thus suppress HER2 activation (page 269 in col 1 in par 3).
It has been established for decades in the art that the formation of an intact antigen-binding site in a conventional antibody requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (Of Record) (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule”, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Further, the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al., Proc. Nat’l Acad. Sci. USA, 79:1979-83 (1982) (Of Record). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. E.g., Abstract. Similarly, Brown et al., J. Immunol., 156(9):3285-91 (1996) (Of Record), teach that although a single amino acid change in CDR2 of heavy chain of a particular antibody was tolerated, the antibody lost binding upon introduction of two amino acid changes in the same region. Brown, p. 3290 and Tables 1 and 2. Table 1 of Brown shows that even a conservative substitution does not ensure that functionality of the antibody is retained. These older citations are supported my more recent discoveries of why these substitutions change antibody activity. Marvin et. al., Biochemistry, 42(23):7077-7083 (2003) (“Of Record) teaches that changes to the heavy and light chains altered binding affinity (Table 2) with changes to the CDR having large impacts but the changes with the largest impact were from residues in the CDR, but not from ones interfacing with the antigen ( Page 7081 in col 1 “Conclusions and Discussion” and Page 7082 in Figure 4).
The earlier work of Rudikoff and Brown is confirmed by Chiu et al., Antibodies, 8(55):1-80. (2019) (Of Record). Chiu teaches that the complementarity-determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary structures that can recognize and bind antigens (Page 4 in 1.2.2 first and last paragraphs and Figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3, HCDR1 and HCDR2 could not predict HCDR3 In the decades since Rudikoff the field has increased understanding of antibody engineering. Structure-Based antibody engineering is unable to predict antibody sequences (Page 6 in 1.2.6, Pages 10-11 in Section 2 in particular second paragraph of page 11). Chiu notes the advancement in antibody engineering but notes it is still not possible to predict the point mutations that would improve affinity in both antibodies and multispecific molecules (Page 51 in lines 6-12).
Bispecific antibodies can vary in structure from traditional antibodies that comprise a VH and VL, but the antigen binding domains still rely on the CDRs for their binding specificity and changes to the CDRs of the first and second heavy chains or the light chains will result in changes to the binding of the bispecific as shown by Chiu and further by Brinkmann (Brinkmann and Kontermann. Mabs. 9(2):182-212. (2017) (Of Record) (abstract, page 188 in col 2 in par 1, page 198 in col 1 in par 3, col 2 in lines 3-19).
In general, absent at least the conserved structure of the CDRs of the first heavy chain, second heavy chain, and light chain of a bispecific antibody, the skilled artisan generally would not be able to visualize or otherwise predict what a bispecific antibody with a particular set of functional properties would look like structurally.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
As explained previously, the art generally accepted that combinations of CDRs within a common light chain and a first and second heavy chain in the context of framework sequences were essential for binding specificity. Changes to residues in the CDRs change not just what the antigen binding molecule binds, but their specificity of domain of the target, and their activity upon binding. As shown by the art a single change in an amino acid in the CDRs changes the function and antibody. The mixing and matching of entire CDRs would also change the function. Thus, there is no shared structure or property provided in the claims. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for antigen-binding molecules other than those that are bispecific antibodies disclosed by the applicant in Table 6 where the sequences have been provided in the application.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know which of the countless combinations encompassed by the claims that meet the highly general structural requirements of the claims would also possess the required functional activity. Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of the antibodies as broadly claimed at the time the application was filed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
The 112a rejection can be overcome by limiting the claims to bispecific antibodies that have fully defined CDRs of the common light chain and the first and second heavy chains and have written support at the time of filing.
Applicant Arguments
Applicant argues that the amendment to the claims overcomes this rejection by the limitations added in the amendment of the claims.
The claims are now limited to 3 common light chains and one second heavy chain. The first heavy chain for claims 1, 5-11, and 14-16 allow for mixing and matching of HCDR2 and HCDR3. Claim 19 is limited to second heavy chains shown in Table 5 of the specification.
Applicant argues Example 8 shows the binding activity of all bispecific antibodies of the claims.
Response to Arguments
Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive.
As stated in both rejections under 35 U.S.C. 112(a) written description for antibodies relies upon an intact binding domain which comes from the CDRs of the bispecific. For the bispecific antibody of the specification and the claims this is from two heavy chains and a common light chain of specific CDRs. It is well known in the art that changes to a single amino acid in the CDRs of an antibody changes its binding activity in unpredictable ways. For claims 1, 5-11, and 14-16 the first heavy chain allows for mixing and matching of HCDRs which would have unpredictable protein structure and binding activity.
All pending claims allows for the mixing and matching of heavy chains and light chains that applicant has not shown binding activity or possession of.
Conclusion
No Claims allowable.
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.
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/F.E./Examiner, Art Unit 1643
/Meera Natarajan/Primary Examiner, Art Unit 1643
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