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 .
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.
Election/Restrictions
Applicant’s election without traverse of an anti-HER2 bispecific antibody that binds domain II and domain IV of the extracellular domain of HER2 in the reply filed on 06/26/2025 is acknowledged.
Claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/26/2025.
Applicant’s election without traverse of an anti-HER2 bispecific comprising HCDR 1, 2, and 3 of SEQ ID NO: 5, 6, and 15, respectively, HCDR 1, 2, and 3, of the VH of SEQ ID NO: 3 or mutant D102E , and a light chain of SEQ ID NO: 1 comprising the substitutions of N30S and F53Y in the reply filed on 06/26/2025 is acknowledged.
Claim Status
Claims 1-20 as filed on 26 June 2025 are pending. Claim 17 is withdrawn. Claims 1-16 and 18-20 are under examination.
Claim Rejections - 35 USC § 112
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 1-16 and 18-20 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 first VH is SEQ ID NO: 4 or a mutant thereof, the second VH is SEQ ID NO: 3, or a mutant thereof, and the light chain is a mutant of SEQ ID NO: 1.
None of the claims limit the CDRs of the second heavy chain.
None of the claims limit the CDRs to set combinations of sequences.
The language mutant thereof in claim 1 allows for any number of mutations to any point in the sequence of the first VH, second VH, and VL including the CDRs of those sequences.
Claim 7 allows for mixing and matching of the CDR combinations of the first heavy chain.
Claim 12 is to a light chain comprising one or more amino acid substitutions from the 6 options listed. This light chain has no requirement for what it binds and allows to changes to the CDRs of the light chain with no defined heavy chain. Claim 13 depends from claim 12 and is to antibodies that comprise a heavy and light chain. It allows for any sequence to heavy chain CDRs with the light chain of claim 12. This would comprise innumerable number of CDR combinations with unknown binding activity.
Claim 18 requires the mutation D102E but does not limit itself to only that mutation and inherits the mutants thereof of claim 1.
The substitutions listed in claims 1-5, 18, and 20 do not limit substitutions or mutations of the sequences to those amino acids allowing for any additional mutations.
Claim 19 limits the CDRs of the first heavy chain to one of the specified combinations, but does not limit the CDRs of the second heavy chain or the light chain.
None of the claims specify the CDRs of the first heavy chain, second heavy chain, and 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) (PTO-892) (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 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 (PTO-892) (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) (PTO-892). 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) (PTO-892), 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) (“Marvin” PTO-892) 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) (“Chiu” PTO-892). 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) (PTO-892) (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.
Summary of Species Disclosed in the original specification
Applicant recites three common light chains in Example 4:
Common light chain M1 which is SEQ ID NO: 1 with an F53Y substitution,
Common light chain M2 which is SEQ ID NO: 1 with F53Y, L54R, and S56T substitutions
Common light chain M3 which is SEQ ID NO: 1 with P96Y substitution.
Applicant recites the following bispecific antibodies with sequences provided in the application:
Light chain of M1 with second heavy chain SEQ ID NO: 3 and first heavy chain comprising HCDR1, 2, and 3 of SEQ ID NO: 5, 6, and 15, respectively.
Light chain of M1 further comprising N30S substitution with second heavy chain SEQ ID NO: 3 and first heavy chain comprising HCDR1, 2, and 3 of SEQ ID NO: 5, 7, and 16, respectively.
Light chain of M1 further comprising N30S substitution with second heavy chain SEQ ID NO: 3 further comprising D102E substitution and first heavy chain comprising HCDR1, 2, and 3 of SEQ ID NO: 5, 6, and 15, respectively.
Light chain of M1 further comprising N30S substitution with second heavy chain SEQ ID NO: 3 further comprising D102E substitution and first heavy chain comprising HCDR1, 2, and 3 of SEQ ID NO: 5, 7, and 16, respectively.
These are all disclosed in Table 6 of the application all have confirmed binding activity in Figure 3.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses 4 bispecific antibodies
Given the variability encompassed by the genus 4 described species therefore cannot be considered representative of the genus.
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-7, 9-16, and 18-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Klein (WO 2016207091 A1) (PTO-892).
Klein teaches tri-specific antibodies that bind to HER2 and a blood-brain barrier receptor wherein it binds domain II and domain IV of the extracellular domains of HER2 (abstract and claim 1).
Klein further teaches pertuzumab which binds domain II of HER2 and trastuzumab which binds domain IV of HER2 (page 2 in lines 15-24).
Klein teaches a pertuzumab/trastuzumab hybrid light chain that comprises N30S and F53Y in SEQ ID NO: 26 in table 33 on page 149, figure 19, and page 127 in lines 8-10. Klein then teaches an antibody that binds domains II and IV of HER2 that comprise a heavy chain of pertuzumab, a heavy chain of trastuzumab, and a common light chain with substitutions of the elected species of N30S and F53Y as required by claims 1-5, 7, 12, and 19-20.
Regarding claims 5-6, 18, and 20, Klein teaches a bispecific antibody comprising a common light chain of trastuzumab with the substitution of F53Y and the substitution of D102E in the trastuzumab heavy chain, to be used with a heavy chain of pertuzumab in table at the end of page 109 to page 110 shown by SEQ ID NO: 79 and SEQ ID NO: 104 in table on page 110. Klein further teaches the modification using the “knob-into-hole” method required by claim 6 (page 56 in lines 27-30).
Regarding claims 9-11, 13, and 16, Klein teaches a prokaryotic host cell comprising a vector comprising a nucleic acid sequence that encodes the heavy and light chains of the antibodies of the invention for producing the antibodies (page 8 in lines 10-16). This would be preparation of an antibody that is multispecific using the light chain of claim 12 as required by claim 13.
Regarding claim 15, Klein teaches a pharmaceutical composition comprising acceptable carries or excipients (abstract and page 30 in lines 27-33).
Claim 1 is to a bispecific comprising the sequences of the claim so it would include molecules that are multi or tri-specific. Klein teaches the tri-specific antibody comprising the binding domains to domains II and IV of HER2 of claim 1 and teaches the tri-specific as part of an immunoconjugate comprising the tubulin inhibitor maytansinoid (page 85 in lines 14-21).
Claims 1, 7, 9-11, 15-16, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fong (WO 2007/097812 A2) (PTO-892).
Fong teaches the light chain of trastuzumab, the heavy chain of trastuzumab, and the heavy chain of pertuzumab (page 2 in lines 26-30 and Figures 1-4). Fong teaches trastuzumab binds domain IV of HER2 (page 3 in lines 22-24). Fond teaches pertuzumab binds domain II of HER2 (page 4 in lines 10-15).
Fong teaches bispecific antibodies that bind two HER2 epitopes (page 26 in lines 21-24).
Fong teaches a bispecific antibody that comprises a first and second heavy chain that bind to different specificities (page 26 in lines 36-38).
Fong teaches substitutions of trastuzumab at amino acids N30, T31, A32, F53, R66, and T94 (page 31 in lines 11-14).
This would teach the bispecific antibody of claims 1, 7, and 19.
Regarding claims 9-11, and 16, Fong teaches a host cell comprising a vector with a nucleic acid encoding the proteins of the invention (page 2 in lines 13-17, page 23 in lines 23-30, and page 27 in lines 5-15).
Regarding claim 15, Fong teaches pharmaceutical compositions including acceptable carrier and excipients (Pages 43-44 in Section III).
Claims 1-5, 7-8, 12-13, and 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xiao (WO 2018/191188 A1) (PTO-892).
Regarding claims 1-3, Xiao teaches bispecific antibodies comprising a pertuzumab heavy chain, a trastuzumab heavy chain, and trastuzumab common light chain. Xiao further teaches the light chain substitution of N30S ([0127]).
Regarding claims 4-5, Xiao teaches the substitution of N30S with P96Y ([0017]).
This would teach the bispecific antibody of claims 1, 7, and 19.
Regarding claim 8, Xiao teaches the fucose modification of antibodies to modify ADCC ([0081]).
Regarding claims 12-13 and 20, Xiao teaches the modified light chain of N30S with P96Y ([0017]) and further teaches the light chains encoded in host cells for producing the bispecific antibodies ([0023]). As the claim 13 lacks any active steps examiner sees Xiao as teaching the requirement of this claim. Xiao further teaches the bispecific antibodies can be Fab, scFv or other formats ([0084]).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA EDGINGTON-GIORDANO whose telephone number is (571)272-8232. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
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/F.E./Examiner, Art Unit 1643
/Meera Natarajan/Primary Examiner, Art Unit 1643