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 .
1. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are pending and being examined. It is noted that the terms ERBB2, ERBB-2, HER-2, and HER2 are used interchangeably, and the terms ERBB3, ERBB-3, HER-3, and HER3 are used interchangeably.
It is noted that instant VH SEQ ID NO:65 (claim 6) comprises CDR SEQ ID NOs:66+67+68 (ERBB2 antibody MF3958) (claim 4); and instant VH SEQ ID NO:110 (claim 6) comprises CDR SEQ ID NOs:111+112+113 (ERBB3 antibody MF3178) (claim 4).
Specification/ Drawings
2. The specification and drawings are objected to. This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831. Specifically, there are no SEQ ID NOs identified with the sequences disclosed in Figures 6-8. 37 CFR 1.831 (c) requires that a reference to a particular sequence identifier (i.e., SEQ ID NO:#) be made in the specification and drawings wherever a reference is made to that sequence:
(c) Where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing XML" in accordance with paragraph (a) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by "SEQ ID NO:" or the like in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a) ), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a) ) in the Brief Description is clear.
Applicants may obviate the objection by amending the Brief Description of the Drawings or the Drawings to identify the sequence(s).
If Applicants choose to amend the Drawings: any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Specification
3. The specification is objected to because of the following informalities: The specification at pages 6, 11, 23, 30, 31, and 33 is missing SEQ ID NO identifiers with the sequences disclosed. Appropriate correction is required.
4. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, for example on pages 8 and 9. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. Amendment to delete http:// to deactivate the live link is sufficient. See MPEP § 608.01
Claim Objections
5. Claim 7 is objected to because of the following informalities: Claim 7 is missing SEQ ID NO identifiers with the sequences claimed. Appropriate correction is required.
6. Claim 8 is objected to because of the following informalities: Claim 8 contains a grammatical error. Claim 8 lists a several cancers without an appropriate conjunction word before the last item to indicate the cancers are alternatively listed. For example, claim 8 should be amended to recite: “The method according to claim 2, wherein the cancer harboring a ERBB3 mutation is selected from the group consisting of: colorectal cancer, gastric cancer, …uterine/endometrial cancer, lung cancer, non-small cell lung cancer, and invasive mucinous adenocarcinoma.
Appropriate correction is required.
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.
7. Claims 2, 4-11, 13, 16-18, 21, 22, 28, and 32 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 2 recites the that the ERBB3 mutation “is an ERBB3 driver mutation that comprises a mutation which promotes and/or is correlated with ligand-independent heterodimerization of ERBB2 and ERBB3 and/or activation of the ERBB2 kinase domain.” The claim is grammatically unclear with regard to how the ERBB3 mutation is associated with “activation of the ERBB2 kinase domain”. Does the ERBB3 mutation promote activation of the ERBB2 kinase domain? Is the ERBB3 mutation correlated with activation of the ERBB2 kinase domain? Or is there another association? How is activation of the ERBB2 kinase domain associated with the claimed ERBB3 mutation? The metes and bounds of the claim cannot be determined. Dependent claims are rejected for encompassing the rejected limitation of claim 2.
8. Claims 4, 8, 22, and 28 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 4 and 22 recite the phrase “preferably” which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 8, 22, and 28 recite the phrase “such as” which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). See suggested amendment for claim 8 above in section 6.
Claim 22 is indefinite in the use of the expressions in parenthesis: “(including anti-PD1 and anti-PD-L1 approved therapies and applicable therapies in clinical development)”, “(with or without radiotherapy)” “(or pemetrexed)” “(i.e. a combination of 5-fluorouracil, leucovorin, and oxaliplatin)” “(i.e. a combination of leucovorin, 5-fluorouracil and irinotecan)” and “(a combination of leucovorin, 5-fluorouracil, irinotecan and oxaliplatin)” in that it is not clear whether these recitations are intended to be part of the claim or not.
Claim 22 also recites the term "i.e." (“for example”) which renders the claim indefinite because it is unclear whether the limitation(s) following the term are part of the claimed invention. See MPEP § 2173.05(d).
9. Claims 22 is further 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 22 recites the phrase: “…or with a combination of TKIs or any of the above, …” It is unclear what limitations the phrase “or any of the above” is referencing. The metes and bounds of the claim cannot be determined.
10. Claim 7 is further 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 7 recites the limitation "wherein the bispecific antibody comprises the variable domain that comprises said first binding site and the variable domain that comprises said second antigen binding site…”. There is insufficient antecedent basis for this limitation in the claim because there is no previous limitation reciting a “variable domain” or one that comprises a first binding site or a second binding site.
11. Claim 7 is further 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 7 recites: “…wherein the bispecific antibody comprises the variable domain that comprises said first antigen binding site and the variable domain that comprises said second antigen binding site, said bispecific antibody comprising a light chain variable region comprising a CDR1 having the sequence (RASQSISSYLN, SEQ ID NO:2), a CDR2 having the sequence (AASSLQS, SEQ ID NO:3), and a CDR3 having the sequence (QQSYSTPPT, SEQ ID NO: 4), according to KABAT numbering or according to the IMGT numbering system, the CDRs of said light chain variable region are QSISSY, AAS and QQSYSTPPT, respectively.
The claim is unclear with regard to what is being referenced by KABAT and IMGT numbering system because there are no numbered amino acid positions being claimed. Further, it is unclear how the CDRs of said light chain variable region can be QSISSY, AAS and QQSYSTPPT when the claim already defined the CDRs of the light chain to be different amino acid sequences of RASQSISSYLN (SEQ ID NO:2), and AASSLQS (SEQ ID NO:3). Clarification is required.
12. Claim 18 is further 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 18 recites: “…in one or more genes selected from the group including BRAF, EGFR,…and PTEN and/or wherein the cancer lacks detectable amplifications in one or more genes selected from the group including c-MET, c-MYC,…and MDM2 amplification…” The claims are unclear with regard to the scope of the genes to select from because the claimed groups “include,” or comprise, the recited genes as well as anything in the universe not listed in the claims, because the claimed groups to select from are not limiting (i.e., an open-ended group). It is unclear what other genes are comprised by, or included, by the claim groups and the metes and bounds of the claim cannot be determined.
Examiner Suggestion: Amend claim 18 to recite: “…in one or more genes selected from the group consisting of: BRAF, EGFR,…and PTEN, and/or [[,]] wherein the cancer lacks detectable amplifications in one or more genes selected from the group consisting of: c-MET, c-MYC,…and MDM2 and/or [[,]] wherein the cancer does not have detectable PTEN loss.”
13. Claim 22 is further 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 22 first recites the limitation “checkpoint inhibitor therapy (including anti-PD1 and anti-PD-L1 approved therapies and applicable therapies in clinical development)” then recites the phrase "the checkpoint inhibitor therapy according to the present invention includes an anti-PD1, anti-PD-L1, and anti-CTLA4 therapeutic moiety and preferably comprises ipilimumab, nivolumab, pembrolizumab, atezolizumab avelumab, durvalumab, or cemiplimab…". The claim is confusing as to what exactly is comprised by “checkpoint inhibitor therapy” because it recites the term twice with two different lists of therapies “included” by it.
Further, there is insufficient antecedent basis for the limitation of “the checkpoint inhibitor therapy according to the present invention” because there is no prior mention specifically of a checkpoint inhibitor therapy that is “according to the present invention”. Clarification is required.
14. Claim 22 is further 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 22 recites the limitation "the VEGFR2 targeted treatment". There is insufficient antecedent basis for this limitation in the claim.
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.
15. Claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method of treatment of a subject having a cancer harboring a ERBB3 mutation, the method comprising administering a bispecific antibody that comprises an antigen binding site that can bind an extracellular part of ERBB2 and an antigen binding site that can bind an extracellular part of ERBB3, wherein the bispecific antibody comprises a first antigen-binding site that binds domain I of ERBB2 and a second antigen-binding site that binds domain III of ERBB3; wherein said ERBB3 mutation is a mutation over the non-mutated sequence according to SEQ ID NO: 1, and said ERBB3 mutation is an ERBB3 driver mutation that comprises a mutation which promotes and/or is correlated with ligand-independent heterodimerization of ERBB2 and ERBB3 and/or activation of the ERBB2 kinase domain.
Thus, the claims identify the bispecific antibody by function only, where the function is to:
Treat a subject having a cancer harboring an ErbB3 mutation that is a driver mutation promoting and/or correlating with ligand-independent heterodimerization of ERBB2 and ERBB3 and/or activating the ERBB2 kinase domain;
Bind an extracellular part of ERBB2 at domain I; and
Bind an extracellular part of ERBB3 at domain III.
No antibody structure is recited.
Dependent claim 4 recites only the variable heavy region CDR 1-3 SEQ ID NOs for the ERBB2 and ERBB3 binding regions, with no light chain sequence, and encompasses a vast genus of CDR sequence variants comprising up to 3 amino acid mutations in any or all of the CDR sequences.
Dependent claim 5 recites only the variable heavy region (VH) SEQ ID NOs for the ERBB2 and ERBB3 binding regions, with no light chain sequence, and encompasses a vast genus of VH sequence variants comprising up to 15 amino acid mutations anywhere in the variable region including the CDR sequences.
Dependent claim 6 recites only the VH sequence of the ERBB2 and ERBB3 binding regions and no light chain VL region.
Claim 7 is unclear with regard to what the recited CDR sequences represent, for the reasons stated in 35 USC 112(b) above.
The instant specification discloses anti-ERBB2 antibodies binding to domain I as: MF2926, MF2930, MF1849; MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, MF2889, MF2913, MF1847, MF3001, MF3003 and MF1898, disclosing VH and CDR 1-3 sequences in Figure 8A. The CDR sequences are structurally distinct for each antibody.
The instant specification discloses anti-ERBB3 antibodies binding to domain III as: MF3178; MF3176; MF3163; MF3099; MF3307; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, disclosing VH and CDR 1-3 sequences in Figure 8B. The CDR sequences are structurally distinct for each antibody.
The instant specification discloses the common light chain sequence in Figure 6 that is paired with the VH sequences in the bispecific antibody, and discloses the VL CDR 1-3 SEQ ID NOs:1-3 (p. 30, 31, and 33).
In the Examples, the specification discloses bispecific antibody MF3958 x MF3178 administered to patients having solid tumors, and molecularly profiling the patient tumors. Example 3 discloses identifying ERBB3 mutations. Example 3 discloses tumor tissue having an ERBB3 mutation lacks the following oncogenic amplifications: c-MET amplification, c-MYC amplification, EGFR amplification, ERBB2 amplification, MDM2 amplification. Tumor tissue having an ERBB3 mutation does not have PTEN loss. In Examples 4 and 5, the specification discloses enrolling a bladder cancer patient with ERBB3 mutation A232V and an ovarian clear cell carcinoma patient with ERBB3 mutation V104M in a clinical trial administering bispecific antibody MF3958 x MF3178. The specification discloses treating cancer by administering a bispecific antibody comprising defined VH CDR 1-3 sequence for the anti-ERBB2 and anti-ERBB3 domains disclosed in Figure 8, comprising the common light chain sequence disclosed in Figure 6, and comprising the heavy chain constant and hinge region sequences disclosed in Figure 7.
Thus, the instant specification describes: (a) 17 structurally distinct VH sequences for 17 anti-ERBB2 antibodies that bind domain I, (b) 25 structurally distinct VH sequences for 25 anti-ERBB3 antibodies that bind domain III, and (c) combining the anti-ERBB2/ERBB3 VH sequences with a common light chain sequence disclosed in Figure 6 to clinically treat cancer. The specification fails to disclose any other bispecific antibodies or sequence variants that function to treat ERBB3 mutated cancer as claimed.
To provide adequate written description and evidence of possession of the claimed bispecific antibody genus required to practice the claimed invention, the instant specification can structurally describe representative anti-ERBB2 domain I VH sequences, anti-ERBB3 domain III VH sequences, and paired light chain VL sequences that function as claimed and listed above, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for antibodies and VH/VL sequences that bind ERBB2 domain I and ERBB3 domain III and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The ERBB2 domain I and ERBB3 domain III antigen provides no information about the structure of an antibody that binds to it and treats cancer.
In this case, the only factor present in the claims is a recitation of the antibody function as listed above, or a partial sequence structure of heavy chain CDRs and VH regions comprising a vast genus of variants with multiple undefined mutations. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only 17 structurally distinct anti-ERBB2 domain I and 25 structurally distinct anti-ERBB3 domain III antibodies paired with a single common light chain sequence, that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the disclosed anti-ERBB2 VH/CDR sequences, anti-ERBB3 VH/CDR sequences, and light chain sequence that function together as a bispecific antibody to treat cancer, the specification fails to provide any other structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequences for the vast genus of antibody variants that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
The claims broadly encompass a vast genus of bispecific antibodies comprising: (1) undefined anti-ERBB2 and anti-ERBB3 binding domains, (2) numerous mutations in the CDR and/or VH sequences, and (3) no defined light chain VH or CDR sequences. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain ERBB2 domain I and ERBB3 domain III binding function and treat cancer. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed bispecific antibodies used in the claimed method, and lack of reasonable structure-function correlation with regards what mutations can occur and still maintain ERBB2 domain I and ERBB3 domain III binding function and cancer-treating function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of bispecific antibodies that bind ERBB2 domain I and ERBB3 domain III that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Amend claim 2 to recite and require the bispecific antibody to comprise, at minimum: (1) the three defined sequences of the VH CDR1-3 of the first antigen-binding domain that binds to domain I of ERBB2; (2) the three defined sequences of the VH CDR1-3 of the second antigen-binding domain that binds to domain III of ERBB3; and (3) the three defined sequences of the VL CDR1-3 of the first and second antigen-binding domain light chains that bind to ERBB2 domain I and ERBB3 domain III. These are the described sequence structures correlated and critical to performing the claimed functions. Examiner further suggests deleting claimed phrases encompassing amino acid differences in the CDR regions.
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.
16. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/130173, Geuijen et al (“Geuijen 2015”); in view of WO 2018/182422, Throsey (corrected as Throsby) et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
Geuijen 2015 teaches a method of treating a subject having HER2+/HER3+ cancer, the method comprising administering to the subject a bispecific antibody comprising a first antigen-binding site that binds to domain I of ERBB2, and a second antigen-binding site that binds to domain III of ERBB3 (p. 3-4; 50-56; 102; 107; claims 1-57);
wherein the antibody comprises first antigen-binding domain comprises the three CDRs or VH region of MF3958 and second antigen-binding domain comprises the three CDRs or VH region of MF3178 (p. 23; 27-28; 31-32; 57); wherein the MF3958 x MF3178 bispecific antibody produced is named PB4188 (p. 94; Examples);
wherein antibody MF3958 comprises VH SEQ ID NO:48 that comprises 100% of instant CDR1-3 SEQ ID NOs:66+67+68 and instant VH SEQ ID NO:65 (Figure 16A); wherein antibody MF3178 comprises VH SEQ ID NO:89 that comprises 100% of instant CDR1-3 SEQ ID NOs:111+112+113 and instant VH SEQ ID NO:110 (Figure 16B) (see sequence alignments below);
wherein the bispecific antibody comprises the common light chain in Figure 16C that comprises instant light chain CDR SEQ ID NOs:2+3+4 (see Figure 16C below):
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wherein the bispecific antibody inhibits ligand-independent (HRG-independent) activation of HER2/HER3 heterodimerization (p. 11; Examples; p. 90-91);
wherein the cancer treated is breast, colorectal, gastric, colon, gastro-esophageal, ovarian, or pancreatic cancer (p. 50-56, 66);
wherein the second antigen-binding domain binds to critical amino acid residue R426 in domain III of ERBB3 (p. 51, 57, 63; Table 14);
Geuijen demonstrates that bispecific antibody PB4188 (MF3958 x MF3178) has superior anti-proliferative activity on HER2 amplified gastric cancer cells compared to individual HER2 and HER3 antibodies, the antibody induces ADCC activity higher than activity induced by combined parental antibodies, PB4188 successfully treated breast tumor xenografts, and PB4188 blocked AKT, ERK, and S6 phosphorylation ( (p. 99-110; Figures 17 and 18). Geuijen demonstrates that bispecific antibody PB4188 reduces HER2:HER3 heterodimerization in breast tumor xenografts (p. 112), and demonstrates PB4188 successfully reduces cell proliferation of either HER2 low (non-amplified) MCF-7 cells or HER2 high (amplified) SKBR-3 and BT-474 cells (Figure 34; p. 80-81).
Geuijen teaches it is known that activating mutations in the ERBB3 receptor have been identified (p. 2, lines 13-14), and teaches the known sequence of ERBB3 NP_001973.2 that is 100% identical to instant SEQ ID NO:1 (see sequence alignment below and see NCBI NP_001973.2).
Geuijen 2015 does not teach:
the cancer of the subject treated harbors an ERBB3 activating mutation that is a driver mutation promoting or correlated to ligand-independent heterodimerization of ERBB2:ERBB3, or activation of the ERBB2 kinase domain (instant claim 2).
the ERBB3 mutation is A232V, V104M, or in P262, G284, Q809 (instant claims 16, 28, 32).
First line therapy (instant claim 21);
Second line therapy after patients has progressed on therapy such as anti-ERBB2 therapy (instant claim 22); and
Treating cancer having no EGFR/ALK mutations (instant claim 18);
As evidenced by Huang, antibody PB4188 has synonyms Zenocutuzumab, and MCLA-128 (p. 3116, col. 2; Table 2).
Throsey discloses essentially the same invention as Geuijen 2015. Throsey teaches a method of treating a subject having ERBB2+/ERBB3+ cancer, the method comprising administering to the subject bispecific antibody MCLA-128. Throsey teaches the subjects treated can have a mutation comprising an NRG1 fusion gene that induces ERBB2:ERBB3 heterodimerization and downstream signaling, and wherein the MCLA-128 antibody comprises the VH region of MF3958 (SEQ ID NO:39) identical to instant SEQ ID NO:65; the VH region of MF3178 (SEQ ID NO:53) identical to instant SEQ ID NO:110 (see sequence alignments below); and the light chain VH comprising CDRs1-3 identical to instant SEQ ID NOs:2-4 (p. 35-37, 43, 45, and 48-49). Cancer patients treated include gastric cancer, colorectal cancer, colon cancer, gastroesophageal cancer, esophageal cancer, endometrial cancer, ovarian cancer, breast cancer, liver cancer, lung cancer, including non-small cell lung cancer, clear cell sarcoma, salivary gland cancer, head and neck cancer, brain cancer, bladder cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, and melanoma (p. 2-6, 15, Figure 7; Examples 3-5; claims 1-21). The bispecific antibody binds to amino acid R426 of ERBB3 (p. 28) and the sequence of ERBB3 is represented by NP_001973.2 (p. 26).
Throsey demonstrates successfully treating human ovarian cancer xenograft in mice by administration of MCLA-128, which produced “significant” antitumor activity against the ovarian cancer xenograft model (Example 3; Tables 3 and 4).
In Example 5, Throsey describes a phase I/II Study of MCLA-128, a full length IgGl Bispecific Antibody Targeting HER2 and HER3, in patients with solid tumors, comprising clinically treating advanced/ metastatic non-small cell lung cancer (NSCLC) with invasive mucinous adenocarcinoma or documented NRG1 fusion. Throsey teaches testing for MCLA-128 activity by assessing markers HER2, HER3, pHER2, pHER3, KRAS, NRAS, and PIK3CA in tumor or blood samples, and molecularly profiling the patients for BRAF mutation status and mutations in genes associated with HER2:HER3 signaling, including molecules in the MAPK and AKT pathway. Throsey further teaches molecularly profiling the patients to document the absence of EGFR/ALK alterations.
Throsey teaches HER2:HER3 dimerization can activate the intracellular tyrosine kinase domains, which undergo autophosphorylation and, in turn, can activate a number of downstream pro-proliferative signaling pathways, including those mediated by mitogen-activated protein kinases (MAPK) and the prosurvival pathway Akt (p. 8-9).
Calvo teaches antibody MCLA-128 (PB4188) is clinically administered to cancer patients to treat advanced epithelial tumors including gastroesophageal junction cancer (GEJ), metastatic breast cancer (MBC), and colorectal cancer (CRC), and MCLA-128 has enhanced ADCC activity (see entire abstract).
Alsina 2018 teaches clinically successfully treating gastric cancer (GC) and GEJ cancer by administering bispecific antibody MCLA-128 (PB4188), wherein patients had progressed previously on trastuzumab (anti-ERBB2) therapy, Alsina teaches MCLA-128 targets HER2/HER3 receptors with enhanced ADCC activity (see entire abstract).
Alsina 2017 Poster teaches clinically treating cancer patients by administering bispecific antibody MCLA-128 (PB4188), wherein the cancer patients have breast, GC/GEJ, ovarian, endometrial, or NSCLC cancer (Objectives & Design). Alsina teaches antibody MCLA-128 functions to block oncogenic signaling via the HER2:HER3 heterodimer, and eliminate tumor cells via enhanced ADCC (Background). Alsina teaches treating breast cancer patients who were heavily pre-treated with 2-5 anti-HER therapy lines (“Antitumor Activity”).
Geujin 2018 teaches MCLA-128 is the clinically developed PB4188 antibody comprising MF3958xMF3178 binding domains (p. 922, box at bottom; Figure 7). Geujin teaches amino acid residue R426 on ERBB3 is critical to MCLA-128/PB4188 binding (p. 930; Figure 7). Geujin demonstrates MCLA-128/PB4188 inhibits HER2:HER3 heterodimerization (p. 933, col. 1; Figure 7G). Geujin teaches MCLA-128/PB4188 is already being used to clinically treat cancers including breast cancer, GC, ovarian cancer, endometrial cancer and NSCLC (p. 933, col. 2).
Schram teaches clinical treatment of cancer patients with MCLA-128, wherein the cancer patients have NRG1 fusion proteins that bind to HER3 and lead to HER2:HER3 heterodimerization, increasing downstream signaling and cell growth. Schram teaches MCLA-128 blocks NRG1 binding and HER2/HER3 heterodimerization. Schram teaches cancers treated included pancreatic, NSCLC, and other solid tumors (see entire abstract). The patients treated failed prior standard therapy for their tumor type and stage disease.
Therefore, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors, including ovarian, gastric cancer, GEJ, and breast cancer by administration of MCLA-128/PB4188 known to function by inhibiting HER2:HER3 heterodimerization and having enhanced ADCC activity.
Jaiswal teaches activating/oncogenic mutations in ERBB3 in human cancers is common. Jaiswal demonstrates and identifies ERBB3 mutational hot spots including residues V104, A232, P262, G284, and Q809 occurring in colon, breast, gastric, lung, and ovarian cancers, which encompass intracellular domain and extracellular domain mutations (p. 604, col. 1-2; Figure 1). Jaiswal demonstrates detection of ERBB3 activating mutations in several cancers in Table S2 including at amino acid positions 60, 104, 232, 262, 284, 809, and 846:
PNG
media_image2.png
634
776
media_image2.png
Greyscale
Jaiswal demonstrates ERBB3 mutations V104M, A232V, P262H, G284R, and Q809R promote downstream signaling in ERBB3, ERBB2, Akt, and ERK (promoting PI3K pathway), promote cell growth, and enhance cell survival (Figures 3, 5). Jaiswal demonstrates that an anti-ERBB3 antibody binding to domain III (ERBB3.2) successfully inhibits signaling in ERBB2, ERBB3, AKT, and ERK in cancer cells comprising ERBB3 mutations P262H, G248R, and Q809R (Figure 7). Jaiswal demonstrates ERBB3.2 antibody successfully enhances survival of mice comprising tumors harboring ERBB3 mutation G284R or Q809R (Figure 8).
Treating cancer patients harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patients comprising tumors harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; (2) Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach the known, predictable anti-tumor mechanism of MCLA-128/PB4188 to inhibit HER2:HER3 heterodimerization, inhibit downstream signaling, and enhance ADCC activity; (3) Geujin 2015 acknowledges cancers harbor ERBB3 activating mutations; (4) Jaiswal demonstrates that solid tumors commonly comprise ERBB3 activating mutations, identifies ERBB3 hotspot mutations, demonstrates these mutations contribute to oncogenic signaling and promote cancer cell growth; and demonstrates successfully treating tumors or inhibiting cancer cells harboring the ERBB3 activating mutations by administration of an anti-ERBB3 antibody that binds to domain III.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Given: (1) the recognized need by the cited art to treat a wide variety of solid tumors expressing HER2/HER3 and the need to inhibit HER2/HER3 oncogenic signaling; (2) the established knowledge that several of these solid tumor types can also encompass ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; (3) the recognized need to treat the wide variety of solid tumors that comprise the ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; and (4) the known solution of treating the wide variety of solid tumors with MCLA-128/PB4188 (binding to HER2 domain I and HER3 domain III) to successfully inhibit HER2/HER3 heterodimerization and downstream signaling; and (5) the known solution of inhibiting tumor cells, inhibiting HER2/HER3 signaling, and treating tumors harboring HER3 activating mutations by administration of a HER3 antibody binding to domain III alone, one of skill in the art could have pursued including HER2+/HER3+ cancer patients harboring ERBB3 activating mutations, in the method of treatment taught by Geujin 2015 with a reasonable expectation of success.
Treating cancer patient progressed on prior therapy such as anti-ERBB2 therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patient who progressed in prior therapy, such as anti-ERBB2 therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, lung, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; and (2) Alsina 2017 and 2018, and Schram teach and demonstrate administering MCLA-128/PB4188 to a subset of solid tumor cancer patients who have progressed after prior lines of therapy, including anti-ERBB2 (trastuzumab) treatment.
Treating cancer patients as first line therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 as primary therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment; and (2) both Geujin 2015 and 2018 and Throsey demonstrate successfully treating cancer in vivo by administering MCLA-128/PB4188 as primary and single agent therapy, wherein Throsey teaches MCLA-128 had significant antitumor activity.
Treating cancer having no EGFR/ALK mutations:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 to cancers lacking EGFR/ALK mutations. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment with MCLA-128/PB4188; and (2) Throsey teaches treating ERBB2+/ERBB3+ cancers with MCLA-128 that test negative for EGFR/ALK mutations.
Sequence alignment of instant CDR SEQ ID NOs:111+112+113 (MF3178) with WO 2015/130173, Geuijen SEQ ID NO:89:
RESULT 1
BCD86321
ID BCD86321 standard; protein; 124 AA.
XX
AC BCD86321;
XX
DT 14-JAN-2016 (revised)
DT 22-OCT-2015 (first entry)
XX
DE Anti-erbB-3 antibody (MF3178) heavy chain variable region, SEQ 89.
XX
KW ErbB-3 protein; Erbb3 tyrosine kinase receptor; HER3 protein; antibody;
KW antibody therapy; breast tumor; cancer; colorectal tumor; cytostatic;
KW heavy chain variable region; lung tumor; metastasis; ovary tumor;
KW pancreas tumor; prophylactic to disease;
KW receptor tyrosine-protein kinase erbB-3; stomach tumor; therapeutic.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /label= CDR1
FT Region 50..66
FT /label= CDR2
FT Region 99..113
FT /label= CDR3
FT /note= "This region is specifically claimed in claim 12"
XX
CC PN WO2015130172-A1.
XX
CC PD 03-SEP-2015.
XX
CC PF 27-FEB-2015; 2015WO-NL050124.
XX
PR 28-FEB-2014; 2014EP-00157351.
XX
CC PA (MERU-) MERUS BV.
XX
CC PI Logtenberg T, Throsby M, Roovers RC;
XX
DR WPI; 2015-51549L/61.
DR N-PSDB; BCD86320.
XX
CC PT New bispecific antibody comprising first antigen-binding site that binds
CC PT epidermal growth factor receptor and second antigen-binding site that
CC PT binds receptor tyrosine-protein kinase erbB-3, useful for treating and
CC PT preventing e.g. tumor.
XX
CC PS Claim 11; SEQ ID NO 89; 120pp; English.
XX
CC The present invention relates to a novel bispecific antibody comprising a
CC first antigen-binding site that binds epidermal growth factor receptor
CC (EGFR) and a second antigen-binding site that binds receptor tyrosine-
CC protein kinase erbB-3 (ErbB-3), wherein the has a half maximal growth
CC inhibitory concentration (IC50) of less than 200 pM for inhibiting EGFR
CC and ErbB-3 ligand induced growth of BxPC3 cells (ATCC CRL-1687) or BxPC3-
CC luc2 cells (Perkin Elmer 125058). The invention also provides: a
CC pharmaceutical composition comprising the bispecific antibody; a method
CC for treating a subject having EGFR, ErbB-3 or EGFR/ErbB-3 positive tumor
CC or at risk of having the tumor; and a method for counteracting the
CC formation of a metastasis in a subject having a EGFR, ErbB-3 or EGFR/ErbB
CC -3 positive tumor. The pharmaceutical composition is useful for treating
CC and preventing cancer such as breast cancer, ovarian cancer, gastric
CC cancer, colorectal cancer, pancreatic cancer, or lung cancer. The present
CC sequence represents a heavy chain variable region of an anti-ErbB-3
CC antibody (MF3178), where the antibody is useful for treating cancer.
CC Note: The present sequence is used as a parent sequence for generating
CC variants (see BCD86329-BCD86348).
CC
CC Revised record issued on 11-JAN-2016 : Update to DE line and PS line.
XX
SQ Sequence 124 AA;
Query Match 89.4%; Score 208.4; Length 124;
Best Local Similarity 44.6%;
Matches 37; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GYYMHW--------------INPNSGGTNYAQKFQG------------------------ 22
|||||| ||||||||||||||||
Db 31 GYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDD 90
Qy 23 --------DHGSRHFWSYWGFDY 37
|||||||||||||||
Db 91 TAVYYCARDHGSRHFWSYWGFDY 113
Sequence alignment of instant VH SEQ ID NOs:110 (MF3178) with WO 2015/130173, Geuijen SEQ ID NO:89:
RESULT 1
BCD86321
ID BCD86321 standard; protein; 124 AA.
XX
AC BCD86321;
XX
DT 14-JAN-2016 (revised)
DT 22-OCT-2015 (first entry)
XX
DE Anti-erbB-3 antibody (MF3178) heavy chain variable region, SEQ 89.
XX
KW ErbB-3 protein; Erbb3 tyrosine kinase receptor; HER3 protein; antibody;
KW antibody therapy; breast tumor; cancer; colorectal tumor; cytostatic;
KW heavy chain variable region; lung tumor; metastasis; ovary tumor;
KW pancreas tumor; prophylactic to disease;
KW receptor tyrosine-protein kinase erbB-3; stomach tumor; therapeutic.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /label= CDR1
FT Region 50..66
FT /label= CDR2
FT Region 99..113
FT /label= CDR3
FT /note= "This region is specifically claimed in claim 12"
XX
CC PN WO2015130172-A1.
XX
CC PD 03-SEP-2015.
XX
CC PF 27-FEB-2015; 2015WO-NL050124.
XX
PR 28-FEB-2014; 2014EP-00157351.
XX
CC PA (MERU-) MERUS BV.
XX
CC PI Logtenberg T, Throsby M, Roovers RC;
XX
DR WPI; 2015-51549L/61.
DR N-PSDB; BCD86320.
XX
CC PT New bispecific antibody comprising first antigen-binding site that binds
CC PT epidermal growth factor receptor and second antigen-binding site that
CC PT binds receptor tyrosine-protein kinase erbB-3, useful for treating and
CC PT preventing e.g. tumor.
XX
CC PS Claim 11; SEQ ID NO 89; 120pp; English.
XX
CC The present invention relates to a novel bispecific antibody comprising a
CC first antigen-binding site that binds epidermal growth factor receptor
CC (EGFR) and a second antigen-binding site that binds receptor tyrosine-
CC protein kinase erbB-3 (ErbB-3), wherein the has a half maximal growth
CC inhibitory concentration (IC50) of less than 200 pM for inhibiting EGFR
CC and ErbB-3 ligand induced growth of BxPC3 cells (ATCC CRL-1687) or BxPC3-
CC luc2 cells (Perkin Elmer 125058). The invention also provides: a
CC pharmaceutical composition comprising the bispecific antibody; a method
CC for treating a subject having EGFR, ErbB-3 or EGFR/ErbB-3 positive tumor
CC or at risk of having the tumor; and a method for counteracting the
CC formation of a metastasis in a subject having a EGFR, ErbB-3 or EGFR/ErbB
CC -3 positive tumor. The pharmaceutical composition is useful for treating
CC and preventing cancer such as breast cancer, ovarian cancer, gastric
CC cancer, colorectal cancer, pancreatic cancer, or lung cancer. The present
CC sequence represents a heavy chain variable region of an anti-ErbB-3
CC antibody (MF3178), where the antibody is useful for treating cancer.
CC Note: The present sequence is used as a parent sequence for generating
CC variants (see BCD86329-BCD86348).
CC
CC Revised record issued on 11-JAN-2016 : Update to DE line and PS line.
XX
SQ Sequence 124 AA;
Query Match 100.0%; Score 685; Length 124;
Best Local Similarity 100.0%;
Matches 124; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
Qy 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDHGSRHFWSYWGFDYWGQGTLV120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDHGSRHFWSYWGFDYWGQGTLV120
Qy 121 TVSS 124
||||
Db 121 TVSS 124
Sequence alignment of instant CDR SEQ ID NOs:66+67+68 (MF3958) with WO 2015/130173, Geuijen SEQ ID NO:48:
RESULT 1
BCD91610
ID BCD91610 standard; protein; 121 AA.
XX
AC BCD91610;
XX
DT 25-FEB-2016 (revised)
DT 22-OCT-2015 (first entry)
XX
DE Anti-erbB-2 antibody heavy chain variable region (MF3958), SEQ ID 48.
XX
KW ERBB2 protein; Erbb2 tyrosine kinase receptor; HER2 protein; antibody;
KW antibody therapy; bladder cancer; brain tumor; breast tumor; cancer;
KW colon tumor; colorectal tumor; cytostatic; endometrioid carcinoma;
KW esophagus tumor; head and neck tumor; heavy chain variable region;
KW imaging; liver tumor; lung tumor; melanoma; metastasis;
KW non-small-cell lung cancer; ovary tumor; pancreas tumor;
KW prophylactic to disease; prostate tumor; renal tumor;
KW salivary gland disease; skin cancer; stomach tumor; therapeutic;
KW phosphorylation.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /note= "CDR1"
FT Region 50..66
FT /note= "CDR2"
FT Region 99..110
FT /note= "CDR3"
XX
CC PN WO2015130173-A1.
XX
CC PD 03-SEP-2015.
XX
CC PF 27-FEB-2015; 2015WO-NL050125.
XX
PR 28-FEB-2014; 2014EP-00157360.
PR 05-MAY-2014; 2014EP-00167066.
XX
CC PA (MERU-) MERUS BV.
XX
CC PI Geuijen CAW, De Kruif CA, Throsby M, Logtenberg T, Bakker ABH;
XX
DR WPI; 2015-51549K/62.
DR N-PSDB; BCD91609.
XX
CC PT New bispecific antibody comprises first antigen-binding site that binds
CC PT receptor tyrosine kinase (ErbB)-2 and second antigen-binding site that
CC PT binds ErbB-3, used for treating subject having ErbB-2, ErbB-3 or ErbB-
CC PT 2/ErbB-3 positive tumor.
XX
CC PS Claim 25; Fig 16A; 239pp; English.
XX
CC The present invention relates to a novel bispecific antibody for treating
CC a subject having a tumor, preferably receptor tyrosine kinase (ErbB)-2,
CC ErbB-3 or ErbB-2/ErbB-3 positive tumor. The bispecific antibody comprises
CC first antigen-binding site that binds ErbB-2 and second antigen-binding
CC site that binds ErbB-3. The invention further discloses: (1) a method for
CC treating the subject having ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive
CC tumor or at risk of having the tumor; (2) a method for counteracting the
CC formation of metastasis in a subject having ErbB-2, ErbB-3 or ErbB-2/ErbB
CC -3 positive tumor; and (3) a pharmaceutical composition comprising the
CC bispecific antibody. The bispecific antibody and pharmaceutical
CC composition are useful for treating a subject having or is at a risk of
CC having a tumor including breast cancer, gastric cancer, colorectal
CC cancer, colon cancer, gastro-esophageal cancer, esophageal cancer,
CC endometrial cancer, ovarian cancer, liver cancer, lung cancer including
CC non-small cell lung cancer, clear cell sarcoma, salivary gland cancer,
CC head and neck cancer, brain cancer, bladder cancer, pancreatic cancer,
CC prostate cancer, kidney cancer, skin cancer, or melanoma cell; for
CC counteracting or inhibiting, phosphorylation of Akt, extracellular signal
CC -regulated kinase (ERK) and/or S6 ribosomal protein; and for
CC counteracting the formation of metastasis in the subject having ErbB-2,
CC ErbB-3 or ErbB-2/ErbB-3 positive tumor. The bispecific antibody is also
CC used for imaging. The invention uses bispecific antibodies with an
CC enhanced internalization property, to the same extent as trastuzumab,
CC which results in the reduced ADCC activity. The present sequence is an
CC anti-erbB-2 antibody heavy chain variable region which is used in the
CC method for treating a subject suffering from ErbB-2, ErbB-3 or ErbB-
CC 2/ErbB-3 positive tumor.
CC
CC Revised record issued on 19-FEB-2016 : Correction of DE line, PS line and
CC keywords.
XX
SQ Sequence 121 AA;
Query Match 87.4%; Score 170.4; Length 121;
Best Local Similarity 42.5%;
Matches 34; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 AYYIN--------------RIYPGSGYTSYAQKFQG------------------------ 22
||||| |||||||||||||||||
Db 31 AYYINWVRQAPGQGLEWIGRIYPGSGYTSYAQKFQGRATLTADESTSTAYMELSSLRSED 90
Qy 23 --------PPVYYDSAWFAY 34
||||||||||||
Db 91 TAVYFCARPPVYYDSAWFAY 110
Sequence alignment of instant VH SEQ ID NOs:65 (MF3958) with WO 2015/130173, Geuijen SEQ ID NO:48:
RESULT 1
BCD91610
(NOTE: this sequence has 11 duplicates in the database searched.
See complete list at the end of this report)
ID BCD91610 standard; protein; 121 AA.
XX
AC BCD91610;
XX
DT 25-FEB-2016 (revised)
DT 22-OCT-2015 (first entry)
XX
DE Anti-erbB-2 antibody heavy chain variable region (MF3958), SEQ ID 48.
XX
KW ERBB2 protein; Erbb2 tyrosine kinase receptor; HER2 protein; antibody;
KW antibody therapy; bladder cancer; brain tumor; breast tumor; cancer;
KW colon tumor; colorectal tumor; cytostatic; endometrioid carcinoma;
KW esophagus tumor; head and neck tumor; heavy chain variable region;
KW imaging; liver tumor; lung tumor; melanoma; metastasis;
KW non-small-cell lung cancer; ovary tumor; pancreas tumor;
KW prophylactic to disease; prostate tumor; renal tumor;
KW salivary gland disease; skin cancer; stomach tumor; therapeutic;
KW phosphorylation.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /note= "CDR1"
FT Region 50..66
FT /note= "CDR2"
FT Region 99..110
FT /note= "CDR3"
XX
CC PN WO2015130173-A1.
XX
CC PD 03-SEP-2015.
XX
CC PF 27-FEB-2015; 2015WO-NL050125.
XX
PR 28-FEB-2014; 2014EP-00157360.
PR 05-MAY-2014; 2014EP-00167066.
XX
CC PA (MERU-) MERUS BV.
XX
CC PI Geuijen CAW, De Kruif CA, Throsby M, Logtenberg T, Bakker ABH;
XX
DR WPI; 2015-51549K/62.
DR N-PSDB; BCD91609.
XX
CC PT New bispecific antibody comprises first antigen-binding site that binds
CC PT receptor tyrosine kinase (ErbB)-2 and second antigen-binding site that
CC PT binds ErbB-3, used for treating subject having ErbB-2, ErbB-3 or ErbB-
CC PT 2/ErbB-3 positive tumor.
XX
CC PS Claim 25; Fig 16A; 239pp; English.
XX
CC The present invention relates to a novel bispecific antibody for treating
CC a subject having a tumor, preferably receptor tyrosine kinase (ErbB)-2,
CC ErbB-3 or ErbB-2/ErbB-3 positive tumor. The bispecific antibody comprises
CC first antigen-binding site that binds ErbB-2 and second antigen-binding
CC site that binds ErbB-3. The invention further discloses: (1) a method for
CC treating the subject having ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive
CC tumor or at risk of having the tumor; (2) a method for counteracting the
CC formation of metastasis in a subject having ErbB-2, ErbB-3 or ErbB-2/ErbB
CC -3 positive tumor; and (3) a pharmaceutical composition comprising the
CC bispecific antibody. The bispecific antibody and pharmaceutical
CC composition are useful for treating a subject having or is at a risk of
CC having a tumor including breast cancer, gastric cancer, colorectal
CC cancer, colon cancer, gastro-esophageal cancer, esophageal cancer,
CC endometrial cancer, ovarian cancer, liver cancer, lung cancer including
CC non-small cell lung cancer, clear cell sarcoma, salivary gland cancer,
CC head and neck cancer, brain cancer, bladder cancer, pancreatic cancer,
CC prostate cancer, kidney cancer, skin cancer, or melanoma cell; for
CC counteracting or inhibiting, phosphorylation of Akt, extracellular signal
CC -regulated kinase (ERK) and/or S6 ribosomal protein; and for
CC counteracting the formation of metastasis in the subject having ErbB-2,
CC ErbB-3 or ErbB-2/ErbB-3 positive tumor. The bispecific antibody is also
CC used for imaging. The invention uses bispecific antibodies with an
CC enhanced internalization property, to the same extent as trastuzumab,
CC which results in the reduced ADCC activity. The present sequence is an
CC anti-erbB-2 antibody heavy chain variable region which is used in the
CC method for treating a subject suffering from ErbB-2, ErbB-3 or ErbB-
CC 2/ErbB-3 positive tumor.
CC
CC Revised record issued on 19-FEB-2016 : Correction of DE line, PS line and
CC keywords.
XX
SQ Sequence 121 AA;
Query Match 100.0%; Score 642; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKLSCKASGYTFTAYYINWVRQAPGQGLEWIGRIYPGSGYTSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKLSCKASGYTFTAYYINWVRQAPGQGLEWIGRIYPGSGYTSY 60
Qy 61 AQKFQGRATLTADESTSTAYMELSSLRSEDTAVYFCARPPVYYDSAWFAYWGQGTLVTVS120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRATLTADESTSTAYMELSSLRSEDTAVYFCARPPVYYDSAWFAYWGQGTLVTVS120
Qy 121 S 121
|
Db 121 S 121
Sequence alignment of instant VH (MF3958) SEQ ID NO:65 with WO 2018/182422 Throsey SEQ ID NO:39:
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 642 100.0 121 BCD91610 -- 11 Anti-erbB-2 antibody heavy chain variable region (MF3958), SEQ ID 48.
ALIGNMENT:
Query Match 100.0%; Score 642; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKLSCKASGYTFTAYYINWVRQAPGQGLEWIGRIYPGSGYTSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKLSCKASGYTFTAYYINWVRQAPGQGLEWIGRIYPGSGYTSY 60
Qy 61 AQKFQGRATLTADESTSTAYMELSSLRSEDTAVYFCARPPVYYDSAWFAYWGQGTLVTVS120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRATLTADESTSTAYMELSSLRSEDTAVYFCARPPVYYDSAWFAYWGQGTLVTVS120
Qy 121 S 121
|
Db 121 S 121
BFR99888
ID BFR99888 standard; protein; 121 AA.
XX
AC BFR99888;
XX
DT 15-NOV-2018 (first entry)
XX
DE Anti-ErbB-2 antibody (MF3958) heavy chain variable region, SEQ ID 39.
XX
KW CD340 protein; Epidermal growth factor receptor 2; ErbB-2 protein;
KW Erbb2 tyrosine kinase receptor; HER-2; HER2 protein; MLN 19 protein;
KW NEU protein; NGL protein; TKR1 protein; antibody; antibody therapy;
KW breast tumor; cancer; cytostatic; heavy chain variable region;
KW lung tumor; metastasis; neu; non-small-cell lung cancer; ovary tumor;
KW therapeutic.
XX
OS Unidentified.
XX
CC PN WO2018182422-A1.
XX
CC PD 04-OCT-2018.
XX
CC PF 03-APR-2018; 2018WO-NL050206.
XX
PR 31-MAR-2017; 2017EP-00164292.
XX
CC PA (MERU-) MERUS NV.
XX
CC PI Throsey M, Geuijen CAW, Maussang-Detaille DA, Logtenberg T;
XX
DR WPI; 2018-77570X/68.
DR N-PSDB; BFR99887.
XX
CC PT Use of bispecific antibody comprising first and second antigen-binding
CC PT sites that bind extracellular parts of erythroblastic leukemia viral
CC PT oncogene homolog (ErbB)-2, ErbB3, respectively, to treat individual with
CC PT ErbB-2 and -3 positive cell.
XX
CC PS Claim 19; SEQ ID NO 39; 103pp; English.
XX
CC The present invention relates to a novel bispecific antibody comprising a
CC first antigen-binding site that binds to an ErbB-2 protein and a second
CC antigen-binding site that binds to an ErbB-3 protein. The bispecific
CC antibody of the present invention can be used for treating an individual
CC having an ErbB-2 positive cell or an ErbB-3 positive cell, where the cell
CC comprises a neuregulin-1 (NRG1) fusion gene comprising at least a portion
CC of the NRG1 gene fused to a sequence from a different chromosomal
CC location. The bispecific antibody can be used for treating cancer
CC selected from breast cancer, ovarian cancer, lung cancer (such as non-
CC small cell lung cancer) and metastasis. The present sequence represents
CC an anti-ErbB-2 antibody (MF3958) heavy chain variable region, where the
CC antibody can be used for treating ErbB-2 positive tumor or ErbB-3
CC positive tumor.
XX
SQ Sequence 121 AA;
Sequence alignment of instant VH (MF3178) SEQ ID NO:110 with WO 2018/182422 Throsey SEQ ID NO:53:
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 685 100.0 124 BCD86321 -- 16 Anti-erbB-3 antibody (MF3178) heavy chain variable region, SEQ 89.
ALIGNMENT:
Query Match 100.0%; Score 685; Length 124;
Best Local Similarity 100.0%;
Matches 124; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
Qy 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDHGSRHFWSYWGFDYWGQGTLV120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDHGSRHFWSYWGFDYWGQGTLV120
Qy 121 TVSS 124
||||
Db 121 TVSS 124
BFR99902
ID BFR99902 standard; protein; 124 AA.
XX
AC BFR99902;
XX
DT 15-NOV-2018 (first entry)
XX
DE Anti-ErbB-3 antibody (MF3178) heavy chain variable region, SEQ ID 53.
XX
KW Epidermal growth factor receptor 3; ErbB-3 protein;
KW Erbb3 tyrosine kinase receptor; HER3 protein; LCCS2 protein; MDA-BF- 1;
KW antibody; antibody therapy; breast tumor; c-ErbB-3; cancer; cytostatic;
KW erbb-3-S; heavy chain variable region; lung tumor; metastasis;
KW non-small-cell lung cancer; ovary tumor; p180-Erbb-3; p45-sErbb-3;
KW p85-sErbb-3; therapeutic.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /note= "Complementarity determining region 1 (CDR1)"
FT Region 50..66
FT /note= "Complementarity determining region 2 (CDR2)"
FT Region 99..113
FT /note= "Complementarity determining region 3 (CDR3)"
XX
CC PN WO2018182422-A1.
XX
CC PD 04-OCT-2018.
XX
CC PF 03-APR-2018; 2018WO-NL050206.
XX
PR 31-MAR-2017; 2017EP-00164292.
XX
CC PA (MERU-) MERUS NV.
XX
CC PI Throsey M, Geuijen CAW, Maussang-Detaille DA, Logtenberg T;
XX
DR WPI; 2018-77570X/68.
DR N-PSDB; BFR99901.
XX
CC PT Use of bispecific antibody comprising first and second antigen-binding
CC PT sites that bind extracellular parts of erythroblastic leukemia viral
CC PT oncogene homolog (ErbB)-2, ErbB3, respectively, to treat individual with
CC PT ErbB-2 and -3 positive cell.
XX
CC PS Claim 19; SEQ ID NO 53; 103pp; English.
XX
CC The present invention relates to a novel bispecific antibody comprising a
CC first antigen-binding site that binds to an ErbB-2 protein and a second
CC antigen-binding site that binds to an ErbB-3 protein. The bispecific
CC antibody of the present invention can be used for treating an individual
CC having an ErbB-2 positive cell or an ErbB-3 positive cell, where the cell
CC comprises a neuregulin-1 (NRG1) fusion gene comprising at least a portion
CC of the NRG1 gene fused to a sequence from a different chromosomal
CC location. The bispecific antibody can be used for treating cancer
CC selected from breast cancer, ovarian cancer, lung cancer (such as non-
CC small cell lung cancer) and metastasis. The present sequence represents
CC an anti-ErbB-3 antibody (MF3178) heavy chain variable region, where the
CC antibody can be used for treating ErbB-2 positive tumor or ErbB-3
CC positive tumor. Note: SEQ ID NO: 112 (see BFR99961), SEQ ID NO: 116 (see
CC BFR99965), SEQ ID No: 119 (see BFR99968), SEQ ID NO: 122-138 (see
CC BFR99971-BFR99987) and BFR99991 are variants of the present sequence.
XX
SQ Sequence 124 AA;
Sequence alignment of instant ERBB3 SEQ ID NO:1 with WO 2015/130173, Geuijen NP_001973.2:
RESULT 1
AASEQ2_12092025_103512
Query Match 100.0%; Score 7292; DB 1; Length 1342;
Best Local Similarity 100.0%;
Matches 1342; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRANDALQVLGLLFSLARGSEVGNSQAVCPGTLNGLSVTGDAENQYQTLYKLYERCEVVM 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRANDALQVLGLLFSLARGSEVGNSQAVCPGTLNGLSVTGDAENQYQTLYKLYERCEVVM 60
Qy 61 GNLEIVLTGHNADLSFLQWIREVTGYVLVAMNEFSTLPLPNLRVVRGTQVYDGKFAIFVM120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GNLEIVLTGHNADLSFLQWIREVTGYVLVAMNEFSTLPLPNLRVVRGTQVYDGKFAIFVM120
Qy 121 LNYNTNSSHALRQLRLTQLTEILSGGVYIEKNDKLCHMDTIDWRDIVRDRDAEIVVKDNG180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LNYNTNSSHALRQLRLTQLTEILSGGVYIEKNDKLCHMDTIDWRDIVRDRDAEIVVKDNG180
Qy 181 RSCPPCHEVCKGRCWGPGSEDCQTLTKTICAPQCNGHCFGPNPNQCCHDECAGGCSGPQD240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RSCPPCHEVCKGRCWGPGSEDCQTLTKTICAPQCNGHCFGPNPNQCCHDECAGGCSGPQD240
Qy 241 TDCFACRHFNDSGACVPRCPQPLVYNKLTFQLEPNPHTKYQYGGVCVASCPHNFVVDQTS300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TDCFACRHFNDSGACVPRCPQPLVYNKLTFQLEPNPHTKYQYGGVCVASCPHNFVVDQTS300
Qy 301 CVRACPPDKMEVDKNGLKMCEPCGGLCPKACEGTGSGSRFQTVDSSNIDGFVNCTKILGN360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CVRACPPDKMEVDKNGLKMCEPCGGLCPKACEGTGSGSRFQTVDSSNIDGFVNCTKILGN360
Qy 361 LDFLITGLNGDPWHKIPALDPEKLNVFRTVREITGYLNIQSWPPHMHNFSVFSNLTTIGG420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LDFLITGLNGDPWHKIPALDPEKLNVFRTVREITGYLNIQSWPPHMHNFSVFSNLTTIGG420
Qy 421 RSLYNRGFSLLIMKNLNVTSLGFRSLKEISAGRIYISANRQLCYHHSLNWTKVLRGPTEE480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 RSLYNRGFSLLIMKNLNVTSLGFRSLKEISAGRIYISANRQLCYHHSLNWTKVLRGPTEE480
Qy 481 RLDIKHNRPRRDCVAEGKVCDPLCSSGGCWGPGPGQCLSCRNYSRGGVCVTHCNFLNGEP540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 RLDIKHNRPRRDCVAEGKVCDPLCSSGGCWGPGPGQCLSCRNYSRGGVCVTHCNFLNGEP540
Qy 541 REFAHEAECFSCHPECQPMEGTATCNGSGSDTCAQCAHFRDGPHCVSSCPHGVLGAKGPI600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 REFAHEAECFSCHPECQPMEGTATCNGSGSDTCAQCAHFRDGPHCVSSCPHGVLGAKGPI600
Qy 601 YKYPDVQNECRPCHENCTQGCKGPELQDCLGQTLVLIGKTHLTMALTVIAGLVVIFMMLG660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 YKYPDVQNECRPCHENCTQGCKGPELQDCLGQTLVLIGKTHLTMALTVIAGLVVIFMMLG660
Qy 661 GTFLYWRGRRIQNKRAMRRYLERGESIEPLDPSEKANKVLARIFKETELRKLKVLGSGVF720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 GTFLYWRGRRIQNKRAMRRYLERGESIEPLDPSEKANKVLARIFKETELRKLKVLGSGVF720
Qy 721 GTVHKGVWIPEGESIKIPVCIKVIEDKSGRQSFQAVTDHMLAIGSLDHAHIVRLLGLCPG780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 GTVHKGVWIPEGESIKIPVCIKVIEDKSGRQSFQAVTDHMLAIGSLDHAHIVRLLGLCPG780
Qy 781 SSLQLVTQYLPLGSLLDHVRQHRGALGPQLLLNWGVQIAKGMYYLEEHGMVHRNLAARNV840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 SSLQLVTQYLPLGSLLDHVRQHRGALGPQLLLNWGVQIAKGMYYLEEHGMVHRNLAARNV840
Qy 841 LLKSPSQVQVADFGVADLLPPDDKQLLYSEAKTPIKWMALESIHFGKYTHQSDVWSYGVT900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 LLKSPSQVQVADFGVADLLPPDDKQLLYSEAKTPIKWMALESIHFGKYTHQSDVWSYGVT900
Qy 901 VWELMTFGAEPYAGLRLAEVPDLLEKGERLAQPQICTIDVYMVMVKCWMIDENIRPTFKE960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 VWELMTFGAEPYAGLRLAEVPDLLEKGERLAQPQICTIDVYMVMVKCWMIDENIRPTFKE960
Qy 961 LANEFTRMARDPPRYLVIKRESGPGIAPGPEPHGLTNKKLEEVELEPELDLDLDLEAEED 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 LANEFTRMARDPPRYLVIKRESGPGIAPGPEPHGLTNKKLEEVELEPELDLDLDLEAEED 1020
Qy 1021 NLATTTLGSALSLPVGTLNRPRGSQSLLSPSSGYMPMNQGNLGESCQESAVSGSSERCPR 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 NLATTTLGSALSLPVGTLNRPRGSQSLLSPSSGYMPMNQGNLGESCQESAVSGSSERCPR 1080
Qy 1081 PVSLHPMPRGCLASESSEGHVTGSEAELQEKVSMCRSRSRSRSPRPRGDSAYHSQRHSLL 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 PVSLHPMPRGCLASESSEGHVTGSEAELQEKVSMCRSRSRSRSPRPRGDSAYHSQRHSLL 1140
Qy 1141 TPVTPLSPPGLEEEDVNGYVMPDTHLKGTPSSREGTLSSVGLSSVLGTEEEDEDEEYEYM 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 TPVTPLSPPGLEEEDVNGYVMPDTHLKGTPSSREGTLSSVGLSSVLGTEEEDEDEEYEYM 1200
Qy 1201 NRRRRHSPPHPPRPSSLEELGYEYMDVGSDLSASLGSTQSCPLHPVPIMPTAGTTPDEDY 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 NRRRRHSPPHPPRPSSLEELGYEYMDVGSDLSASLGSTQSCPLHPVPIMPTAGTTPDEDY 1260
Qy 1261 EYMNRQRDGGGPGGDYAAMGACPASEQGYEEMRAFQGPGHQAPHVHYARLKTLRSLEATD 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 EYMNRQRDGGGPGGDYAAMGACPASEQGYEEMRAFQGPGHQAPHVHYARLKTLRSLEATD 1320
Qy 1321 SAFDNPDYWHSRLFPKANAQRT 1342
||||||||||||||||||||||
Db 1321 SAFDNPDYWHSRLFPKANAQRT 1342
NOTE: The US Patent and US Patent Applications rejected under obviousness double patenting below that qualify as prior art are also rejected under 35 USC 103 as primary references, each in view of the secondary references of record, as set forth below. For the sake of compact prosecution, these rejections are condensed and abbreviated due to the redundant nature of their disclosures.
17. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over any of the following US Patents or US Patent Application Publications as the primary reference:
US Patent 11,279,770;
US Patent 12,139,548;
US Patent Application Publication 2022/0348683 (Application 17/675,431);
US Patent Application Publication 20240158532 (Application 18/419,527); or
US Patent Application Publication 20240158531 (Application 18/419,491);
each in view of WO 2018/182422, Throsey (Throsby) et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The applied references have a common assignee with the instant application. Based upon the earlier effectively filed date of the references, they constitute prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
US Patent 11,279,770 – is the US 371 filing of WO 2015/130173, Geuijen et al (“Geuijen 2015”) and comprises the same disclosure as Geuijen 2015 as set forth above;
US Patent 12,139,548 - claims priority to WO 2015/130173, Geuijen et al (“Geuijen 2015”) and comprises the same disclosure as Geuijen 2015 as set forth above;
US Patent Application Publication 2022/0348683 (Application 17/675,431) – claims priority to WO 2015/130173, Geuijen et al (“Geuijen 2015”) and comprises the same disclosure as Geuijen 2015 as set forth above;
US Patent Application Publication 20240158532 (Application 18/419,527) – claims priority to WO 2015/130173, Geuijen et al (“Geuijen 2015”) and comprises the same disclosure as Geuijen 2015 as set forth above; and
US Patent Application Publication 20240158531 (Application 18/419,491) - claims priority to WO 2015/130173, Geuijen et al (“Geuijen 2015”) and comprises the same disclosure as Geuijen 2015 as set forth above.
Each of the primary references does not teach:
the cancer of the subject treated harbors an ERBB3 activating mutation that is a driver mutation promoting or correlated to ligand-independent heterodimerization of ERBB2:ERBB3, or activation of the ERBB2 kinase domain (instant claim 2).
the ERBB3 mutation is A232V, V104M, or in P262, G284, Q809 (instant claims 16, 28, 32).
First line therapy (instant claim 21);
Second line therapy after patients has progressed on therapy such as anti-ERBB2 therapy (instant claim 22); and
Treating cancer having no EGFR/ALK mutations (instant claim 18);
As evidenced by Huang, antibody PB4188 has synonyms Zenocutuzumab, and MCLA-128 (p. 3116, col. 2; Table 2).
Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018, Schram, and Jaiswal teach as set forth above, and render obvious the deficient limitations listed above, for the same reasons stated above in section 16.
18. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over any of the following US Patents or US Patent Application Publications as the primary reference:
US Patent 12,247,078 – claims priority to WO 2018/182422, Throsey et al (Throsey corrected as Throsby in this US Patent);
US Patent 11,780,925 claims priority to WO 2018/182422, Throsey et al (Throsby); or
US Patent Application Publication 2024/0199747 (Application 18/449,460) claims priority to WO 2018/182422, Throsey et al (Throsby);
each in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The applied references have a common assignee with the instant application. Based upon the earlier effectively filed date of the references, they constitute prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
US Patent 12,247,078 – claims priority to WO 2018/182422, Throsey et al (Throsby), and comprises the same disclosure as Throsey as set forth above;
US Patent 11,780,925 claims priority to WO 2018/182422, Throsey et al (Throsby), and comprises the same disclosure as Throsey as set forth above; or
US Patent Application Publication 2024/0199747 (Application 18/449,460) claims priority to WO 2018/182422, Throsey et al (Throsby), and comprises the same disclosure as Throsey as set forth above;
Each of the primary references does not teach:
the cancer of the subject treated harbors an ERBB3 activating mutation that is a driver mutation promoting or correlated to ligand-independent heterodimerization of ERBB2:ERBB3, or activation of the ERBB2 kinase domain (instant claim 2).
the ERBB3 mutation is A232V, V104M, or in P262, G284, Q809 (instant claims 16, 28, 32).
First line therapy (instant claim 21);
Second line therapy after patients has progressed on therapy such as anti-ERBB2 therapy (instant claim 22); and
As evidenced by Huang, antibody PB4188 has synonyms Zenocutuzumab, and MCLA-128 (p. 3116, col. 2; Table 2).
Geuijen 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018, Schram, and Jaiswal teach as set forth above in section 16.
Treating cancer patients harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patients comprising tumors harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R. One would have been motivated to, and have a reasonable expectation of success to, because: (1) each primary reference, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; (2) each primary reference, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach the known, predictable anti-tumor mechanism of MCLA-128/PB4188 to inhibit HER2:HER3 heterodimerization, inhibit downstream signaling, and enhance ADCC activity; (3) Geujin 2015 acknowledges cancers harbor ERBB3 activating mutations; (4) Jaiswal demonstrates that solid tumors commonly comprise ERBB3 activating mutations, identifies ERBB3 hotspot mutations, demonstrates these mutations contribute to oncogenic signaling and promote cancer cell growth; and demonstrates successfully treating tumors or inhibiting cancer cells harboring the ERBB3 activating mutations by administration of an anti-ERBB3 antibody that binds to domain III.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Given: (1) the recognized need by the cited art to treat a wide variety of solid tumors expressing HER2/HER3 and the need to inhibit HER2/HER3 oncogenic signaling; (2) the established knowledge that several of these solid tumor types can also encompass ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; (3) the recognized need to treat the wide variety of solid tumors that comprise the ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; and (4) the known solution of treating the wide variety of solid tumors with MCLA-128/PB4188 (binding to HER2 domain I and HER3 domain III) to successfully inhibit HER2/HER3 heterodimerization and downstream signaling; and (5) the known solution of inhibiting tumor cells, inhibiting HER2/HER3 signaling, and treating tumors harboring HER3 activating mutations by administration of a HER3 antibody binding to domain III alone, one of skill in the art could have pursued including HER2+/HER3+ cancer patients harboring ERBB3 activating mutations, in the method of treatment taught by each primary reference with a reasonable expectation of success.
Treating cancer patient progressed on prior therapy such as anti-ERBB2 therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patient who progressed in prior therapy, such as anti-ERBB2 therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) each of the primary references, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, lung, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; and (2) Alsina 2017 and 2018, and Schram teach and demonstrate administering MCLA-128/PB4188 to a subset of solid tumor cancer patients who have progressed after prior lines of therapy, including anti-ERBB2 (trastuzumab) treatment.
Treating cancer patients as first line therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 as primary therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) each primary reference, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment; and (2) both Geujin 2015 and 2018 and each primary reference demonstrate successfully treating cancer in vivo by administering MCLA-128/PB4188 as primary and single agent therapy, wherein each primary reference teaches MCLA-128 had significant antitumor activity.
19. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 12,195,551, claiming priority to 2017; in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey (Throsby) et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by NCBI protein sequence for NP_001973.2 (printed December 2025).
The applied references have a common assignee with the instant application. Based upon the earlier effectively filed date of the references, they constitute prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
US Patent 12,195,551 discloses and claims treating ERbB2+/ERBB3+ breast cancer in a subject compromising administering to the subject a bispecific antibody comprising anti-ERBB2 VH SEQ ID NO:42 and anti-ERBB3 VH SEQ ID NO:57 that are 100% identical to instant SEQ ID NOs:65 and 110, respectively, and comprises light chain SEQ ID NO:81 that comprises the instantly claimed VL CDRs (claims 1-9); and wherein the cancer does not have ERBB2 gene amplification (claim 2; Example 4). The patent discloses the bispecific antibody is PB4188 (MCLA-128); recognizes ligand-independent heterodimerization of ERBB2:ERBB3 occurs resulting in growth signals to cancer cells; and treating patients with bispecific antibody MCLA-128 as second line therapy after they have progressed on prior therapy (Figure 12; Example 4); wherein ERBB3 sequence is represented by NP_001973.2 (col. 9, lines 18-30) that is 100% identical to instant SEQ ID NO:1 as evidenced by NCBI NP_001973.2; wherein the bispecific antibody binds required amino acid R426 of ERBB3 (col. 18 lines 48 to col. 19, line 12). The patent exemplifies successfully treating treatment-naïve breast cancer xenografts by administration of MCLA-128 (Examples 1 and 2). The patent exemplifies antibody MCLA-128 successfully inhibits ERBB2:ERBB3 heterodimers and downstream PI3K signaling (Example 3).
The US Patent does not teach the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the cancer received prior therapy with an anti-ERBB2 therapy; the treatment is first line therapy; or treating patients lacking EGFR/ALK mutations.
Geuijen 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018, Schram, and Jaiswal teach as set forth above in section 16.
Treating cancer patients harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patients comprising tumors harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the US Patent, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; (2) the US Patent, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach the known, predictable anti-tumor mechanism of MCLA-128/PB4188 to inhibit HER2:HER3 heterodimerization, inhibit downstream signaling, and enhance ADCC activity; (3) Geujin 2015 acknowledges cancers harbor ERBB3 activating mutations; (4) Jaiswal demonstrates that solid tumors commonly comprise ERBB3 activating mutations including breast cancer, identifies ERBB3 hotspot mutations, demonstrates these mutations contribute to oncogenic signaling and promote cancer cell growth; and demonstrates successfully treating tumors or inhibiting cancer cells harboring the ERBB3 activating mutations by administration of an anti-ERBB3 antibody that binds to domain III.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Given: (1) the recognized need by the cited art to treat a wide variety of solid tumors expressing HER2/HER3 and the need to inhibit HER2/HER3 oncogenic signaling; (2) the established knowledge that several of these solid tumor types, including breast cancer, can also encompass ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; (3) the recognized need to treat the wide variety of solid tumors that comprise the ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; and (4) the known solution of treating the wide variety of solid tumors with MCLA-128/PB4188 (binding to HER2 domain I and HER3 domain III) to successfully inhibit HER2/HER3 heterodimerization and downstream signaling; and (5) the known solution of inhibiting tumor cells, inhibiting HER2/HER3 signaling, and treating tumors harboring HER3 activating mutations by administration of a HER3 antibody binding to domain III alone, one of skill in the art could have pursued including HER2+/HER3+ breast cancer patients harboring ERBB3 activating mutations, in the method of treatment taught by the US Patent with a reasonable expectation of success.
Treating cancer patient progressed on prior therapy such as anti-ERBB2 therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patient who progressed in prior therapy, such as anti-ERBB2 therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the US Patent, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, lung, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; (2) the US Patent teaches treating patients with MCLA-128 that progressed on prior therapy; and (3) Alsina 2017 and 2018, and Schram teach and demonstrate administering MCLA-128/PB4188 to a subset of solid tumor cancer patients who have progressed after prior lines of therapy, including anti-ERBB2 (trastuzumab) treatment.
Treating cancer patients as first line therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 as primary therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the US Patent, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment; and (2) both Geujin 2015 and 2018, Throsey, and the US Patent demonstrate successfully treating cancer in vivo by administering MCLA-128/PB4188 as primary and single agent therapy, wherein Throsey teaches MCLA-128 had significant antitumor activity.
Treating cancer having no EGFR/ALK mutations:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 to cancers lacking EGFR/ALK mutations. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the US Patent, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment with MCLA-128/PB4188; and (2) Throsey teaches treating ERBB2+/ERBB3+ cancers with MCLA-128 that test negative for EGFR/ALK mutations.
20. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2022/0372166 (Application 17/755,196), claiming priority to Oct. 2020; in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey (Throsby) et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by NCBI protein sequence for NP_001973.2 (printed December 2025).
The applied references have a common assignee/inventor with the instant application. Based upon the earlier effectively filed date of the references, they constitute prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
US Patent Application Publication 2022/0372166 teaches a method of treating a subject that has an ErbB2 and ErbB3 positive cancer, comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein VH SEQ ID NOs:82 and 97 (Figure 4A and 4B) are 100% identical to instant SEQ ID NOs:65 and 110, respectively, and wherein the light chain comprises the sequence in Figure 1 that comprises the instantly claimed VL CDRs; and wherein the cancer does not have ERBB2 gene amplification (claim 2; Example 4). US 2022/0372166: discloses the bispecific antibody is PB4188 (MCLA-128) ([169]); recognizes ligand-independent heterodimerization of ERBB2:ERBB3 occurs resulting in growth signals to cancer cells ([141]); teaches treating lung cancer patients with bispecific antibody MCLA-128 as second line therapy after they have progressed on prior afatinib therapy and the patients are identified has lacking mutations in EGFR, KRAS, EGFR, cKIT-BRCA1-2, MET, ROS, RET, and ALK (Example 2; [15]); teaches treating various solid tumors including ovarian, colorectal, pancreatic, breast (Example 1; [15]; claim 9); teaches the ERBB3 sequence is represented by NP_001973.2 ([33]) that is 100% identical to instant SEQ ID NO:1 as evidenced by NCBI NP_001973.2; and teaches the bispecific antibody binds required amino acid R426 of ERBB3 ([146]).
US 2022/0372166 does not teach the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; or that the bispecific antibody treatment is first line therapy.
Geuijen 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018, Schram, and Jaiswal teach as set forth above in section 16.
Treating cancer patients harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patients comprising tumors harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2022/0372166, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including lung, breast, ovarian, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; (2) US 2022/0372166, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach the known, predictable anti-tumor mechanism of MCLA-128/PB4188 to inhibit HER2:HER3 heterodimerization, inhibit downstream signaling, and enhance ADCC activity; (3) Geujin 2015 acknowledges cancers harbor ERBB3 activating mutations; (4) Jaiswal demonstrates that solid tumors commonly comprise ERBB3 activating mutations including lung, ovarian, and colorectal cancer, identifies ERBB3 hotspot mutations, demonstrates these mutations contribute to oncogenic signaling and promote cancer cell growth; and demonstrates successfully treating tumors or inhibiting cancer cells harboring the ERBB3 activating mutations by administration of an anti-ERBB3 antibody that binds to domain III.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Given: (1) the recognized need by the cited art to treat a wide variety of solid tumors expressing HER2/HER3 and the need to inhibit HER2/HER3 oncogenic signaling; (2) the established knowledge that several of these solid tumor types, including breast cancer, can also encompass ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; (3) the recognized need to treat the wide variety of solid tumors that comprise the ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; and (4) the known solution of treating the wide variety of solid tumors with MCLA-128/PB4188 (binding to HER2 domain I and HER3 domain III) to successfully inhibit HER2/HER3 heterodimerization and downstream signaling; and (5) the known solution of inhibiting tumor cells, inhibiting HER2/HER3 signaling, and treating tumors harboring HER3 activating mutations by administration of a HER3 antibody binding to domain III alone, one of skill in the art could have pursued including HER2+/HER3+ lung, ovarian and colorectal cancer patients harboring ERBB3 activating mutations, in the method of treatment taught by US 2022/0372166 with a reasonable expectation of success.
Treating cancer patients as first line therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 as primary therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2022/0372166, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment; and (2) both Geujin 2015 and 2018, and Throsey demonstrate successfully treating cancer in vivo by administering MCLA-128/PB4188 as primary and single agent therapy, wherein Throsey teaches MCLA-128 had significant antitumor activity.
21. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2020/0291130 (Application 16/499,723) published September 17, 2020, and claiming priority to 2019; in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey (Throsby) et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by NCBI protein sequence for NP_001973.2 (printed December 2025).
The applied references have a common assignee with the instant application. Based upon the earlier effectively filed date of the references, they constitute prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
US Patent Application Publication 2020/0291130 teaches a method of treating a subject having ERBB2/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences instantly claimed, wherein ERBB2 VH is SEQ ID NOs:39 or 81, and ERBB3 VH is SEQ ID NOs: 53 or 82 ([95]) that are 100% identical to instant SEQ ID NOs:65 and 110, respectively, and wherein the light chain comprises the same CDR sequences ([53-56]) as the instantly claimed VL CDRs; wherein the bispecific antibody is PB4188 ([91]; Figure 2; Example 1); wherein the ERBB3 sequence is represented by NP_001973.2 ([33]) that is 100% identical to instant SEQ ID NO:1 as evidenced by NCBI NP_001973.2 ([59]); wherein the bispecific antibody requires amino acid R426 of ERBB3 to bind ([66]); wherein the bispecific antibody inhibits HER2:HER3 heterodimerization (Figure 6; Example 3), wherein ligand-independent heterodimerization of ERBB2:ERBB3 results in growth signals to cancer cells ([60]); and wherein cancer treated encompasses ovarian, gastric, gastro-esophageal; colorectal, lung cancers ([20]).
US 2020/0291130 does not teach the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the cancer lacks EGFR/ALK mutation; the cancer received prior therapy with an anti-ERBB2 therapy; or the treatment is first line therapy.
Geuijen 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018, Schram, and Jaiswal teach as set forth above in section 16.
Treating cancer patients harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patients comprising tumors harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2020/0291130, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; (2) US 2020/0291130, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach the known, predictable anti-tumor mechanism of MCLA-128/PB4188 to inhibit HER2:HER3 heterodimerization, inhibit downstream signaling, and enhance ADCC activity; (3) Geujin 2015 acknowledges cancers harbor ERBB3 activating mutations; (4) Jaiswal demonstrates that solid tumors commonly comprise ERBB3 activating mutations including lung, breast, ovarian, gastric, and colorectal cancer, identifies ERBB3 hotspot mutations, demonstrates these mutations contribute to oncogenic signaling and promote cancer cell growth; and demonstrates successfully treating tumors or inhibiting cancer cells harboring the ERBB3 activating mutations by administration of an anti-ERBB3 antibody that binds to domain III.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Given: (1) the recognized need by the cited art to treat a wide variety of solid tumors expressing HER2/HER3 and the need to inhibit HER2/HER3 oncogenic signaling; (2) the established knowledge that several of these solid tumor types, including colorectal, ovarian, gastric, and lung, can also encompass ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; (3) the recognized need to treat the wide variety of solid tumors that comprise the ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; and (4) the known solution of treating the wide variety of solid tumors with MCLA-128/PB4188 (binding to HER2 domain I and HER3 domain III) to successfully inhibit HER2/HER3 heterodimerization and downstream signaling; and (5) the known solution of inhibiting tumor cells, inhibiting HER2/HER3 signaling, and treating tumors harboring HER3 activating mutations by administration of a HER3 antibody binding to domain III alone, one of skill in the art could have pursued including HER2+/HER3+ cancer patients harboring ERBB3 activating mutations, in the method of treatment taught by US 2020/0291130 with a reasonable expectation of success.
Treating cancer patient progressed on prior therapy such as anti-ERBB2 therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patient who progressed in prior therapy, such as anti-ERBB2 therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2020/0291130, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, lung, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; and (2) Alsina 2017 and 2018, and Schram teach and demonstrate administering MCLA-128/PB4188 to a subset of solid tumor cancer patients who have progressed after prior lines of therapy, including anti-ERBB2 (trastuzumab) treatment.
Treating cancer patients as first line therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 as primary therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2020/0291130, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment; and (2) both Geujin 2015 and 2018, and Throsey successfully treating cancer in vivo by administering MCLA-128/PB4188 as primary and single agent therapy, wherein Throsey teaches MCLA-128 had significant antitumor activity.
Treating cancer having no EGFR/ALK mutations:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 to cancers lacking EGFR/ALK mutations. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2020/0291130, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment with MCLA-128/PB4188; and (2) Throsey teaches treating ERBB2+/ERBB3+ cancers with MCLA-128 that test negative for EGFR/ALK mutations.
22. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2021/0206875 (Application 16/499,144), claiming priority to 2018; in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey (Throsby) et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by NCBI protein sequence for NP_001973.2 (printed December 2025).
The applied references have a common assignee with the instant application. Based upon the earlier effectively filed date of the references, they constitute prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
US Patent Application Publication 2021/0206875 teaches a method of treating a subject having ERBB2/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences instantly claimed, wherein ERBB2 VH is SEQ ID NOs:39 (Figure 16A), and ERBB3 VH is SEQ ID NOs: 53 (Figure 16B) that are 100% identical to instant SEQ ID NOs:65 and 110, respectively, and wherein the light chain comprises the same CDR sequences (Figure 16C) as the instantly claimed VL CDRs; wherein the bispecific antibody is PB4188 ([50]; [69]; [138]; [173]; [341-357]; Example 1); wherein the ERBB3 sequence is represented by NP_001973.2 ([39]) that is 100% identical to instant SEQ ID NO:1 as evidenced by NCBI NP_001973.2; wherein the bispecific antibody requires amino acid R426 of ERBB3 to bind ([44]; [182]; [74]; [140]; [163]); wherein the bispecific antibody inhibits HER2:HER3 heterodimerization and ligand-independent cell proliferation ([334]; [40]); and wherein cancer treated encompasses ovarian, gastric, gastro-esophageal; colorectal, lung cancers ([138]; [141]; [160]); wherein MCLA-128 was demonstrated to successfully treat breast cancer xenografts (Examples 2).
US 2021/0206875 does not teach the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the cancer received prior therapy with an anti-ERBB2 therapy; the treatment is first line therapy; or the cancer lacks EGFR/ALK mutation.
Geuijen 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018, Schram, and Jaiswal teach as set forth above in section 16.
Treating cancer patients harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patients comprising tumors harboring ERBB3 activating mutations V104M, A232V, P262H, G284R, or Q809R. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2021/0206875, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; (2) US 2021/0206875, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach the known, predictable anti-tumor mechanism of MCLA-128/PB4188 to inhibit HER2:HER3 heterodimerization, inhibit downstream signaling, and enhance ADCC activity; (3) Geujin 2015 acknowledges cancers harbor ERBB3 activating mutations; (4) Jaiswal demonstrates that solid tumors commonly comprise ERBB3 activating mutations including lung, breast, ovarian, gastric, and colorectal cancer, identifies ERBB3 hotspot mutations, demonstrates these mutations contribute to oncogenic signaling and promote cancer cell growth; and demonstrates successfully treating tumors or inhibiting cancer cells harboring the ERBB3 activating mutations by administration of an anti-ERBB3 antibody that binds to domain III.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Given: (1) the recognized need by the cited art to treat a wide variety of solid tumors expressing HER2/HER3 and the need to inhibit HER2/HER3 oncogenic signaling; (2) the established knowledge that several of these solid tumor types, including breast, colorectal, ovarian, gastric, and lung, can also encompass ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; (3) the recognized need to treat the wide variety of solid tumors that comprise the ERBB3 activating mutations that promote HER2/HER3 oncogenic signaling; and (4) the known solution of treating the wide variety of solid tumors with MCLA-128/PB4188 (binding to HER2 domain I and HER3 domain III) to successfully inhibit HER2/HER3 heterodimerization and downstream signaling; and (5) the known solution of inhibiting tumor cells, inhibiting HER2/HER3 signaling, and treating tumors harboring HER3 activating mutations by administration of a HER3 antibody binding to domain III alone, one of skill in the art could have pursued including HER2+/HER3+ cancer patients harboring ERBB3 activating mutations, in the method of treatment taught by US 2021/0206875 with a reasonable expectation of success.
Treating cancer patient progressed on prior therapy such as anti-ERBB2 therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patient who progressed in prior therapy, such as anti-ERBB2 therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2021/0206875, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram all teach or demonstrate successful treatment of a wide variety of solid tumors including breast, ovarian, lung, gastric, GEJ, and colorectal cancers with MCLA-128/PB4188; and (2) Alsina 2017 and 2018, and Schram teach and demonstrate administering MCLA-128/PB4188 to a subset of solid tumor cancer patients who have progressed after prior lines of therapy, including anti-ERBB2 (trastuzumab) treatment.
Treating cancer patients as first line therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 as primary therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2021/0206875, Geujin 2015, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment; and (2) both Geujin 2015 and 2018, Throsey, and US 2021/0206875 successfully treating cancer in vivo by administering MCLA-128/PB4188 as primary and single agent therapy, wherein Throsey teaches MCLA-128 had significant antitumor activity.
Treating cancer having no EGFR/ALK mutations:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer MCLA-128/PB4188 to cancers lacking EGFR/ALK mutations. One would have been motivated to, and have a reasonable expectation of success to, because: (1) US 2021/0206875, Geujin 2015, Throsey, Calvo, Alsina 2018, Alsina 2017, Geujin 2018 and Schram recognize that ERBB2+/ERBB3+ cancers are in need of treatment with MCLA-128/PB4188; and (2) Throsey teaches treating ERBB2+/ERBB3+ cancers with MCLA-128 that test negative for EGFR/ALK mutations.
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.
23. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,279,770 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The US Patent claims an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein SEQ ID NOs:48 and 63 are 100% identical to instant SEQ ID NOs:65 and 110, respectively.
The US Patent claims:
1. A bispecific antibody comprising a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences of AYYIN (SEQ ID NO:49), RIYPGSGYTSYAQKFQG (SEQ ID NO:50), and PPVYYDSAWFAY (SEQ ID NO:51) and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87; and a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences GYYMH (SEQ ID NO:64), WINPNSGGTNYAQKFQG (SEQ ID NO:65), and DHGSRHFWSYWGEFDY (SEQ ID NO:66) and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87.
2. The bispecific antibody of claim 1, which is afucosylated in order to enhance antibody dependent cellular cytotoxicity (ADCC).
3. The bispecific antibody of claim 1, wherein the bispecific antibody comprises two different immunoglobulin heavy chains with compatible heterodimerization domains.
4. The bispecific antibody of claim 3, wherein the compatible heterodimerization domains are compatible immunoglobulin heavy chain CH3 heterodimerization domains.
5. A pharmaceutical composition comprising the bispecific antibody of claim 1.
6. A method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor the method comprising: administering to the subject the antibody of claim 1 or the pharmaceutical composition of claim 5.
7. A method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor, the method comprising:
administering to the subject:
the bispecific antibody of claim 1, and
at least one additional therapeutic agent.
8. The bispecific antibody of claim 1, wherein the antibody comprises the light chain variable region comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLOSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNEYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 87).
9. The method of claim 7, wherein said at least one additional therapeutic agent is selected from afatinib, laptinib, neratinib, BYL719, MK-2206, everolimus, saracatinib, paclitaxel, vorinostat.
10. The bispecific antibody of claim 1, wherein the first binding arm comprises a heavy chain variable region comprising SEQ ID NO: 48, the second binding arm comprises a heavy chain variable region comprising SEQ ID NO: 63, and both the first and second binding arms comprise a light chain variable region comprising SEQ ID NO: 87.
11. The bispecific antibody of claim 1, wherein the first binding arm comprises a heavy chain comprising SEQ ID NO: 88, the second binding arm comprises a heavy chain comprising SEQ ID NO: 89, and both the first and second binding arms comprise a light chain comprising SEQ ID NO: 87.
12. The method of claim 6, wherein the tumor is a ErbB-2/ErbB-3 positive tumor.
13. The method of claim 6, wherein the tumor is a ErbB-2 positive tumor.
14. The method of claim 6, wherein the tumor is a ErbB-3 positive tumor.
15. The method of claim 7, wherein the tumor is a ErbB-2/ErbB-3 positive tumor.
16. The method of claim 7, wherein the tumor is a ErbB-2 positive tumor.
17. The method of claim 7, wherein the tumor is a ErbB-3 positive tumor.
The US Patent does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation, the cancer received prior therapy; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
24. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,195,551 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The US Patent claims an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein SEQ ID NOs:42 and 57 are 100% identical to instant SEQ ID NOs:65 and 110, respectively. The US Patent also claims treating cancer that lacks ERBB2 gene amplification.
The US Patent claims:
1. A method of treating a hormone receptor positive breast cancer in a subject, comprising administering to the subject in need thereof a combination of a therapeutically effective amount of an ErbB-2/ErbB-3 bispecific antibody and a therapeutically effective amount of tamoxifen, fulvestrant, or letrozole, wherein the bispecific antibody is administered at a flat dose of 750 mg, wherein the bispecific antibody has an antigen binding site that can bind an extra-cellular part of ErbB-2 and an antigen binding site that can bind an extra-cellular part of ErbB-3;
wherein the antigen binding site that can bind an extra-cellular part of ErbB-2 comprises a variable domain with a heavy chain variable region comprising at least the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 43, 44, and 45, respectively, and
wherein the antigen binding site that can bind an extra-cellular part of ErbB-3 comprises a variable domain with a heavy chain variable region comprising at least the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 58, 59, and 60, respectively;
wherein each of the heavy chain variable regions is paired with a light chain variable region (VL) comprising the CDR1, CDR2 and CDR3 sequences according to SEQ ID NO: 169, SEQ ID NO: 170 and SEQ ID NO: 171, respectively.
2. The method of claim 1, wherein the hormone receptor positive breast cancer is an immunohistochemistry ErbB-2+ cancer or an immunohistochemistry ErbB-2++ without ErbB-2 gene amplification cancer.
3. The method of claim 1, wherein the hormone receptor positive breast cancer is ER-positive with low HER2 expression metastatic breast cancer (MBC), wherein the low HER2 expression is defined as IHC 1+, or IHC 2+ combined with negative FISH.
4. The method of claim 1, wherein the bispecific antibody can reduce a ligand-induced receptor function of ErbB-3 on a ErbB-2 and ErbB-3 positive cell.
5. The method of claim 1, wherein each of the heavy chain variable regions is paired with the light chain variable region of the light chain according to SEQ ID NO: 81.
6. The method of claim 1, wherein the antigen binding site that can bind an extra-cellular part of ErbB-2 comprises a variable domain with a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 42.
7. The method of claim 1, wherein the antigen binding site that can bind an extra-cellular part of ErbB-3 comprises a variable domain with a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 57.
8. The method of claim 1, wherein the bispecific antibody is administered weekly, biweekly, every 3 weeks, or every 4 weeks.
9. The method of claim 1, wherein the bispecific antibody is administered every 3 weeks.
The US Patent does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
25. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,780,925 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The US Patent claims an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same MF3598 CDRs (SEQ ID NOs:40-42) same MF3178 CDRs (SEQ ID NOs:55-57) and same light chain sequences, wherein SEQ ID NOs:40-42 are 100% identical to instant SEQ ID NOs:66-68, and SEQ ID NOs:55-57 are 100% identical to instant SEQ ID NOs:111-113.
The US Patent claims
1. A method of treating a cancer in a subject, wherein the cancer comprises an ErbB-2 and ErbB-3 positive cancer cell, the method comprising administering a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3 to the subject, wherein the cell comprises an NRG1 fusion gene comprising at least a portion of the NRG1-gene fused to a sequence from a different chromosomal location;
the first antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:40, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:41, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:42;
the second antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:54, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:55, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:56; and
wherein the first antigen binding site and the second antigen binding site comprise a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:75, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:76, and a light chain CDR3 comprising the amino acid sequence SEQ ID NO:77.
2. The method of claim 1, wherein the NRG1 fusion gene comprises at least the 3′ end of the NRG1 gene fused to a 5′ sequence from a different chromosomal location.
3. The method of claim 1, wherein the cell is a breast cancer cell, an ovarian cancer cell, a lung cancer cell, a non-small cell lung cancer, or a metastasis thereof.
4. A method of treating cancer in a subject, wherein the cancer comprises an ErbB-2 and ErbB-3 positive tumor, the method comprising administering a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2 and a second antigen-binding site that can bind an extracellular part of ErbB-3 to the subject, wherein one or more cells of the cancer express an NRG1 fusion gene comprising at least the 3′ end of the NRG1 gene fused to a 5′ sequence from a different chromosomal location; wherein
the first antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:40, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:41, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:42;
the second antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:54, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:55, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:56; and
wherein the first antigen binding site and the second antigen binding site comprise a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:75, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:76, and a light chain CDR3 comprising the amino acid sequence SEQ ID NO:77.
5. The method of claim 4, wherein the tumor is a breast tumor, an ovarian tumor, a lung tumor, a non-small cell lung tumor, or a metastasis thereof.
6. The method of claim 4, wherein the NRG1-fusion gene expresses a protein that comprises an NRG1 EGF-like domain.
7. The method of claim 6, wherein the NRG-fusion is a fusion of NRG1 and a gene on human chromosome 8.
8. The method of claim 7, wherein the gene on human chromosome 8 encodes an excreted protein or a cellular membrane associated protein.
9. The method of claim 4, wherein the NRG1 fusion gene is a fusion of the 3′ end of the NRG1-gene with the 5′ sequence of one of the genes selected from the group consisting of CD74; DOC4; TNFRSF10B; CLU; VAMP2; SLC3A2; RBPMS; WRN; SDC4; KIF13B; SLECA2; PDE7A; ATP1B1; CDK1; BMPR1B; MCPH1; and RAB2IL1.
10. The method of claim 4, wherein the cell or tumor is of an epithelial origin.
11. The method of claim 4, wherein the individual has undergone a therapy targeted towards EGFR inhibition.
12. The method of claim 4, wherein a ErbB-1 cell-surface receptor density; a ErbB-2 cell-surface receptor density; a ErbB-3 cell-surface receptor density; a ErbB-4 cell-surface receptor density, or a combination thereof on cells of the tumor has been determined.
13. The method of claim 12, wherein the tumor has less than 400,000 ErbB-1 cell-surface receptors per cell or less than 200,000 ErbB-1 cell-surface receptors per cell.
14. The method of claim 4, further comprising administering to the individual an ErbB-1 inhibitor.
15. The method of claim 14, wherein the ErbB-1 inhibitor is cetuximab.
The US Patent does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy. The US Patent does not claim the full VH sequences of MF3598 and MF3178 antibodies.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references teach and render obvious the known VH sequences of the MF3598 and MF3178 antibodies for construction of the bispecific antibody for the reasons stated above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
26. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,247,078 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The US Patent claims an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein SEQ ID NOs:39 and 53 are 100% identical to instant SEQ ID NOs:65 and 110, respectively.
The US Patent claims:
1. A method of treating non-small cell lung cancer or pancreatic cancer in a subject, wherein the method comprises administering to the subject a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3, wherein cells of said cancer comprise an NRG1 fusion gene comprising at least a portion of the NRG1-gene fused to a sequence from a different chromosomal location;
the first antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:40, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:42; and
the second antigen-binding site comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:54, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 55, and a heavy chain CDR3 comprising the amino acid sequence SEQ ID NO:56; and
wherein the first antigen binding site and the second antigen binding site comprise a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:75, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:76, and a light chain CDR3 comprising the amino acid sequence SEQ ID NO:77.
2. The method of claim 1, wherein the NRG1 fusion gene comprises at least the 3′ end of the NRG1-gene fused to a 5′ sequence from a different chromosomal location.
3. The method of claim 1, wherein the cancer is non-small cell lung cancer.
4. The method of claim 3, wherein the non-small cell lung cancer is of the invasive mucinous adenocarcinoma subtype.
5. The method of claim 1, wherein the cancer is pancreatic cancer.
6. The method of claim 1, wherein the cancer is a metastasis of non-small cell lung cancer.
7. The method of claim 1, wherein the NRG1-fusion gene expresses a protein that comprises an NRG1 EGF-like domain.
8. The method of claim 1, wherein the NRG-fusion is a fusion of NRG1 and a gene on human chromosome 8.
9. The method of claim 8, wherein the gene on human chromosome 8 encodes an excreted protein or a cellular membrane associated protein.
10. The method of claim 1, wherein the NRG1 fusion gene is a fusion of the 3′ end of the NRG1-gene with the 5′ sequence of one of the genes selected from the group consisting of CD74; DOC4; TNFRSFIOB; CLU; VAMP2; SLC3A2; RBPMS; WRN; SDC4; KIF13B; SLECA2; PDE7A; ATP1B1; CDK1; BMPR1B; MCPH1 and RAB2IL1.
11. The method of claim 1, wherein the cell is of an epithelial origin.
12. The method of claim 1, wherein the subject has undergone a therapy targeted towards EGFR inhibition.
13. The method of claim 1, wherein a ErbB-1 cell-surface receptor density; a ErbB-2 cell-surface receptor density; a ErbB-3 cell-surface receptor density; a ErbB-4 cell-surface receptor density, or a combination thereof on the cell has been determined.
14. The method of claim 13, characterized in that the cell has less than 400,000 ErbB-1 cell-surface receptors per cell, or less than 200,000 ErbB-1 cell-surface receptors per cell.
15. The method of claim 1, further comprising administering to the subject an ErbB-1 inhibitor.
16. The method of claim 15, wherein the ErbB-1 inhibitor is cetuximab.
17. The method of claim 1, wherein the first antigen-binding site comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:39.
18. The method of claim 1, wherein the second antigen-binding site comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:53.
19. The method of claim 1, wherein the first antigen binding site and the second antigen binding site comprise a light chain comprising the amino acid sequence of SEQ ID NO: 78.
20. The method of claim 1, wherein the bispecific antibody comprises the first antigen-binding site comprising the amino acid sequence of SEQ ID NO:39, the second antigen-binding site comprising the amino acid sequence of SEQ ID NO:53, and the common light chain comprising the amino acid sequence of SEQ ID NO: 78.
The US Patent does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
27. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,139,548 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The US Patent claims an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein SEQ ID NOs:48 and 63 are 100% identical to instant SEQ ID NOs:65 and 110, respectively.
The US Patent claims:
1. A method of treating a human subject having an ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor comprising administering to the subject a bispecific antibody comprising:
a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences of AYYIN (SEQ ID NO:49), RIYPGSGYTSYAQKFQG (SEQ ID NO:50), and PPVYYDSAWFAY (SEQ ID NO:51), respectively, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87; and
a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences GYYMH (SEQ ID NO:64), WINPNSGGTNY AQKFQG (SEQ ID NO:65), and DHGSRHFWSYWGFDY (SEQ ID NO:66), respectively, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87.
2. The method of claim 1, wherein the antibody comprises the light chain comprising the amino acid sequence
(SEQ ID NO: 87) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY AASSLOSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNEYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC.
3. The method of claim 1, wherein the first binding arm comprises a heavy chain variable region comprising SEQ ID NO: 48, the second binding arm comprises a heavy chain variable region comprising SEQ ID NO: 63, and both the first and second binding arms comprise a light chain variable region comprising SEQ ID NO: 87.
4. The method of claim 1, wherein the first binding arm comprises a heavy chain comprising SEQ ID NO: 88, the second binding arm comprises a heavy chain comprising SEQ ID NO: 89, and both the first and second binding arms comprise a light chain comprising SEQ ID NO: 87.
5. The method of claim 1, wherein the bispecific antibody comprises two different immunoglobulin heavy chains with compatible heterodimerization domains.
6. The method of claim 5, wherein the compatible heterodimerization domains are compatible immunoglobulin heavy chain CH3 heterodimerization domains.
7. The method of claim 1, wherein the subject is administered a pharmaceutical composition comprising the bispecific antibody.
8. The method of claim 1, further comprising administering to the subject at least one additional therapeutic agent, selected from BYL719, MK-2206, everolimus, saracatinib, paclitaxel, and vorinostat.
9. The method of claim 1, wherein the tumor is an ErbB-2/ErbB-3 positive tumor.
10. The method of claim 1, wherein the tumor is an ErbB-2 positive tumor.
11. The method of claim 1, wherein the tumor is an ErbB-3 positive tumor.
12. The method of claim 8, wherein the tumor is an ErbB-2/ErbB-3 positive tumor.
13. The method of claim 8, wherein the tumor is an ErbB-2 positive tumor.
14. The method of claim 8, wherein the tumor is an ErbB-3 positive tumor.
15. The method of claim 1, wherein the tumor is a breast tumor, gastric tumor, colorectal tumor, colon tumor, gastro-esophageal tumor, esophageal tumor, endometrial tumor, ovarian tumor, liver tumor, lung tumor including non-small cell lung tumor, clear cell sarcoma, salivary gland tumor, head and neck tumor, brain tumor, bladder tumor, pancreatic tumor, prostate tumor, kidney tumor, skin tumor, or melanoma.
16. The method of claim 1, wherein the subject has an ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor having less than 1,000,000 ErbB-2 cell-surface receptors per tumor cell.
17. A method of treating a human subject having an ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor comprising administering to the subject a bispecific antibody comprising a first and second binding arm;
wherein the first binding arm specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising SEQ ID NO: 48, and the second binding arm specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising SEQ ID NO: 63, and wherein both the first and second binding arms comprise a light chain variable region comprising SEQ ID NO: 87.
18. The method of claim 1, wherein the antibody comprises the light chain variable region comprising the amino acid sequence
(SEQ ID NO: 176) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY AASSLOSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTF GQGTKVEIK.
19. The method of claim 1, wherein the bispecific antibody is an IgG antibody.
20. The method of claim 1, wherein CDR numbering of the heavy chain CDR1, CDR2, and CDR3 sequence is according to Kabat.
The US Patent does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
28. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36, 40, 49, 51, 53-56, 58-71 of copending Application No. 17/675,431 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The copending claims recite an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein SEQ ID NOs:48 and 63 are 100% identical to instant SEQ ID NOs:65 and 110, respectively.
The copending application does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
29. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 66, 72, 76-83 and 91 of copending Application No. 16/499,144 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The copending claims recite an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR (MF3598 and MF3178) sequences and light chain sequences instantly claimed.
The copending application does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy. The copending application does not claim the full VH sequences of MF3598 and MF3178 that comprise the recited CDR sequences.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references teach and render obvious the full VH sequences of MF3598 and MF3178. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
30. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-19, 21, 22, 24, 25, 27, 35, 37 of copending Application No. 16/499,723 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The copending claims recite an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR sequences (MF3598 SEQ ID NOs:40-42; and MF3178 SEQ ID NOs:54-56) and light chain sequences instantly claimed.
The copending application does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy. The copending application does not claim the full VH sequences of MF3598 and MF3178 that comprise the recited CDR sequences.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references teach and render obvious the full VH sequences of MF3598 and MF3178. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
31. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-16, 18, 20-23 of copending Application No. 17/755,196 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The copending claims recite an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein SEQ ID NOs:82 and 97 are 100% identical to instant SEQ ID NOs:65 and 110, respectively.
The copending application does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
32. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 18/449,460 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The copending claims recite an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the CDR sequences from the same MF3598 and MF3178 antibodies and same and light chain instantly claimed.
The copending application does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy. The copending application does not claim the full CDR1-3 and VH sequences of MF3598 and MF3178 or the light chain sequence.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references teach and render obvious the full CDR1-3 and VH sequences of MF3598 and MF3178 and shared light chain sequence. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
33. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 58-78 of copending Application No. 18/419,492 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The copending claims recite an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the CDR sequences from the same MF3598 and MF3178 antibodies and same and light chain instantly claimed, and claims the antibody is PB4188.
The copending application does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy. The copending application does not claim the full CDR1-3 and VH sequences of MF3598 and MF3178 or the light chain sequence, that are also comprised in bispecific antibody PB4188 (MCLA-128).
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references teach and render obvious the full CDR1-3 and VH sequences of MF3598 and MF3178 and shared light chain sequence, that also make up PB4188. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
34. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 58-73 of copending Application No. 18/419,527 in view of WO 2015/130173, Geuijen et al (“Geuijen 2015”); WO 2018/182422, Throsey et al, published October 2018; Calvo et al (Cancer Research, 2016, 76(14 Suppl); Abstract CT050); Alsina et al (Annals of Oncology, October 2018, Vol. 29, Supp 8, viii223-viii224) (“Alsina 2018”); Alsina et al (J Clin Oncol 35, no. 15_suppl (2017): 2522) (“Alsina 2017”); Geujin et al (Cancer Cell, May 14, 2018, 33:922-936) (“Geujin 2018”); Schram et al (Annals of Oncology, October 2019, Vol. 30, Suppl 5; page v317; 685TiP); and Jaiswal et al (Cancer Cell, 2013, 23:603-617); as evidenced by Huang et al (Journal of Cancer Research and Clinical Oncology, 2020, 146:3111-3122) and NCBI protein sequence for NP_001973.2 (printed December 2025).
The copending claims recite an overlapping method with the instant claims for treating ERBB2+/ERBB3+ cancer comprising administering a bispecific antibody with the same CDR and VH (MF3598 and MF3178) sequences and light chain sequences, wherein SEQ ID NOs:48 and 63 are 100% identical to instant SEQ ID NOs:65 and 110, respectively.
The copending application does not claim that the cancer harbors an activating ERBB3 mutation such as V104M, A232V, P262H, G284R, or Q809R; the ERBB3 comprises wild type R426 residue; the cancer does not comprise EGFR/ALK mutation; the cancer received prior therapy; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach as set forth above, and render obvious treating ERBB2+/ERBB3+ cancer population having ERBB3 activating mutations by administering the claimed bispecific antibody for the reasons set forth in the rejection under 35 USC 103 above. The combined references also teach the limitations of the bispecific antibody requiring the presence of amino acid R26 in ERBB3 for the bispecific antibody to function, and selecting patients with no EGFR/ALK mutations for treatment with the bispecific antibody, rendering obvious these limitations for the reasons set forth above. The combined references also teach and successfully demonstrate treating cancer as first line therapy, and treating cancer patients progressed on prior therapy including anti-ERBB2 treatment, rendering obvious first line treatment and second line treatment of the bispecific antibody for the reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
35. Conclusion: No claim is allowed.
36. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642