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. The Amendment filed June 3, 2026 in response to the Office Action of March 3, 2026, is acknowledged and has been entered. Claims 2, 4-11, 13, 16, 18, 21, 22, 28, 32-37 are now pending and being examined. Claims 2, 4, 7, 8, 18, 22, 28 are amended. Claims 32-37 are new.
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).
Rejections Maintained
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.
2. Claim 7 remains 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.
Response to Arguments
3. Applicants argue the claims are amended to address the rejection.
4. The arguments have been considered but are not persuasive because claim 7 was not amended to address the rejection.
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.
5. Claims 2, 4-11, 13, 16-18, 21, 22, 28, 32-37 remain/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 recites a single light chain variable region CDR1-3 SEQ ID NOs:5, AAS, and 6, with no heavy chain variable region or CDR sequences.
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.
Response to Arguments
6. Applicants argue that the claimed invention resides in the therapeutic application of the bispecific antibodies in a defined clinical context, rather than in the structural definition of the antibody genus. Applicants argue that this distinction is critical under Federal Circuit case law. Applicants argue that the Federal Circuit's recent decision in Teva Pharmaceuticals Int'l GmbH v. Eli Lilly & Co., No. 24-1094 (Fed. Cir. Apr. 16, 2026), is directly applicable. In Teva, the court held that method-of-treatment claims reciting administration of a genus of antibodies can satisfy the written description requirement even where the specification discloses only a limited number of species, where the relevant antibody class is well known and a skilled artisan would understand that the class is suitable for the claimed therapeutic use. As the court explained, the claims at issue were directed to "methods of using humanized anti-CGRP antagonist antibodies to treat headache," and the specification-together with the state of the art-supported the claimed use of that class without requiring disclosure of all structural variants. Teva, slip op. at 14. The court further clarified that such claims are properly analyzed as method-of-use claims, not as claims requiring full characterization of the entire antibody genus. Id. at 17. The present case is analogous. The Office Action itself acknowledges that bispecific antibodies targeting ERBB2 and ERBB3, including those binding ERBB2 domain I and ERBB3 domain III, are known in the art and have been used to treat multiple cancers via inhibition of HER2/HER3 signaling. (Office Action, pp. 21-23).
Applicants argue that the Office Action also cites multiple references demonstrating clinical use of such antibodies and their established mechanisms of action. (Office Action, pp. 17-25). Thus, the record confirms that the relevant antibody genus is not newly discovered but is part of a well-characterized and established technology platform, similar to the anti-CGRP antibodies at issue in Teva.
7. The arguments have been considered but are not persuasive. Examiner maintains that the claimed bispecific antibody comprising a first antigen-binding site to domain I of HER2 and a second antigen-binding site to domain III of HER3 is critical to performing the claimed method of treating a subject having cancer harboring an ERBB3 mutation. If the claimed genus of bispecific antibodies is not adequately described, then the method of using them is not adequately described.
The fact patterns in the Teva Pharmaceuticals decision are not commensurate in scope with the instant application, therefore the decision is not applicable here. In Teva Pharmaceuticals, the claim recites:
A method for reducing incidence of or treating headache in a human, comprising administering to the human an effective amount of an anti-CGRP antagonist antibody, wherein said anti-CGRP antagonist antibody is a . . . humanized monoclonal antibody
Unlike in Teva Pharmaceuticals, the instant claims require administering a bispecific antibody binding to specific domains on two different antigens, wherein the antibody comprises two distinct heavy chain sequences and a common light chain. Unlike in Teva Pharmaceuticals, the instant claims do not recite that the bispecific antibody antagonizes the proteins they bind, HER2 and/or HER3. Unlike in Teva Pharmaceuticals, the instant specification does not establish that the vast genus of bispecific antibodies binding to domain I of HER2 and domain III of HER3 all predicably function to treat cancer. The instant specification does not establish that the simple act of an antibody binding to domain I of HER2 and domain III of HER3 inherently, necessarily, or predictably produces a therapeutic effect for treating cancer. Those of ordinary skill in the art recognize that antibodies can bind to domain I of HER2 or domain III of HER3 and simply bind without any antagonist or cancer-treating effects, or even have agonistic effects. Antibody-antigen binding does not necessitate antagonist function or cancer-treating function.
Solely in response to arguments, and to demonstrate evidence of arguments, Examiner points to Pedersen et al (Mol Cancer Ther (2015) 14 (3): 669–680). Pedersen teaches producing monoclonal antibodies that bind to different domains of HER2, including to domain I. Pedersen isolated four monoclonal antibodies that bind to domain I of HER2 (Figure 1A below). One of these domain I antibodies is “4387”. Antibody 4387 was determined to be agonistic to HER2, while the others had some antagonist effect (See Figure 1B). Antibody 4387 increased tumor cell viability and failed to treat cancer in vivo (Figures 1B and 1D below).
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Therefore, the genus of antibodies binding to domain I of HER2 are not established as inherently having HER2-inhibition function or cancer-treating function.
Given this general knowledge of antibodies in the art, one would understand that NOT any member of the genus would work in the claimed method, unlike the fact pattern in Teva Pharmaceuticals.
Contrary to arguments, the Non-final Office action of March 3, 3036 does not demonstrate the vastly claimed genus of bispecific antibodies binding to domain I of HER2 and domain III of HER3 are well established in the prior art. This is because the cited prior art in the Office action, WO 2015/130173, Geuijenb and WO 2018/182422, Throsey (Throsey/Throsby), teach the identical limited species of bispecific antibody disclosed in the specification and instantly claimed, comprising the same few exemplary CDRs, VH, and common light chain sequences.
8. Applicants argue that the specification further provides substantial disclosure of the relevant antibody class. Applicants argue the specification discloses numerous structurally distinct anti-ERBB2 and anti-ERBB3 variable heavy chain sequences and their pairing into bispecific antibodies using a common light chain. Applicants argue the specification also describes clinical administration of such bispecific antibodies to patients, including patients harboring ERBB3 mutations, and explains their mechanism of action in inhibiting HER2/HER3 heterodimerization and downstream signaling pathways. This disclosure demonstrates that Applicants were in possession of the claimed therapeutic method.
Applicants argue the Office Action nevertheless concludes that written description is lacking because the specification does not disclose a "representative number" of antibody sequences across the claimed genus and does not establish sufficient structure-function correlation. Applicants argue that this reasoning improperly applies standards developed for claims directed to new compositions or unknown functional genera.
Applicants argue that the Office Action's reliance on cases such as University of California V. Eli Lilly, Enzo Biochem, and Univ. of Rochester V. Searle is therefore misplaced. Those cases concern claims to compositions or functional genera where the underlying structures were unknown or insufficiently characterized. By contrast, the present claims incorporate an established antibody class and are directed to a specific therapeutic application of that class. Applicants argue that the Federal Circuit explained in Teva, such method-of-treatment claims are not subject to a requirement to define the entire structural diversity of the antibody genus.
Applicants argue that additional Federal Circuit precedent confirms this distinction. In Ajinomoto Co. V. ITC, 932 F.3d 1342, 1359 (Fed. Cir. 2019), the court recognized that written description does not require detailed disclosure of subject matter already known in the art where the invention lies in a new application of that subject matter. Likewise, in In re Herschler, 591 F.2d 693, 701 (CCPA 1979), the court held that disclosure of limited species may be sufficient where a known class is used in a claimed method and its functionality is established. Applicants argue these principles are consistent with the reasoning in Teva and apply here.
Applicant disagrees that the antibodies are defined or claimed by function only. The claims recite specific binding interactions with defined domains of ERBB2 and ERBB3, and the specification provides concrete structural examples corresponding to those binding characteristics. Applicants argue that when considered together with the well-established knowledge of bispecific antibody engineering, this disclosure is sufficient to demonstrate possession of the claimed method.
Applicants argue the Office Action's emphasis on the breadth of the antibody genus does not alter the analysis. Under controlling precedent, including Teva, the proper inquiry is whether the specification reasonably conveys that the inventors possessed the claimed invention. Here, the specification discloses multiple antigen-binding embodiments, their combination into bispecific formats, and their use in treating cancers characterized by ERBB3 mutations. (Office Action, pp. 12-14). This disclosure, combined with the knowledge in the art, demonstrates possession of the claimed method of treatment. For at least the foregoing reasons, Applicant respectfully submits that the specification adequately describes the claimed invention.
9. The arguments have been carefully considered but are not persuasive. A stated above, the fact patterns in Teva are different from the instant application and claims, therefore the decision in Teva is not applicable here.
Contrary to arguments, the bispecific antibodies of the claims are defined or claimed by function only, for example, claim 2 does not recite any antibody sequence structure and claims the antibody by functions only. Claims 4, 5, 6, and 7 recite only a partial sequence structure requiring the presence of only a single first VH sequence or CDRs, only a single second VH sequence or CDRs, or only the light chain CDRs.
Examiner relied upon the precedential decisions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) (“Lilly”) and Enzo Biochem, Inc. V. Gen-Probe Inc. (Fed. Cir. 2002) (“Enzo”) as the standards for determining adequate written description of the instant claims. Contrary to arguments, Examiner maintains these precedential decisions are relevant and applicable to the claimed methods, as already explained in the rejection of record. Examiner established that:
The bispecific antibody binding to domain I of HER2 and domain III of HER3 is a critical component for performing the claimed function of treating cancer harboring a HER3 mutation, therefore the antibody is an essential component of the invention.
the claims identify the antibody by function only without any sequence structure recited or with only partial sequence structure recited;
other than for the disclosed 17 domain I HER2 antibodies and 25 domain III HER3 antibodies and common light chain sequence, the specification fails to provide the critical or shared core structure correlated to, and responsible for, the cancer-treating function that is possessed by the broadly claimed genus of bispecific antibodies that is required to perform the claimed method;
these 17 species of domain I HER2 antibodies and 25 species of domain III HER3 antibodies are structurally distinct and do not share any sequence homology across the vast genus that would allow one to immediately recognize any shared, critical antibody sequences that would function as claimed, therefore these species do not provide the necessary structure-function correlation required for one of ordinary skill in the art to recognize members of the genus that would function as claimed; and
the specification fails to provide a representative number of species of bispecific antibodies that bind to domain I of HER2 and domain III of HER2 and function to treat cancer because the genus of such HER2 and HER3 binding sites is vast, with exponential variability in CDR sequences.
If the claimed genus of bispecific antibodies is not adequately described, then the method of using them is not adequately described.
MPEP 2163 states:
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed."
In the instant case, the genus of bispecific antibodies binding to domain I of HER2 and domain III of HER3 and required to treat a subject having cancer harboring an ERBB3 mutation is vast, encompassing an exponential number of unknown sequences of CDR variants. Contrary to arguments, the breadth of the genus of antibodies required to practice the claimed method is highly relevant to determining what species would be representative of them. The 17 species of HER2 domain I antibodies, 25 species of domain III HER3 antibodies, and common light chain sequence are not sufficiently representative of the enormous sequence variability of the antibodies required to practice the invention. Solely in response to arguments, Examiner points Edwards et al J. Mol. Biol. (2003) 334, 103–118) as evidence demonstrating that a single antigen produced over 1,000 structurally distinct antibodies binding to it due to the many different VDJ combinations of the human immune repertoire. Edwards screened the antibodies’ ability to inhibit binding to the protein’s receptor, finding that only 40% of these antibodies inhibited the binding of protein antigen to its receptors on B-cell lines (abstract). Edwards demonstrates that the genus of antibodies binding to a single protein antigen is enormously vast and structurally and functionally diverse, therefore, 17 species of HER2 domain I antibodies, 25 species of domain III HER3 antibodies, and common light chain is not sufficiently representative of the claimed bispecific antibodies binding to two antigens in order to practice the claimed method for treating cancer harboring a HER3 mutation correlated with ligand-independent heterodimerization of HER2/HER3 and/or activation of HER2 kinase domain.
MPEP 2163 states:
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." Id.
In the instant case, other than for the 17 species of HER2 domain I antibodies and 25 species of domain III HER3 antibodies and shared light chain, the instant specification does not disclose sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed bispecific antibody required to practice the claimed method, i.e., a known or disclosed correlation between function and structure coupled to the claimed functional characteristics, across the vast genus of bispecific antibodies, that would allow one of ordinary skill in the art to immediately envision the bispecific antibodies that would function as claimed. The disclosed exemplary 17 species of domain I HER2 antibodies, 25 species of domain III HER3 antibodies, and single light chain are structurally distinct and do not share any sequence homology across the vast genus that would allow one to immediately recognize any shared, critical antibody sequences that would function as claimed, therefore these species do not provide the necessary structure-function correlation required for one of ordinary skill in the art to recognize members of the genus that would function as claimed. Therefore, contrary to arguments, Applicants have not established the claimed antibody class or therapeutic class of bispecific antibodies required to practice the invention.
Contrary to arguments, Examiner maintains the decision in Rochester v. Searle is relevant to the instant case. As stated in the rejection:
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.
Knowledge of routine methods of making and screening for antibodies binding to antigens does not place Applicants in possession of every bispecific antibody binding to the claimed HER2 and HER3 domains, therefore does not place Applicants in possession of methods utilizing the vast genus of bispecific antibodies.
MPEP 2163 states:
However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
Therefore, contrary to arguments, routine methods of antibody production and screening to a known antigen (i.e., domain I of HER2 or domain III of HER3) does not place Applicants in possession of antibodies that bind to them. Logically, if routine methods of antibody production and screening to a known antigen does not place Applicants in possession of a genus antibodies that bind to them, then knowledge of such routine methods cannot place Applicants in possession of methods using the genus antibodies. The specification fails to adequately describe the product to which the claimed method uses, therefore it also fails to adequately describe the claimed method.
Maintained Rejections
Claim Rejections - 35 USC § 103
(addressing claim amendments)
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.
10. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 remain/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:5+AAS+6 (see Figure 16C below):
PNG
media_image4.png
144
758
media_image4.png
Greyscale
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, pancreatic, or bladder 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_image5.png
634
776
media_image5.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 the instantly claimed 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.
11. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 remain/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.
12. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, 32, and 37 remain/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.
13. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, 32, and 37 remain/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.
14. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, 32, and 37 remain/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.
15. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, 32, and 37 remain/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.
16. Claim(s) 2, 4-11, 13, 16-18, 21, 22, 28, 32, and 37 remain/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.
Response to Arguments over 35 USC 103 rejections
17. Applicants argue that the Examiner used improper hindsight reasoning to reconstruct the claimed invention. Applicants argue the claims require treating a specific cancer patient population having a HER3 mutation in SEQ ID NO:1 that is correlated with ligand-independent heterodimerization of HER3/HER2 and/or activation of HER2 kinase domain. Applicants argue the cited prior art teaches blocking ligand-dependent activation of HER3, whereas the claims are direct at treating cancer having ligand-independent activation of HER3 resulting from a HER3 activating mutation. Applicants argue the cited prior art does not teach or suggest applying the method of Geujin or Throsby to patients having a HER3 mutations resulting in ligand-independent activation of HER3. Applicants argue Examiner relied upon an “obvious to try” rationale. Applicants argue that Examiner did not identify a finite number of predictable solutions taught by the cited art to treat the claimed patient population, and the prior art does not provide a reasonable expectation of success for the prior art to treat the claimed patient population.
18. The arguments have been considered but are not persuasive. In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, Geujin teaches treating HER2/HER3+ cancers with the same antibody instantly claimed, Geujin and the secondary references established the function of the bispecific antibody is to physically block dimerization of HER/HER3 and have enhanced ADCC activity, and the secondary references demonstrate successfully treating HER2/HER3+ cancers with the bispecific antibody. Geujin teaches it is known that HER3+ cancers encompass a subpopulation of cancers with activating HER3 mutations and Jaiswal identified known activating HER3 mutations in cancer that have oncogenic activity with HER2. Jaiswal further demonstrated the expected success of inhibiting the activated mutant HER3 and treating cancer by administering an anti-HER3 antibody binding to domain III. Therefore, the cited prior art provides not only the suggestion, but the means and motivation to treat a subset of HER2/HER3+ cancer patients harboring the instantly claimed HER3 activating mutations correlated with ligand-independent heterodimerization of HER2/HER3 by administering to the patients a bispecific antibody MCLA-128/PB4188 known to bind to HER3 domain III and to inhibit HER2/HER3 dimerization that contributes to oncogenesis.
Although Applicants argue the cited references teach inhibiting ligand-dependent heterodimerization of HER3/HER2, the cited references establish that the bispecific antibody MCLA-128/PB4188 functions to treat cancer by physically inhibiting HER2/HER3 dimerization, thereby inhibiting HER2/HER3 oncogenic signaling and tumor growth, regardless of how heterodimerization was triggered. Although Applicants argue the claimed HER3 mutations result in ligand-independent HER2/HER3 heterodimerization, the end result is the same for ligand-independent and ligand-dependent dimerization: HER2/HER3 heterodimerization that results in oncogenic signaling and tumor growth. The secondary references established the known blocking function of MCLA-128/PB4188 to physically block heterodimerization of HER2/HER3 and to inhibit oncogenic signaling. The secondary references further teach or demonstrate successful clinical treatment of a wide variety of solid tumors, including ovarian, gastric cancer, GEJ, and breast cancer by administration of MCLA-128/PB4188, which is established to physically inhibit HER2:HER3 heterodimerization and have enhanced ADCC activity regardless of mechanism driving heterodimerization (ligand-dependent or ligand-independent). Therefore, the cited prior art provides both motivation and reasonable expectation of success to include a subset of HER2/HER3+ patients that have the known instantly claimed HER3 activating mutations, for treatment with bispecific antibody MCLA-128/PB4188.
As stated in the rejection of record:
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 the instantly claimed ERBB3 activating mutations, in the method of treatment taught by Geujin 2015 with a reasonable expectation of success.
New Rejections
(necessitated by amendments)
Claim Rejections - 35 USC § 103
19. New claim(s) 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/130173, Geuijen et al (“Geuijen 2015”); 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 applied to claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 above, and further in view of Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019).
Geuijen 2015; Throsby, Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach a method for treating a subject having HER2/HER3+ cancer harboring a HER3 activating mutation comprising administering to the subject a bispecific antibody MCLA-128/PB4188, wherein the HER3 activating mutation is correlated with ligand-independent HER3 heterodimerization of HER/HER3, wherein the subject has progressed after receiving prior anti-HER2 therapies or trastuzumab, as set forth above.
The combined references do not teach the subject has progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Oh recognizes cancer HER2+ cancer patients can harbor HER3 mutations (p. 34, col. 2) and reviews numerous known clinical therapies for HER2+ cancer patients having a variety of different solid tumors, therapies including trastuzumab, pertuzumab, lapatinib, capecitabine, cisplatin, and regorafenib, recognizing the patients can progress and become refractory to prior therapies, requiring 2nd, 3rd, and 4th line treatments (p. 33-45; Figures 1 and 2; Tables 1 and 2).
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 in the method of the combined references that have progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Oh recognize that HER2+ cancer patients can become refractory to prior therapies, needing 2nd line or more therapies; (2) Oh teaches known clinical therapies for HER2+ cancer patients include any of chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. Given the cited prior art recognizes the need to treat patients diagnosed with cancer, including those who have become refractory to any prior therapies, it is well within the level of the ordinary skilled artisan to treat cancer patients in the method of the combined references who have progressed after any prior therapies including chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
20. New claim(s) 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over:
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 combination with 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 applied to claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 above, and further in view of Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019).
US Patent 11,279,770; US Patent 12,139,548; US Patent Application Publication 2022/0348683; US Patent Application Publication 20240158532; or US Patent Application Publication 20240158531; each in combination with Throsby, Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach a method for treating a subject having HER2/HER3+ cancer harboring a HER3 activating mutation comprising administering to the subject a bispecific antibody MCLA-128/PB4188, wherein the HER3 activating mutation is correlated with ligand-independent HER3 heterodimerization of HER/HER3, wherein the subject has progressed after receiving prior anti-HER2 therapies or trastuzumab, as set forth above.
The combined references do not teach the subject has progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Oh recognizes cancer HER2+ cancer patients can harbor HER3 mutations (p. 34, col. 2) and reviews numerous known clinical therapies for HER2+ cancer patients having a variety of different solid tumors, therapies including trastuzumab, pertuzumab, lapatinib, capecitabine, cisplatin, and regorafenib, recognizing the patients can progress and become refractory to prior therapies, requiring 2nd, 3rd, and 4th line treatments (p. 33-45; Figures 1 and 2; Tables 1 and 2).
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 in the method of the combined references that have progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Oh recognize that HER2+ cancer patients can become refractory to prior therapies, needing 2nd line or more therapies; (2) Oh teaches known clinical therapies for HER2+ cancer patients include any of chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. Given the cited prior art recognizes the need to treat patients diagnosed with cancer, including those who have become refractory to any prior therapies, it is well within the level of the ordinary skilled artisan to treat cancer patients in the method of the combined references who have progressed after any prior therapies including chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
21. New claim(s) 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over:
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 combination with 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 applied to claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 above, and further in view of Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019).
US Patent 12,247,078; US Patent 11,780,925; or US Patent Application Publication 2024/0199747, each in combination with Geuijen 2015; Throsby; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach a method for treating a subject having HER2/HER3+ cancer harboring a HER3 activating mutation comprising administering to the subject a bispecific antibody MCLA-128/PB4188, wherein the HER3 activating mutation is correlated with ligand-independent HER3 heterodimerization of HER/HER3, wherein the subject has progressed after receiving prior anti-HER2 therapies or trastuzumab, as set forth above.
The combined references do not teach the subject has progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Oh recognizes cancer HER2+ cancer patients can harbor HER3 mutations (p. 34, col. 2) and reviews numerous known clinical therapies for HER2+ cancer patients having a variety of different solid tumors, therapies including trastuzumab, pertuzumab, lapatinib, capecitabine, cisplatin, and regorafenib, recognizing the patients can progress and become refractory to prior therapies, requiring 2nd, 3rd, and 4th line treatments (p. 33-45; Figures 1 and 2; Tables 1 and 2).
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 in the method of the combined references that have progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Oh recognize that HER2+ cancer patients can become refractory to prior therapies, needing 2nd line or more therapies; (2) Oh teaches known clinical therapies for HER2+ cancer patients include any of chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. Given the cited prior art recognizes the need to treat patients diagnosed with cancer, including those who have become refractory to any prior therapies, it is well within the level of the ordinary skilled artisan to treat cancer patients in the method of the combined references who have progressed after any prior therapies including chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
21. New claim(s) 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 12,195,551, claiming priority to 2017; 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 applied to claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 above, and further in view of Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019).
US Patent 12,195,551; Geuijen 2015; Throsby; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach a method for treating a subject having HER2/HER3+ cancer harboring a HER3 activating mutation comprising administering to the subject a bispecific antibody MCLA-128/PB4188, wherein the HER3 activating mutation is correlated with ligand-independent HER3 heterodimerization of HER/HER3, wherein the subject has progressed after receiving prior anti-HER2 therapies or trastuzumab, as set forth above.
The combined references do not teach the subject has progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Oh recognizes cancer HER2+ cancer patients can harbor HER3 mutations (p. 34, col. 2) and reviews numerous known clinical therapies for HER2+ cancer patients having a variety of different solid tumors, therapies including trastuzumab, pertuzumab, lapatinib, capecitabine, cisplatin, and regorafenib, recognizing the patients can progress and become refractory to prior therapies, requiring 2nd, 3rd, and 4th line treatments (p. 33-45; Figures 1 and 2; Tables 1 and 2).
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 in the method of the combined references that have progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Oh recognize that HER2+ cancer patients can become refractory to prior therapies, needing 2nd line or more therapies; (2) Oh teaches known clinical therapies for HER2+ cancer patients include any of chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. Given the cited prior art recognizes the need to treat patients diagnosed with cancer, including those who have become refractory to any prior therapies, it is well within the level of the ordinary skilled artisan to treat cancer patients in the method of the combined references who have progressed after any prior therapies including chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
22. New claim(s) 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2022/0372166, claiming priority to Oct. 2020; 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 applied to claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 above, and further in view of Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019).
US Patent Application Publication 2022/0372166; Geuijen 2015; Throsby; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach a method for treating a subject having HER2/HER3+ cancer harboring a HER3 activating mutation comprising administering to the subject a bispecific antibody MCLA-128/PB4188, wherein the HER3 activating mutation is correlated with ligand-independent HER3 heterodimerization of HER/HER3, wherein the subject has progressed after receiving prior anti-HER2 therapies or trastuzumab, as set forth above.
The combined references do not teach the subject has progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Oh recognizes cancer HER2+ cancer patients can harbor HER3 mutations (p. 34, col. 2) and reviews numerous known clinical therapies for HER2+ cancer patients having a variety of different solid tumors, therapies including trastuzumab, pertuzumab, lapatinib, capecitabine, cisplatin, and regorafenib, recognizing the patients can progress and become refractory to prior therapies, requiring 2nd, 3rd, and 4th line treatments (p. 33-45; Figures 1 and 2; Tables 1 and 2).
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 in the method of the combined references that have progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Oh recognize that HER2+ cancer patients can become refractory to prior therapies, needing 2nd line or more therapies; (2) Oh teaches known clinical therapies for HER2+ cancer patients include any of chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. Given the cited prior art recognizes the need to treat patients diagnosed with cancer, including those who have become refractory to any prior therapies, it is well within the level of the ordinary skilled artisan to treat cancer patients in the method of the combined references who have progressed after any prior therapies including chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
23. New claim(s) 33-36 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; 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 applied to claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 above, and further in view of Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019).
US Patent Application Publication 2020/0291130; Geuijen 2015; Throsby; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach a method for treating a subject having HER2/HER3+ cancer harboring a HER3 activating mutation comprising administering to the subject a bispecific antibody MCLA-128/PB4188, wherein the HER3 activating mutation is correlated with ligand-independent HER3 heterodimerization of HER/HER3, wherein the subject has progressed after receiving prior anti-HER2 therapies or trastuzumab, as set forth above.
The combined references do not teach the subject has progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Oh recognizes cancer HER2+ cancer patients can harbor HER3 mutations (p. 34, col. 2) and reviews numerous known clinical therapies for HER2+ cancer patients having a variety of different solid tumors, therapies including trastuzumab, pertuzumab, lapatinib, capecitabine, cisplatin, and regorafenib, recognizing the patients can progress and become refractory to prior therapies, requiring 2nd, 3rd, and 4th line treatments (p. 33-45; Figures 1 and 2; Tables 1 and 2).
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 in the method of the combined references that have progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Oh recognize that HER2+ cancer patients can become refractory to prior therapies, needing 2nd line or more therapies; (2) Oh teaches known clinical therapies for HER2+ cancer patients include any of chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. Given the cited prior art recognizes the need to treat patients diagnosed with cancer, including those who have become refractory to any prior therapies, it is well within the level of the ordinary skilled artisan to treat cancer patients in the method of the combined references who have progressed after any prior therapies including chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
24. New claim(s) 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2021/0206875, claiming priority to 2018; 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 applied to claims 2, 4-11, 13, 16-18, 21, 22, 28, 32 and 37 above, and further in view of Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019).
US Patent Application Publication 2021/0206875; Geuijen 2015; Throsby; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; and Jaiswal (the combined references) teach a method for treating a subject having HER2/HER3+ cancer harboring a HER3 activating mutation comprising administering to the subject a bispecific antibody MCLA-128/PB4188, wherein the HER3 activating mutation is correlated with ligand-independent HER3 heterodimerization of HER/HER3, wherein the subject has progressed after receiving prior anti-HER2 therapies or trastuzumab, as set forth above.
The combined references do not teach the subject has progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Oh recognizes cancer HER2+ cancer patients can harbor HER3 mutations (p. 34, col. 2) and reviews numerous known clinical therapies for HER2+ cancer patients having a variety of different solid tumors, therapies including trastuzumab, pertuzumab, lapatinib, capecitabine, cisplatin, and regorafenib, recognizing the patients can progress and become refractory to prior therapies, requiring 2nd, 3rd, and 4th line treatments (p. 33-45; Figures 1 and 2; Tables 1 and 2).
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 in the method of the combined references that have progressed after prior therapies with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Oh recognize that HER2+ cancer patients can become refractory to prior therapies, needing 2nd line or more therapies; (2) Oh teaches known clinical therapies for HER2+ cancer patients include any of chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib. Given the cited prior art recognizes the need to treat patients diagnosed with cancer, including those who have become refractory to any prior therapies, it is well within the level of the ordinary skilled artisan to treat cancer patients in the method of the combined references who have progressed after any prior therapies including chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib.
Maintained Rejections
(addressing amendments)
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.
25. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/ 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); Jaiswal et al (Cancer Cell, 2013, 23:603-617); and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; or the bispecific antibody treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; Jaiswal; and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
26. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617); and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; or the bispecific antibody treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; Jaiswal and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
27. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617); and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; or the bispecific antibody 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; Jaiswal and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
28. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617) and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; or the bispecific antibody treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; Jaiswal; and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
29. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617); and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; or the bispecific antibody treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; Jaiswal; and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
Response to Arguments over US Patents
30. Applicants argue that the claims of each of the above-listed patents relate to MCLA-128 and its use in treating ERBB3-positive cancers that exhibit different mechanisms of oncogenesis. Accordingly, for the same reasons set forth above, the pending claims are patentably distinct from the claims of the reference patents.
31. The arguments have been considered but are not persuasive for the reasons set forth above in the response to arguments for rejections under 35 USC 103.
32. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617) and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; 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; Jaiswal; and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
33. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617) and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; 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; Jaiswal; and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
34. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617); and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 claims also recite treating cancer in a subject that has progressed after prior therapy with a tyrosine kinase inhibitor (lapatinib, canertinib, neratinib, afatinib, and more) or chemotherapy (gemcitabine, capecitabine, carboplatin, taxane, 5-FU, and more).
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 with immune checkpoint inhibitor pembrolizumab or VEGFR2 inhibitor regorafenib; or the bispecific antibody treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; Jaiswal and Oh (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. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 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); Jaiswal et al (Cancer Cell, 2013, 23:603-617); and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; 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; Jaiswal; and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
36. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617) and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; 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; Jaiswal and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
37. Claims 2, 4-11,13, 16-18, 21, 22, 28, 32-37 remain/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); Jaiswal et al (Cancer Cell, 2013, 23:603-617); and Oh et al (Nature Reviews, 2020, Vol. 17, p. 33-48; published online September 2019); 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 with chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib; or the treatment is first line therapy.
Geuijen 2015; Throsey; Calvo; Alsina 2018; Alsina 2017; Geujin 2018; Schram; Jaiswal, and Oh (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. Oh and the combined references render obvious treating patients who have progressed on prior therapies including prior treatment with any of trastuzumab, chemotherapy (capecitabine, cisplatin), immune checkpoint inhibitor pembrolizumab, TKI inhibitor (lapatinib, afatinib, or neratinib), or VEGFR2 inhibitor regorafenib, for the reasons stated above in the rejections under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments over copending US Patent Applications
38. Applicants argue the claims of each of the above-listed patents relate to MCLA-128 and its use in treating ERBB3-positive cancers that exhibit different mechanisms of oncogenesis. Accordingly, for the same reasons set forth above, the pending claims are patentably distinct from the claims of the reference patents. Applicant asserts that the above-described amendments, remarks, and arguments overcome all of the outstanding objections and rejections such that all that remains are the provisional rejections under obviousness-type double patenting.
The arguments have been considered but are not persuasive for the reasons set forth above in the response to arguments for rejections under 35 USC 103.
39. All other objections and rejections recited in the Office Action mailed March 3, 2026 are hereby withdrawn in view of amendments. The provisional rejection of claims on the ground of nonstatutory double patenting over copending Application No. 17/675,431 is withdrawn in view of the application being abandoned.
40. Conclusion: No claim is allowed.
Conclusion
41. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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