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 .
Notice of New Examiner
This case has been transferred to a new examiner for continued examination. Any further communications regarding this case may be directed to the contact information included in the conclusion of this office action.
Election/Restrictions
As previously noted, Applicant’s election, without traverse, of claims 1, 7, 14, 17, 26-29, 34-35 and 40-41 (group III), drawn to a method of treating cancer comprising administering a multispecific antigen-binding molecule or antibody comprising a first antigen binding domain having selective binding activity to an FGFR3 S249C mutant; and a second antigen-binding domain having T cell receptor complex-binding activity, in the office action filed 03/03/2025, is acknowledged.
Applicant’s further election, without traverse, of the species of multispecific antigen binding molecule comprising SEQ ID NOs for the variable heavy and light regions as well as their corresponding framework and hypervariable regions from the genus of multispecific antigen binding molecules, in the reply filed on 05/05/2025 is acknowledged (see remarks, page 8-9). However, upon further consideration and in view of applicant’s amendment, said species restriction requirement filed 03/03/2025 has been withdrawn. Claims 7, 17, 34-35 and 40-41 are being examined with all HVR sequences claimed (SEQ ID NOs:17-34 and 59-64).
As described below, claims 7 and 17 are allowed. Claims 20-23, 25, 30-33, and 36-39 are rejoined because they require all of the limitations of an allowable claim.
Response to Amendment
The amendment filed 6 January 2026 is acknowledged. Claims 7, 17, 19, 20, 21, and 28 are amended. Claims 14 and 16 are canceled.
Claim Status
Claims 1-13, 15, 17, and 19-41 are pending. Claims 2-6, 8-13, 15, 19, 24 are withdrawn from consideration as described in the Restriction/Election section above. Claims 1, 7, 17, 20-23, 25-41 are under examination in the instant office action.
Information Disclosure Statement
The corrected IDS field 1/6/2026 is acknowledged. Applicant amended the IDS to fix a typographical error in NPL74. The reference and correction have been considered. All of the other references are struck through because they are duplicates of the references on the IDS dated 5/5/2025, which have already been considered as noted on the 1449 dated 7/7/2025.
Withdrawal of Rejections
The rejection of claims 1 and 26-27 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph for scope of enablement is withdrawn in view of Applicant’s arguments and reconsideration by the Examiner.
The rejection of claims 7 and 17 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is withdrawn in view of the amendments to the claims, Applicant’s arguments, and reconsideration by the Examiner.
The rejection of claims 14 and 28-29 under 35 U.S.C. 102(a)(1) as being anticipated by GORBENKO et al (Hybridoma. 2009 Aug;28(4):295-300. PMID: 19663703. Listed on IDS filed 07/08/2022) is withdrawn in view of the amendments to the claims.
The rejection of claims 1 and 26-27 under 35 U.S.C. 103 as being unpatentable over ECKELMAN et al (WO 2018191438 A1; published 10/18/2018; listed on IDS filed 07/08/2022) in view of GORBENKO et al (Hybridoma. 2009 Aug;28(4):295-300. PMID: 19663703. Listed on IDS filed 07/08/2022) is withdrawn in view of the Applicant’s arguments.
Claim Objections- New, necessitated by amendment
Claims 36-39 and 40-41 are objected to under 37 CFR 1.75 as being a substantial duplicate of claims 21-23, 25, and 28-29. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claims 28-29 be found allowable, claims 40-41 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(b)- New, necessitated by amendment
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.
Claim 20 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 20 is indefinite for the recitation of wherein the antigen-binding molecule is a “(c) human antibody”. It is unclear how the instantly claimed antibody could be fully human because the HVRs of claim 17 are rabbit HVRs (Specification Example 2, [0241]).
Claim Rejections - 35 USC § 112(a)- Written Description- New
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 26, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1, the claim is directed towards a multispecific antigen-binding molecule comprising a first antigen-binding molecule having selective binding activity to an FGFR3 S249C mutant; and a second antigen-binding domain having T cell receptor complex binding activity.
Regarding claims 26 and 27, the methods are directed at a method of treating any generic cancer, or a cancer expressing FGFR3 S249C comprising administering the antigen-binding molecule of claim 17 to a patient in need thereof.
Scope of the claimed genus
Claim 1 recites a genus of polypeptides comprising an antibody binding fragment which specifically binds to FGFR3 S249C and to a T cell receptor complex component, recited only by function and not structure. There is no structure of the antibodies required by claim 1. Claims 26 and 27 are directed towards methods of treating any generic cancer, or a cancer expressing FGFR S249C mutation, and therefore do not further restrict the structure of the instantly claimed bispecific antibody.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Regarding anti-FGFR3 S249C antibodies, the instant claim is directed towards antibodies that have “selective” binding activity for FGFR3 S249C. The instant specification states regarding “selective”: “As used herein, "selectivity" or "selective" refers to different binding abilities to wild- type and mutant proteins. In one embodiment, for the degree of binding of an anti-FGFR3 S249C mutant antibody to an FGFR3 S249C mutant protein and a wild-type FGFR3 protein, the term means that these binding activities of the antibody are comparable or higher than that when the antibody is added to cell lines expressing mutant and wild-type FGFR3 at the same level at concentrations differing by at least 10 times, 100 times, or more. For example, when the value indicating the binding activity of the antibody added to the mutant cell line at 0.1 pg/mL is equal to or is greater than the value indicating the binding activity of the antibody added to the wild-type cell line at least 1 pg/mL or 100 pg/mL, it means that the antibody "shows selectivity for the mutant over the wild-type". Thus, the limiting part of the definition in the specification is that “selective refers to different binding abilities to wild-type and mutant proteins”, which means that an antibody that has “selective binding activity to an FGFR3 S249C” when it binds to FGFR3 differently than to any generic other wildtype protein.
Other antibodies that bind differently to FGFR3 S249C and FGFR3 WT are known in the art. For example, U.S. 20100247531 to Ashkenazi et. al. teaches the anti-FGFR3 antibody R3Mab that binds to inhibit the growth of Ba/F3 cell lines via FGFR signaling. The R3Mab antibody had an IC50 of approximately <100 ng/ml in blocking FGF1-dependent FGFR signaling (Fig 9A), whereas the inhibition of Ba/F3 expressing FGFR3S249C had an IC50 of approximately 1-3 ng/ml (Fig. 9E; also see [0618]). Gorbenko et al (Hybridoma. 2009 Aug;28(4):295-300. PMID: 19663703. Listed on IDS filed 07/08/2022) teach monoclonal antibodies specifically targeting FGFR3/S249C over wild type FGFR3 (e.g., abstract).
Summary of Species disclosed in the original specification
The instant specification discloses three species of antibody that were positively selected by screening for binding to FGFR3 S249C but not to FGFR3 WT: FGA0002, FGA0005, and FGA0007 (Example 1, [0244]). The specification teaches three species of bivalent antibodies with these antigen binding domains (Table 3), each with the same anti-TCR complex binding domain comprising SEQ ID NOs: 11 and 12. The specification teaches that one of the bispecific antibodies, FGA0002/CD3-TRAB show strong TDCC activity against cells expressing FGFR S249C, but only weak activity at high concentration against cells expressing FGFR3 wildtype (Example 8, [0267]). There are no examples of additional anti FGFR3 antigen binding domains, or alternate residues or structure/function analysis of the requirements of the antigen-binding domains of the instant anti-FGFR3 S249C antibody correlated to the anti-FGFR3 S249C binding activity. Thus, a person of ordinary skill in the art would not be able, a priori, from the instant disclosure, to determine which antibodies or changes to the instant antibodies would result in anti-FGFR3 S239C binding regions which maintain the described binding activity in order to predictably describe the genus of methods of treatment as claimed.
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of variants to describe all methods of treating with a bispecific antibody with two antigen-binding domains to FGF3R S249C and to any generic TCR complex component to allow for predictability within the genus of methods of treatment.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the protein FGFR3 S249C. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 1 at the time of filing. Regarding claims 26 and 27, the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement- New
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 26-28, 34, and 40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating:
1) a cancer expressing FGFR3 S249C and 2) comprising administering a multispecific antibody having selective binding activity to an FGFR3 S249C mutant wherein the antigen-binding domain specific for FGFR3 S249C comprises an antigen-binding domain comprising: any one of the following sets of six HVRs:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 17,HVR-H2 comprising the amino acid sequence of SEQ ID NO: 18, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22;
(b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28; or
(c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 29,HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 31, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32,HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34,
does not reasonably provide enablement for a method of treating: 1) any cancer regardless of antigen expression; 2) a multispecific antigen-binding molecule comprising a first antigen-binding domain having selective binding activity to an FGFR3 S249C mutant; and a second antigen-binding domain having T cell receptor complex-binding activity wherein the multispecific molecule is defined only by the activity of the antigen binding regions.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention
Regarding claim 1, 26, and 27, claim 1 recites a genus of polypeptides comprising an antibody binding fragment which specifically binds to FGFR3 S249C and to a T cell receptor complex component, recited only by function and not structure. There is no structure of the antibodies required by claim 1. Claims 26 and 27 are directed towards methods of treating any generic cancer, or a cancer expressing FGFR S249C mutation, and therefore do not further restrict the structure of the instantly claimed bispecific antibody. Thus, claim 27 resolves issue (1) above but does not resolve the scope of enablement of antibody structure.
Regarding claims 28, 34, and 40, the claims are directed to a method of treating cancer comprising administering the antigen-binding molecule of claim 17 to a patient in need thereof or a method of treating cancer comprising administering the multispecific antigen-binding molecule of claim 7, respectively. The antigen-binding molecule of 17 is an isolated binding molecule comprising a set of HVR regions as described above, and therefore resolves issue (2) above but does not require target antigen expression in the tumor.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art
Fibroblast growth factor family proteins (FGRs) and their cognate receptors (FGFRs) are involved in cell proliferation, migration and differentiation; missense mutations to the FGFR3 receptor in humans are implicated in a number of cancer disease states including urothelial cancer (Ibrahim et al. 2019. Bladder Cancer. 2019;5(2):87-102. doi:10.3233/BLC-180205; PTO-892 dated 7/7/2025). One of the most common aberrant FGFR3 mutations is S249C (60%) resulting in constitutively activated FGFR3, even in the absence of its ligands, through ligand-independent dimerization (Ibrahim et al, page 90, left column, ¶2). Gorbenko et al (Hybridoma. 2009 Aug;28(4):295-300. PMID: 19663703. Listed on IDS filed 07/08/2022) discloses the generation of monoclonal antibodies targeting FGFR3 (title) as well as several hybridoma clones that showed higher binding affinity and towards FGFR3/S249C compared to FGFR3wt protein (see figure 2). Gorbenko does disclose that upon expansion, several of the clones lost the ability to bind FGFR3 and their goal to generate an antibody specific for FGFR3/S249C but not WT FGFR3 remained unrealized (see abstract; see also page 299, left column, first full ¶). Casadei et al (Ther Adv Med Oncol. 2019 Nov 25;11:1758835919890285. PMID: 31803255; PTO-892 dated 7/7/2025) reviews clinical trials for several FGFR inhibitors (not specifically targeted to S249C mutation), and demonstrates the potential usefulness and several challenges associated with specifically targeting activating mutations such as S249C (see section titled “Infigratinib”; see also section titled “mechanisms of resistance”). Balderes et. al. (U.S. 20150165067 A1; published 18 June 2015) teaches a method of treating a cancer expressing FGFR3 or mutant FGFR3 comprising an FGFR3 antibody (‘Antibody 1’) wherein the expression level of FGFR3 was correlated with the efficacy of the treatment (see e.g. [0148]).
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Regarding anti-FGFR3 S249C antibodies, the instant claim is directed towards antibodies that have “selective” binding activity for FGFR3 S249C. The instant specification states regarding “selective”: “As used herein, "selectivity" or "selective" refers to different binding abilities to wild- type and mutant proteins. In one embodiment, for the degree of binding of an anti-FGFR3 S249C mutant antibody to an FGFR3 S249C mutant protein and a wild-type FGFR3 protein, the term means that these binding activities of the antibody are comparable or higher than that when the antibody is added to cell lines expressing mutant and wild-type FGFR3 at the same level at concentrations differing by at least 10 times, 100 times, or more. For example, when the value indicating the binding activity of the antibody added to the mutant cell line at 0.1 pg/mL is equal to or is greater than the value indicating the binding activity of the antibody added to the wild-type cell line at least 1 pg/mL or 100 pg/mL, it means that the antibody "shows selectivity for the mutant over the wild-type". Thus, the limiting part of the definition in the specification is that “selective refers to different binding abilities to wild-type and mutant proteins”, which means that an antibody that has “selective binding activity to an FGFR3 S249C” when it binds to FGFR3 S249C differently than to any generic other wildtype protein.
Other antibodies that bind differently to FGFR3 S249C and FGFR3 WT are known in the art. For example, U.S. 20100247531 to Ashkenazi et. al. teaches the anti-FGFR3 antibody R3Mab that binds to inhibit the growth of Ba/F3 cell lines via FGFR signaling. The R3Mab antibody had an IC50 of approximately <100 ng/ml in blocking FGF1-dependent FGFR signaling (Fig 9A), whereas the inhibition of Ba/F3 expressing FGFR3S249C had an IC50 of approximately 1-3 ng/ml (Fig. 9E; also see [0618]). Gorbenko et al (Hybridoma. 2009 Aug;28(4):295-300. PMID: 19663703. Listed on IDS filed 07/08/2022) teach monoclonal antibodies specifically targeting FGFR3/S249C over wild type FGFR3 (e.g., abstract). Additionally, other bispecific antibodies targeting to a tumor antigen (e.g. FGFR3) and binding to a part of the TCR complex (CD3) are known in the art. For example, Eckelman et. al. (WO 2018191438 A1; published 10/18/2018; listed on IDS filed 07/08/2022) discloses multispecific polypeptide constructs that bind components of the T cell receptor complex (CD3)(e.g., ¶0009) and FGFR3 (e.g., ¶0020 and ¶0044). Eckelman further discloses a method of treating a disease or condition in a subject, the method comprising administering, to a subject in need thereof, a therapeutically effective amount of any of the provided multispecific conjugates or pharmaceutical compositions. In some embodiments, the disease or condition is a tumor or a cancer (¶0094).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The specification provides direction for the generation and assessment of preferred embodiments of mono-specific anti-FGFR3 S249C mutant antibodies and bi-specific anti-FGFR3 S249C/CD3 antibodies. In example 2, preparation of anti-hFGFR3 S249C mutant antibodies were generated by immunizing rabbits via Helios Gene Gun and in vivo gene transfer followed by monoclonal antibody screening using FGR3-expressing cell lines (CHO DXB11s cells, hFGFR3/CHO DXB11s cells, and hFGFR3 $249C/CHO DXB11s cells) ([0240-0243]). The preparation of bi-valent or bi-specific antibody comprising anti-hFGFR3 S249C binding domain and a CD3 binding domain were then generated ([0246-0252]; see tables 3-5 for antibody structures and associated SEQ ID NOs). These mono-specific and bi-specific antibodies were assessed for their binding capacity and binding specificity against cell lines expressing both WT and mutant (S249C) FGFR3 (examples 4-6, [253-261]). Finally, T cell-dependent cellular cytotoxicity activity of the mono-specific antibody clones was also assessed (example 7, [0262-0267]).
Conclusion
Applicant does not have enablement to perform a genus of methods comprising a method of treating any generic cancer, wherein the cancer does not express the target antigen FGFR3 S249C. It would take undue experimentation to determine which cancers that do not express the target antigen could be treated in the method as claimed.
Applicant does not have enablement to make and use a genus comprising administering multispecific antibodies comprising any first antigen-binding domain selective for FGFR3 S249C and second antigen-binding domain binding to any T-cell receptor complex defined only by function. It would take undue experimentation to determine all of the binding domains that meet the instant functional limitations and have the T-cell recruitment to FGFR3 S249C-expressing tumors as claimed.
Response to Arguments
Applicant argues regarding the previous scope of enablement rejection of claims 1, 26, and 27 that “Given the predictable nature of the art and the extensive guidance provided in the specification—including detailed working examples—a person skilled in the art would be able to make and use the invention” (Remarks 1/6/2026 p. 9-10). This is not persuasive, as described in the new scope of enablement rejection above. As described in the state of the art section above, the art is highly unpredictable in regards to 1) treatment of cancers that do not express the target antigen; and 2) the predictability of antigen-binding domains described only by function and not by structure. Although, as Applicant argues (See p. 10 ¶2-3), the field of TCR binding domains is highly developed, Applicant’s claim 1 offers no structure whatsoever to the FGFR3 S249C binding domain, which is the crucial inventive concept as described by Applicant. Applicant argues that unlike in Amgen v. Sanofi, the TCR antigen binding domain does not constitute the point of patentability (Remarks p. 10 ¶3). This is persuasive, but is moot in view of the new scope of enablement rejection above. Although Applicant’s specification offers enablement for the three specific FGFR3 antigen-binding domains described in the specification, as described in the scope of enablement rejection above, it would take undue experimentation to make and use the entire genus of anti-FGFR3 S249C binding antibodies and to determine which may be used effectively in the claimed methods of treating cancer because the art and the specification do not allow reliable prediction between the structure of the antigen-binding determinant region of the antibody. Applicant argues that given the art and the working examples in the specification, a person of ordinary skill in the art would be able to make and use the instant antigen binding molecules with no more than routine experimentation (Remarks p. 11). This is not persuasive because, although a person of ordinary skill in the art would be able to screen for antigen-binding molecules that bind to FGFR3 S249C and TCR complex-binding molecule, the binding of FGFR3 S249C to the antigen binding molecule is on its own insufficient to make and use the invention; a person of ordinary skill in the art would further need to repeat all of the experiments in the instant Examples, the same as the current inventors, for each and every FGFR3 S249C antibody that is not disclosed by the instant specification for 1) binding to FGFR3 S249C and binding affinity; 2) FGFR3 S249C antagonist and/or agonist activity; and 3) in vitro cytotoxicity via recruitment of T cells (e.g. Example 7) for FGFR3 binding domains that have yet to be invented in combination with any generic TCR complex binding domain, which constitutes a combinatorial combination of trillions of potential bispecific antibodies encompassed by the claims. While the experimentation could be considered routine for a smaller group of FGFR3 S249C antibodies, even several hundred, it cannot be considered routine due to the breadth and unpredictability of the scope of the claims for a person of ordinary skill in the art to make and use the genus of bispecific antibodies claimed only by function.
Regarding the enablement rejection of claims 7 and 17 (Remarks p. 12), these arguments are moot in view of the withdrawal of the rejection, above.
Claim Rejections - 35 USC § 103- New
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over ECKELMAN et al (WO 2018191438 A1; published 10/18/2018; listed on IDS filed 07/08/2022) in view of BALDERES et. al. (U.S. 20150165067 A1; published 18 June 2015).
Claim interpretation: Instant claim 1 is directed towards multispecific binding molecules comprising a first antigen binding domain having “selective binding activity to an FGFR3 S249C mutant”. The instant specification states regarding “selective”: “As used herein, "selectivity" or "selective" refers to different binding abilities to wild- type and mutant proteins. In one embodiment, for the degree of binding of an anti-FGFR3 S249C mutant antibody to an FGFR3 S249C mutant protein and a wild-type FGFR3 protein, the term means that these binding activities of the antibody are comparable or higher than that when the antibody is added to cell lines expressing mutant and wild-type FGFR3 at the same level at concentrations differing by at least 10 times, 100 times, or more. For example, when the value indicating the binding activity of the antibody added to the mutant cell line at 0.1 pg/mL is equal to or is greater than the value indicating the binding activity of the antibody added to the wild-type cell line at least 1 pg/mL or 100 pg/mL, it means that the antibody "shows selectivity for the mutant over the wild-type". Thus, the limiting part of the definition in the specification is that “selective refers to different binding abilities to wild-type and mutant proteins”, which means that an antibody that has “selective binding activity to an FGFR3 S249C” when it binds to FGFR3 differently than to any generic other wildtype protein.
Regarding claim 1, ECKELMAN discloses multispecific polypeptide constructs that bind components of the T cell receptor complex (CD3)(e.g., ¶0009) and FGFR3 (e.g., ¶0020 and ¶0044). Regarding claim 26, ECKELMAN further discloses a method of treating a disease or condition in a subject, the method comprising administering, to a subject in need thereof, a therapeutically effective amount of any of the provided multispecific conjugates or pharmaceutical compositions. In some embodiments, the disease or condition is a tumor or a cancer (¶0094).
ECKELMAN differs from invention of instant claims 1 and 26-27 by not specifically disclosing that the multi-specific binding agents (antibodies or antigen binding fragments) that the anti-FGFR3 fragments selectively bind to FGFR S249C mutations, and do not specifically recite a method of treating cancer wherein the cancer expresses an FGFR S249C mutation.
This deficiency is resolved by BALDERES.
BALDERES teaches drug conjugates comprising an anti-FGFR3 binding moiety for targeted tumor killing (Abstract). BALDERES teaches Antibody 1, which binds to and neutralizes FGF1 activity on the FGFR3 isoform IIIb S249C mutant with an IC50 of 2.17 nM while it binds to wildtype FGFR3 isoform IIIb with an average IC50 of 4.20 nM (reads on selective binding of FGFR3 S249C, see claim interpretation above). BALDERES further teaches that a conjugate comprising the Antibody 1 is cytotoxic against bladder tumor and multiple myeloma cell lines, including a UMUC-14 bladder cancer cell lines expressing mutant FGFR3 S249C[0146-0148], Table 5. BALDERES teaches a method of administering the conjugate comprising antibody 1 to a xenograft model using UMUC-14 FGFR3 mutant tumor cells (Table 7) and that the conjugate resulted in a complete regression in 10/10 animals in the UMUC-14 xenograft [0185-0188].
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to substitute the Antibody 1 anti-FGFR3 antibody of BALDERES into the multi-specific anti-FGFR3 and anti-CD3 molecule of ECKELMAN in order to benefit from a particular embodiment of an anti-FGFR3 binding domain that is sufficient to target a cytotoxic payload to a tumor cell as taught by BALDERES and to perform a method of treating a cancer expressing FGFR3 S249C mutation with the multi-specific comprising Antibody and an anti-CD3 binding domain in order to target T cells to tumors as taught by ECKELMAN using an anti-FGFR3 S249C binding antibody as taught by BALDERES. This would have a reasonable expectation of success because a person of ordinary skill in the art would build embodiments of the invention of ECKELMAN by using art-known antigen-binding domains to target the desired tumor antigen such as FGFR3 as taught by ECKELMAN; and would reasonably expect Antibody 1 of BALDERES to maintain its FGFR3 S249C in a binding format of targeting a T cell rather than a cytotoxic drug to a tumor.
Response to Arguments
Applicant argues regarding the 103 rejection of claims 1, 26, and 27 as being unpatentable over Eckelman in view of Gorbenko that a person of ordinary skill in the art would not have had reason to look at Gorbenko and their failed attempt produce an antibody that specifically recognizes the FGFR3 S249C mutant but not the FGFR wild-type protein, and that the failure of Gorbenko would not have had a reasonable basis for expecting that the multispecific polypeptide constructs of Eckelman could be successfully modified to contain the antigen-binding domains of Gorbenko (Remarks p. 13-15). This is persuasive, but the Arguments are moot in view of the new 103 rejection, above, which does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. The Examiner would like to note, however, that regarding the argued limitation of “specifically recognizing the FGFR3 S249C mutant but not the FGFR wild-type protein”, this limitation is not required by the claims, as described in the claim interpretation section of the new 103, above.
Allowable Subject Matter
Claims 1, 20, 26, 27, 28, 34, and 40 are rejected.
Claims 7, 17, 21-23, 25, and 30-33 are allowed.
Claims 29, 35, and 41 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 20 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Claims 36-39 and 40-41 are objected to or have a warning as duplicate claims to allowed claims 21-23 and 25, rejected claim 28, and objected to claim 29 as described above.
Conclusion
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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