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 .
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 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.
Priority
The instant application, filed 09/20/2022, is a 371 filing of PCT/US2021/023755, filed 03/23/2021, and claims domestic benefit to US provisional application 62/993,622, filed 03/23/2020.
Status of Claims/Application
The preliminary amendment of 05/23/2023 is acknowledged. Claims 1, 7, 9-10, 15-16, 24, 26, 37-38, 42, 58-60, and 64 are amended and claims 11-14, 17-23, 25, 27-36, 39-41, 43-44, 46-57, 61-63, and 65-91 are cancelled. Claims 1-10, 15-16, 24, 26, 37-38, 42, 45, 58-60, and 64 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/23/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112(a)
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 26 and 38 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.
The instant claims ultimately depend on claim 1 and limit the FGFR3 targeting moiety to being an antibody, or antigen-binding fragment thereof, having the recited amino acid sequences.
Claim 26 recites that the antibody or antigen-binding fragment thereof, comprises “at least one” CDR selected from the heavy and light chain CDRs recited. Each of the CDR sequences are recited as including the SEQ ID NO identified “or an amino acid sequence differing in 1 or 2 amino acids therefrom”. As such, claim 26 encompasses a genus of antibody structures which are limited by as little as a single CDR that can have up to two modifications.
Claim 38 depends on claim 26 and recites that the antibody or antigen-binding fragment thereof comprises a heavy chain variable region “with at least 85% identity” with the amino acids corresponding to positions 1-127 of SEQ ID NO: 8; and a light chain variable region “with at least 85% identity” with the amino acids corresponding to positions 1-107 of SEQ ID NO: 9. As claim 26 only requires a single one of the recited CDRs with up to two modifications, claim 38 encompasses a genus of antibody structures which include those with modifications in the CDRs of the heavy and light chain variable regions.
The claims further require that the antibody or antigen-binding fragment function in targeting FGFR3.
As such, claims 26 and 38 encompass a genus of antibody structures which are limited by as little as a single CDR that has up to two modifications and are claimed to have the recited function of targeting FGFR3.
The instant disclosure, however, does not describe a representative number of species of the claimed genus performing the claimed function, nor does the disclosure identify a structure-function relationship that could be used to predictably identify which of the claimed amino acid sequences could be used or modified in what way in order to arrive at an antibody or antigen-binding fragment thereof with the claimed function. This is particularly the case as the claims do not require a full complement of 6 CDRs, specifically 3 from the heavy chain variable region and 3 from the light chain variable region, which are the art recognized binding region of antibodies.
The examples of the instant disclosure studied the synthesis of compounds B and C (which are shown in Figures 2 and 3 as including a chelating group with a linker and a protective group), the conjugation of an anti-FGFR3 antibody to the compounds, and the addition of the radionuclide 225Ac (Examples 2-5). The examples further describe the effects of the 225Ac-anti-FGFR3 conjugates on tumor growth and survival, as well as biodistributions of 177Lu-DOTA-anti-EGFR3 and 111In-DOTA-anti-FGFR3 conjugates. The only antibody identified in the examples as being used in the conjugates is MFGR1877S (vofatamab). The examples do not describe the use of any other species of the claimed genus of antibodies nor do the examples demonstrate a predictable structure-function correlation between antibody structure and binding function. It is noted that, with regard to modified polypeptides, the specification does discuss polypeptide modifications including conservative and non-conservative substitutions ([00158]-[00160] as well as modifications made to optimize in vivo characteristics ([00157]); however, no structure-function correlation is disclosed that would allow for the predictable modification of the claimed antibody sequences and the identification of FGFR3 targeting antibodies.
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus.
For example, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses similar challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and teaches that these methods are not robust enough yet to yield predictable results. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is not suitable for binding to FGFR3 as recited in the claimed conjugates.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published two years after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable years after the effective filing date. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that even years after the effective filing date of the claimed invention even modifications using conservative substitution were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable modification of the claimed sequences while maintaining FGFR3 binding function. Therefore, instant claims 26 and 38 are found to not meet the written description requirement.
It is noted that there would be support for variation in the heavy and light chain variable regions of claim 38 if the full complement of 6 CDRs were limited to 100% identity.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-9, 24, 45, 59-60, and 64 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0030194 A1 (Burak, E.S., et al) 31 Jan 2019.
US’194 teaches that radiolabelled targeting moieties, or radioconjugates, are typically prepared by using a bifunctional chelator to append a radiolabel to a biological molecule while maintaining target affinity. Bifunctional chelates structurally may contain a chelate, a linker, and a cross-linking group or targeting moiety. By modifying the linker region of the bifunctional chelate, pharmacokinetic advantages can be obtained that can increase the excretion of radioactivity (page 1, [0002]). US’194 teaches linkers that enhance the excretion of a chelating moiety, or a metal complex thereof, when conjugated to a therapeutic moiety, a targeting moiety, or a cross-linking group (page 1, [0004]).
US’194 teaches a compound having the structure (page 1, [0004]-[0011]; page 24, claim 1):
A-L1-(L2)n-B (Formula 1);
wherein A is a chelating moiety or a metal complex thereof;
L1 is optionally substituted C1-C6 alkyl, substituted C1-C6 heteroalkyl, or substituted aryl or heteroaryl;
B is a therapeutic moiety, a targeting moiety, or a cross-linking group;
n is 1-5; and
each L2, independently, has the structure -X1-L3-Z1 (Formula 2),
wherein X1 is C=O(NR1), C=S(NR1), OC=O(NR1), NR1C=O(O), NR1C=O(NR1), -CH2PhC=O(NR1), -CH2Ph(NH)C=S(NR1), O, or NR1; wherein R1 is H or optionally substituted C1 -C6 alkyl or optionally substituted C1 -C6 heteroalkyl, substituted aryl or heteroaryl;
L3 is optionally substituted C1-C50 alkyl or optionally substituted C1 -C50 heteroalkyl or C5-C20 polyethylene glycol; and
Z1 is CH2, C=O, C=S, OC=O, NR1C=O, or NR1 and R1 is a hydrogen or optionally substituted C1-C6 alkyl, or pyrrolidine-2,5-dione.
It is noted that, in the formula A-L1-(L2)n-B, “L1-(L2)n” represents a linker that links the chelating moiety or metal complex thereof (A) to the therapeutic moiety, targeting moiety, or cross-linking group (B). As such, the formula also meets the limitation of claim 1 Formula 1-a. This is further supported by Fig. 1, which discloses a schematic depicting the general structure of a conjugate comprising a chelate, a linker, and a targeting moiety (bottom) (page 11, [0121]).
US’194 further teaches that B is a targeting moiety and that targeting moieties include any molecule or part of a molecule that binds to a given target (page 13, [0136]). US’194 teaches that a reference polypeptide described can include a target-binding domain that binds to a target of interest, for example an antigen, and includes antibodies or antigen binding fragments thereof. US’194 provides a list of exemplary targets, e.g, antigens, which includes FGFR3 (page 13, [0136]-[0139]).
US’194 further teaches that the metal complex of the chelating moiety comprises a radionuclide suitable for complexing to the compound of formula I including 212Bi, 213Bi, 225Ac, 212Pb, and 227Th (page 25, claim 5). US’194 teaches that the metal is an alpha-emitting radionuclide and is Ac225 or the progeny, or daughter isotopes, thereof (page 26, claims 20-21).
US’194 further teaches that the compound is selected from the group consisting of the following two structures (page 25, claim 16):
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where B is the therapeutic moiety, a targeting moiety, or a cross-linking group.
US’194 further teaches a pharmaceutical compositions comprising therapeutically effective amounts of the compounds disclosed and pharmaceutically acceptable carriers (page 16, [0190]-[0191]). Also disclosed are methods of detecting and/or treating cancer, the methods including administering to a subject in need thereof the pharmaceutical composition in an effective amount (page 3, [0042]). US’194 further teaches that the cancers include breast cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, multiple myeloma or acute myeloid leukemia (page 3, [0046]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to try an anti-FGFR3 targeting antibody as the targeting moiety (B) in the composition and methods disclosed by US’194. US’194 discloses a finite number of antigen targets for the antibodies disclosed including FGFR3. One of ordinary skill in the art would have been able to pursue these antigen targets with a reasonable expectation of success as US’194 demonstrates that FGFR3 was a known antigen that was considered for targeting with the targeting moieties/antibodies of the disclosed radioconjugates.
Claims 1-10, 15-16, 24, 26, 37-38, 42, 45, 59-60, and 64 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0030194 A1 (Burak, E.S., et al) 31 Jan 2019 in view of US 2016/0243228 A1 (Holash, J. and S. Lau) 25 Aug 2016 as evidenced by Janeway CA Jr, et al (2001) Immunobiology: The immune system in health and disease 5th Edition. New York: Garland Science; The structure of a typical antibody molecule; 6 pages.
The teachings of US’194 are as discussed in detail above.
While US’194 teaches FGFR3 as an antigen target in a list of potential antigen targets, the prior art further supports the selection of an antibody targeting FGFR3 in the conjugates and methods of US’194. US’194 does not disclose that the antibody has the structures recited in instant claims 26, 37, 38, or 42.
US’228 teaches that FGFR3 harbors both oncogenic and tumor suppressive properties. FGFR3 is frequently mutated in certain cancers, but in some normal tissues it can limit cell growth and promote cell differentiation. The human FGFR antagonistic monoclonal antibody MFGR1877S (CAS No. 1312305-12-6), referred to as B-701 or BM2, was the first FGFR antibody to enter clinical development. B-701 is a lyophilized form of MGFR1877A. US’228 teaches that B-701 was in early clinical development for the treatment of metastatic bladder cancer. B-701 was originally identified through phage display then recombined with a human IgG1 backbone. B-701 binds with high affinity to both wild-type and mutant FGFR3, including the most prevalent mutations found in bladder cancer and achondroplasia (dwarfism), including FGFR3-IIIbR248C, FGFR3-IIIbK652E, FGFR3-IIIbY375C, FGFR3-IIIbS249C, and FGFR3-IIIbG372C, while exhibiting no cross-reactivity with other FGFRs. B-701 had also been previously evaluated for safety in patients with t(4:14) translocated multiple myeloma, clinical trial NCT01122875 (page 2, [0013]). US’228 teaches that B-701 comprises HCDRs 1-3 of SEQ ID NOs: 1-3, respectively and LCDRs 1-3 of SEQ ID NOs: 4-6, respectively. B-701 further comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10 (page 3, [0025]). The sequences disclosed by US’228 for B-701 comprise sequences that are identical to those of instant claims 26, 37, and 38 as shown in the ABSS alignments below:
US’228, SEQ ID NO: 1 aligned with instant SEQ ID NO: 1:
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US’228, SEQ ID NO: 2 aligned with instant SEQ ID NO: 2:
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US’228, SEQ ID NO: 3 aligned with instant SEQ ID NO: 3:
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US’228, SEQ ID NO: 3 aligned with instant SEQ ID NO: 4:
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US’228, SEQ ID NO: 4 aligned with instant SEQ ID NO: 5:
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US’228, SEQ ID NO: 5 aligned with instant SEQ ID NO: 6:
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US’228, SEQ ID NO: 6 aligned with instant SEQ ID NO: 7:
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US’228, SEQ ID NO: 9 aligned with instant SEQ ID NO: 8:
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US’228, SEQ ID NO: 10 aligned with instant SEQ ID NO: 9:
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As shown in the ABSS alignments above, the sequences taught by US’228 for the heavy and light chain of B-701 (MGFR1877S) are identical to instant SEQ ID NOs: 8 and 9, respectively. As such, amino acids in positions 1-127 and 1-107, respectively, are also identical.
US’228 further teaches methods in which the FGFR3 inhibitor is administered to treat cancers including bladder cancer, breast cancer, cancers of the colon and rectum, brain cancer, head and neck cancer, liver cancer, lung cancer, prostate cancer, myeloma, leukemia, and Hodgkin and non-Hodgkin lymphoma (pages 2-3, [0017]-[0019]).
While US’228 does not disclose the molecular weight of MGFR1877S, the molecular weight of MGFR1877S is an inherent property of the antibody. As MGFR1877S is an IgG1 antibody, the antibody would be expected to have a molecular weight of approximately 150 kDa, as evidenced by Janeway which teaches that IgG antibodies have a molecular weight of approximately 150 kDa with two 50 kDa heavy chains and two 25 kDa light chains (page 2, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to try an anti-FGFR3 targeting antibody as the targeting moiety in the composition and methods disclosed by US’194. US’194 discloses a finite number of antigen targets for the disclosed antibodies including FGFR3. One of ordinary skill in the art would have been able to pursue these antigen targets with a reasonable expectation of success as US’194 demonstrates that FGFR3 was a known antigen that was considered for targeting with the targeting moieties/antibodies of the disclosed radioconjugates. The selection of an antibody targeting FGFR3 is further supported by US’228, which teaches that FGFR3 antibodies, including MGFR1877S, were in clinical development for the treatment of cancers further demonstrating the targeting of FGFR3 in cancer treatment.
It would have further been prima facie obvious to modify the radioimmunoconjugates of US’194 by using the MGFR1877S antibody disclosed by US’228 as the targeting moiety, which is shown in the structures as variable “B”. It would have been obvious to use this antibody as US’228 teaches that MGFR1877S was the first FGFR antibody to enter clinical development and was known to bind to both wildtype and mutant FGFR3 with high affinity while exhibiting no cross reactivity with other FGFRs. One of ordinary skill in the art would have had a reasonable expectation of success in using MGFR1877S as US’194 teaches the targeting of the FGFR3 antigen, which is the target of MGFR1877S. Additionally, US’194 and US’228 teach the treatment of overlapping cancers such as breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, myeloma, and leukemia, demonstrating a further nexus among the art (page 3, [0046]).
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0030194 A1 (Burak, E.S., et al) 31 Jan 2019 in view of US 2016/0243228 A1 (Holash, J. and S. Lau) 25 Aug 2016 as applied to claims 1 and 45 above, and in further view of Mushtaq, S., et al (2019) Recent advances in biorthogonal click chemistry for efficient synthesis of radiotracers and radiopharmaceuticals Molecules 24(3567) 1-30 and Dennler, P. et al (2015) Antibody Conjugates: From heterogeneous populations to defined reagents Antibodies 4; 197-224.
The combination of US’194 and US’228 teach the radioimmunoconjugate of claim 45 as discussed in detail above.
As discussed in detail above, US’194 teaches a radiolabeled targeting moiety with the following structure (page 25, claim 16) and also teaches that the chelator (on the left of the structure) is a metal chelator comprising Ac225 (page 26, claim 21).
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The combination of US’194 and US’228, however, do not explicitly disclose the configuration of the chelator with the Ac225 or that MFGR18775S is conjugated to the linker with an amine group, NH-, from a lysine unit that is part of the antibody.
Mushtaq teaches a conjugate comprising a DOTA chelator, which has the same structure as the chelator disclosed by US’194, and 225Ac, a useful therapeutic radioisotope (page 11, paragraph 2; Figure 11, page 12). The conjugate is shown below and the configuration of the chelator with 225Ac is shown on the right:
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Dennler teaches that monoclonal antibodies and their derivatives are currently the fastest growing class of therapeutics. Even if naked antibodies have proven their value as successful biopharmaceuticals, they suffer from some limitations. To overcome suboptimal therapeutic efficacy, immunoglobulins are conjugated with toxic payloads to form antibody drug conjugates and with chelating systems bearing radioisotopes to form radioimmunoconjugates. Classical conjugation via amino acid residues is still the most commonly used method to produce antibody conjugates and is suitable for most in vitro applications (abstract).
Dennler further teaches that lysine is one of the most commonly used amino acid residues for linking substrates to antibodies because they are usually exposed on the surface of the antibody and are thereby easily accessible (page 199, 2.1). Dennler further provides an overview of functional groups and their reaction products with corresponding amino acid residues in Figure 2 on page 200, shown below, which demonstrates that lysine has an exposed NH2 group that forms an amine attachment with a functional group.
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the compound disclosed by US’194 and US’228 to have the chelator and 225Ac configured according to the structure shown in Mushtaq and to conjugate the FGFR3 antibody to the compound of US’194 using a lysine conjugation method as taught by Dennler. It would have been obvious to have the chelator-225Ac configuration of Mushtaq as Mushtaq demonstrates the configuration for the same chelator of US’194 and 225Ac, which is also suggested by US’194. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. It would have been obvious to use a lysine conjugation method to attach the FGFR3 antibody as Dennler teaches that lysine is one of the most commonly used amino acid residues for linking substrates to antibodies because they are surface exposed and easily accessible. An ordinarily skilled artisan would have reasonably expected such conjugation to result in an amine (NH-) group attached to the carboxyl group of compound disclosed by US’194 based on the teachings of Dennler which demonstrate that lysine has a NH2 group that reacts with functional groups comprising a hydroxyl group to form structures comprising a NH-C=O attachment. One of ordinary skill in the art would have had a reasonable expectation of success as Dennler is teaching methods of linking substrates including to antibodies and the compound taught by the combination of US’194 and US’228 is drawn to conjugates comprising antibodies.
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.
US 11,191,854 B2
Claims 1-10, 15-16, 24, 26, 37-38, 42, 45, 58-60, and 64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,191,854 B2 in view of US 2016/0243228 A1 (Holash, J. and S. Lau) 25 Aug, 2016 US 2019/0030194 A1 (Burak, E.S., et al) 31 Jan 2019, Mushtaq, S., et al (2019) Recent advances in biorthogonal click chemistry for efficient synthesis of radiotracers and radiopharmaceuticals Molecules 24(3567) 1-30 and Dennler, P. et al (2015) Antibody Conjugates: From heterogeneous populations to defined reagents Antibodies 4; 197-224 as evidenced by Janeway CA Jr, et al (2001) Immunobiology: The immune system in health and disease 5th Edition. New York: Garland Science; The structure of a typical antibody molecule; 6 pages.
US’854 claims a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, where Formula I is
A-L1-(L2)n-B; and is defined as in US’854, claim 1, which overlaps with structures of the instant invention.
US’854 further claims species of the compound including the following:
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Where B is a human or humanized IgG antibody or antigen binding fragment thereof (claim 9).
US’854 further claims that the metal is an alpha-emitting radionuclide, and is 225Ac or a progeny thereof (claims 13-14). US’854 further claims a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.
US’854 differs from the instantly claimed method in that US’854 does not claim that the antibody is an FGFR3 antibody, specifically MFGR1877S, the configuration of 225Ac in the compound, or that the antibody is attached via an amine group from a lysine in the antibody. US’854 also does not teach a method of treating cancer comprising administering a composition comprising the radioimmunoconjugate.
The teachings of US’194, US’228, Mushtaq, Dennler, and Janeway are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’854 to substitute MGFR1877S, an anti-FGFR3 antibody, as taught by US’228, in position B of Formula I and to use the conjugate in a method of treating cancer as supported by US’194. It would have further been obvious to configure the metal chelate according to Mushtaq and to conjugate the antibody using a lysine group on the antibody as taught by Dennler. It would have been obvious to use MGFR1877S as the antibody in position B as US’194 teaches radioimmunoconjugates that have the same structure of the species claimed in US’854 and teaches that position B can be a targeting moiety that targets an antigen including FGFR. Additionally, US’228 teaches that MGFR1877S was the first FGFR antibody to enter clinical development and was known to bind to both wild type and mutant FGFR3 with high affinity while exhibiting no cross reactivity with other FGFRs further demonstrating FGFR3 as a valid antigen target. One of ordinary skill in the art would have had a reasonable expectation of success in using MGFR1877S as US’194 teaches the same compound with an antibody targeting the FGFR3 antigen, which is the target of MGFR1877S. Additionally, US’194 and US’228 teach the treatment of overlapping cancers such as breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, myeloma, and leukemia, demonstrating a further nexus among the art (page 3, [0046]). It would have further been obvious to use the radioimmunoconjugate in the treatment of the cancers disclosed by US’228 as US’194 teaches administration of the radioimmunoconjugate to treat cancer and US’228 establishes that the cancers disclosed express FGFR3 that can be targeted with the antibody.
It would have been obvious to have the chelator and 225Ac configured according to the structure shown in Mushtaq and to conjugate the FGFR3 antibody to the compound claimed in US’854 using a lysine conjugation method as taught by Dennler. It would have been obvious to have the chelator-225Ac configuration of Mushtaq as Mushtaq demonstrates the configuration for the same chelator of US’854 and US’194 and 225Ac, which is also suggested by both US’854 and US’194. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. It would have been obvious to use a lysine conjugation method to attach the FGFR3 antibody as Dennler teaches that lysine is one of the most commonly used amino acid residues for linking substrates to antibodies because they are surface exposed and easily accessible. An ordinarily skilled artisan would have reasonably expected such conjugation to result in an amine (NH-) group attached to the carboxyl group of compound disclosed by US’194 based on the teachings of Dennler which demonstrate that lysine has a NH2 group that reacts with functional groups comprising a hydroxyl group to form structures comprising a NH-C=O attachment. One of ordinary skill in the art would have had a reasonable expectation of success as Dennler is teaching methods of linking substrates to antibodies and the compound taught by the combination of US’854, US’194, and US’228 is drawn to conjugates comprising antibodies.
Copending 18/568,234
Claims 1-9, 24, 45, 60, and 64 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 7-11, 12-15, 18-23, and 25-26 of copending application 18/568,234. The claims of the copending applications are not identical but they are not patentably distinct.
App’234 claims a method of treating a patient having cancer comprising administering a 225Ac-radioimmunoconjugate where the conjugate comprises 225Ac chelated with a compound having the formula A-L1-X-L2-Z-B, where the variables are as defined in App’234, claim 1, which overlaps with structures of the instant invention. App’234 further claims compounds of formula I or II, which have the following structures (claim 5):
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App’234 further claims that B is a targeting moiety comprising an antibody or an antigen-binding fragment thereof (claim 7). App’234 further claims that the antibody is selected from a group which includes a fibroblast growth factor receptor 3 (FGFR3) antibody or antigen binding fragment thereof (claim 8). App’234 further claims that the cancer is selected from the group consisting of breast, non-small cell lung, small cell lung, pancreatic, head and neck, prostate, colorectal, cervical, endometrial, sarcoma, adrenocortical, neuroendocrine, Ewing’s sarcoma, multiple myeloma, and acute myeloid leukemia (claim 23).
As App’234 claims radioimmunoconjugates with structures overlapping those of the instant claims and teaches that the targeting moiety is an FGFR3 targeting antibody or fragment thereof, it would have been obvious to modify the claims of App’234 to arrive at the instantly claimed invention. As such, the claims of App’234 and the instantly claimed invention are obvious variants of each other.
Claims 10, 15-16, 26, 37-38, 42, and 58-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 7-11, 12-15, 18-23, and 25-26 of copending application 18/568,234 as discussed above regarding claims 1 and 7 and in further view of US 2016/0243228 A1 (Holash, J. and S. Lau) 25 Aug, 2016 US 2019/0030194 A1 (Burak, E.S., et al) 31 Jan 2019, Mushtaq, S., et al (2019) Recent advances in biorthogonal click chemistry for efficient synthesis of radiotracers and radiopharmaceuticals Molecules 24(3567) 1-30 and Dennler, P. et al (2015) Antibody Conjugates: From heterogeneous populations to defined reagents Antibodies 4; 197-224 as evidenced by Janeway CA Jr, et al (2001) Immunobiology: The immune system in health and disease 5th Edition. New York: Garland Science; The structure of a typical antibody molecule; 6 pages.
The claims of App’234 overlap with instant claims 1 and 7 as discussed above.
App’234 differs from the instant claims in that App’234 does not claim the structure of the FGFR3 antibody or the compound disclosed in claim 58. App’234 also does not expressly claim a composition comprising the radioimmunoconjugate.
The teachings of US’228, US’194, Mushtaq, Dennler, and Janeway are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’234 to use the MGFR1877S antibody disclosed by US’228 as the targeting moiety, which is shown in the structures as variable “B”. It would have been obvious to use this antibody as US’228 teaches that MGFR1877S was the first FGFR antibody to enter clinical development and was known to bind to both wild-type and mutant FGFR with high affinity while exhibiting no cross reactivity with other FGFRs. One of ordinary skill in the art would have had a reasonable expectation of success in using MGFR1877S as App’234 claims that the targeting moiety is an FGFR3 antibody, and MGFR1877S is an FGFR3 antibody. Additionally, App’234 and US’228 teach the treatment of overlapping cancers such as breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, myeloma, and leukemia, demonstrating a further nexus among the art (page 3, [0046]).
It would have further been obvious to include the radioimmunoconjugate in a pharmaceutical composition based on the teachings of US’194 which taches the same form of conjugates and their inclusion in pharmaceutical compositions. Thus, one of ordinary skill in the art would have had a reasonable expectation of success.
It would have been obvious to modify the conjugate to have the chelator and 225Ac configured according to the structure shown in Mushtaq and to conjugate the FGFR3 antibody to the compound of using a lysine conjugation method as taught by Dennler. It would have been obvious to have the chelator-225Ac configuration of Mushtaq as Mushtaq demonstrates the configuration for the same chelator of US’194 and 225Ac, which is also suggested by US’194. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. It would have been obvious to use a lysine conjugation method to attach the FGFR3 antibody as Dennler teaches that lysine is one of the most commonly used amino acid residues for linking substrates to antibodies because they are surface exposed and easily accessible. An ordinarily skilled artisan would have reasonably expected such conjugation to result in an amine (NH-) group attached to the carboxyl group of compound disclosed by US’194 based on the teachings of Dennler which demonstrate that lysine has a NH2 group that reacts with functional groups comprising a hydroxyl group to form structures comprising a NH-C=O attachment. One of ordinary skill in the art would have had a reasonable expectation of success as Dennler is teaching methods of linking substrates to antibodies and the compound claimed by App’234 is drawn to conjugates comprising antibodies.
This is a provisional nonstatutory double patenting rejection.
Copending 17/791,824
Claims 1-10, 15-16, 24, 26, 37-38, 42, 45, 58-60, and 64 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 30, 34-35, 39, 54-57, 60-61, 63-65, 68, 70, 72, 75, 85, 90, and 92 of copending application 17/791,824 in view of US 2016/0243228 A1 (Holash, J. and S. Lau) 25 Aug, 2016 US 2019/0030194 A1 (Burak, E.S., et al) 31 Jan 2019, Mushtaq, S., et al (2019) Recent advances in biorthogonal click chemistry for efficient synthesis of radiotracers and radiopharmaceuticals Molecules 24(3567) 1-30 and Dennler, P. et al (2015) Antibody Conjugates: From heterogeneous populations to defined reagents Antibodies 4; 197-224 as evidenced by Janeway CA Jr, et al (2001) Immunobiology: The immune system in health and disease 5th Edition. New York: Garland Science; The structure of a typical antibody molecule; 6 pages.
App’824 claims a method of inducing CD8 T cell infiltration in a subject comprising administering a radioimmunoconjugate comprising the structure A-L-B, where A is a metal complex of a chelating moiety, where the metal complex comprises 225Ac or a progeny thereof, L is a linker, and B is a targeting moiety capable of binding a first tumor-associated antigen expressed by at least some cells in the tumor (claim 1). App’824 further claims that the administration result in slowing or inhibiting progression of the tumor or regression of the tumor (claims 56-57), indicating treatment of the tumor. App’824 further claims the following structures for A-L, which overlap with those of the instant claims:
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App’824 further claims that the linker, L, has the structure -L1-(L2)n- as shown in Formula I-b which shows a structure of A-L1-(L2)n-B and defines the variables according to App’824, claim 61, which overlap with the structures of the instant claims.
App’824 further claims that the targeting moiety is an antibody or an antigen-binding fragment thereof with a molecular weight of at least 100 kDa (claim 65). App’824 claims the subject administered the radioimmunoconjugate is in need of treatment or prevention of cancer (claim 72).
App’824 differs from the instantly claimed method in that App’824 does not claim that the antibody is an FGFR3 antibody, specifically MFGR1877S, the configuration of 225Ac in the compound, or that the antibody is attached via an amine group from a lysine in the antibody.
The teachings of US’194, US’228, Mushtaq, Dennler, and Janeway are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’824 to substitute MGFR1877S, an anti-FGFR3 antibody, as taught by US’228, in position B of the conjugates as supported by US’194. It would have further been obvious to configure the metal chelate according to Mushtaq and to conjugate the antibody using a lysine group on the antibody as taught by Dennler. It would have been obvious to use MGFR1877S as the antibody in position B as US’194 teaches radioimmunoconjugates that have the same structure of the species claimed in App’824 and teaches that position B can be a targeting moiety that targets an antigen including FGFR. Additionally, US’228 teaches that MGFR1877S was the first FGFR antibody to enter clinical development and was known to bind to both wild type and mutant FGFR3 with high affinity while exhibiting no cross reactivity with other FGFRs further demonstrating FGFR3 as a valid antigen target. One of ordinary skill in the art would have had a reasonable expectation of success in using MGFR1877S as US’194 teaches the same compound with an antibody targeting the FGFR3 antigen, which is the target of MGFR1877S. Additionally, US’194 and US’228 teach the treatment of overlapping cancers such as breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, myeloma, and leukemia, demonstrating a further nexus among the art (page 3, [0046]). It would have further been obvious to use the radioimmunoconjugate in the treatment of the cancers disclosed by US’228 as App’824 and US’194 teach administration of the radioimmunoconjugate to treat cancer and US’228 establishes that the cancers disclosed express FGFR3 that can be targeted with the antibody.
It would have been obvious to have the chelator and 225Ac configured according to the structure shown in Mushtaq and to conjugate the FGFR3 antibody to the compounds claimed in App’824 using a lysine conjugation method as taught by Dennler. It would have been obvious to have the chelator-225Ac configuration of Mushtaq as Mushtaq demonstrates the configuration for the same chelator of App’824 and US’194 and 225Ac, which is also suggested by both App’824 and US’194. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. It would have been obvious to use a lysine conjugation method to attach the FGFR3 antibody as Dennler teaches that lysine is one of the most commonly used amino acid residues for linking substrates to antibodies because they are surface exposed and easily accessible. An ordinarily skilled artisan would have reasonably expected such conjugation to result in an amine (NH-) group attached to the carboxyl group of compound disclosed by US’194 based on the teachings of Dennler which demonstrate that lysine has a NH2 group that reacts with functional groups comprising a hydroxyl group to form structures comprising a NH-C=O attachment. One of ordinary skill in the art would have had a reasonable expectation of success as Dennler is teaching methods of linking substrates to antibodies and the compou