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 .
Information Disclosure Statement
The information disclosure statement filed on April 3, 2025 is acknowledged and has been considered by the examiner.
Specification
The abstract of the disclosure is objected to because it is too short (31 words). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Interpretation
The examiner interprets the phrase “optionally substituted” in claim 10 to mean that the chemical group following the phrase may be present in either the substituted or unsubstituted form, rather than that the substituted group is optionally included in the list of options. For example, “optionally substituted C1-C6 alkyl” relating to L1 in this claim is interpreted to mean that among the options for the structure of L1 are unsubstituted C1-C6 alkyl groups and substituted C1-C6 alkyl groups.
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 10 and 11 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
The disclosure does not provide methods of treating a patient having cancer using a radioimmunoconjugate of structure A-L-B as defined in instant claim 1 wherein the “L” group of the radioimmunoconjugate possesses representative number of the structures described in claims 10 and 11. Descriptions of the methods of making Compound B (Figure 2) and Compound C (Figure 3) and 111In and 225Ac radioimmunoconjugates of Compound C are provided, along with examples of the use of radioimmunoconjugates of Compound C. However, these compounds are not representative of the full scope of “L” group structures in the scope of claim 10 and 11. Specifically, the L3 group of claim 10 allows for optionally substituted C1-C50 alkyl or optionally substituted C1-C50 heteroalkyl groups and the L3 group of claim 11 may comprise (CH2CH2O)2-20 or (CH2CH2O)2-20—C1-C6 alkyl. However, the provided examples only include (CH2CH2O)3—C2 alkyl and non-substituted C10 alkyl structures for the L3 group. The length and composition of a linker group in a radioimmunoconjugate can have a significant impact on the function and efficacy of the molecule. Thus, the disclosed examples are not a representative number of species. It is not clear that all methods within the scope of claims 10 and 11 using the claimed molecular structures would share similar properties to those disclosed through examples. Therefore, it is understood that the specification does not provide sufficient written support to describe all embodiments of the claimed methods wherein the radioimmunoconjugate contains an “L” group as defined in claims 10 and 11.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 19 and 20 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18, from which claims 19 and 20 depend, requires the metal complex comprises an alpha emitter. Claims 19 and 20 provide specific options of alpha-emitting radionuclides, such as 225Ac, but also allow for the complexed metal to be progeny of said radionuclides. Progeny are the products of radionuclides in a decay chain. While some progeny of 225Ac and other listed radionuclides are also alpha emitters, not all progeny of these radionuclides possess this property. Therefore, as the scope of these claims includes metal isotopes that are not alpha emitters, claims 19 and 20 fail to include all the limitations of the claim upon which they depend and are therefore rejected.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-6, 10-15, and 17-24 are rejected under 35 U.S.C. 103 as being unpatentable over Burak (US 10,093,741 B1 – provided by applicant in IDS filed April 3, 2025) in view of Buchsbaum (Buchsbaum, D. J.; et al., Cancer Res., 1992) and Moreau (Moreau, P.; et al., Leukemia, 2011).
Burak teaches radioimmunoconjugates of insulin-like growth factor-1 receptor targeting monoclonal antibodies (column 1, lines 20-26). These antibodies include AVE1642 (column 2, lines 62-67). The radioimmunoconjugates include a chelating moiety and a linking group, which may be take possess several structures (column 1, line 27 through column 2, line 16). Burak also teaches the use of these radioimmunoconjugates for the treatment of cancer (column 5, lines 25-38).
Burak does not teach co-administering an IGF-1R targeting radioimmunoconjugate with a cold IGF-1R targeting molecule.
Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). More specifically, Buchsbaum teaches administering both antibodies to mice bearing Human B-Lineage Lymphoma xenograft tumors (pg. 638, Establishment of Human B-Lineage Lymphoma Xenografts in Athymic Nude Mice and Biodistribution studies). Buchsbaum teaches injecting 100 µg unlabeled antibody 2 hours prior to dosing 2.5 µCi radiolabeled antibody (pg. 638, Results, first paragraph). Buchsbaum teaches that this pre-administration of the unlabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which 36 µg unlabeled antibody was dosed 3 hours prior to injection of 4 µg radioimmunoconjugate (pg. 639, right column, first paragraph). In this method, at three days after administration, there was more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen (pg. 639, Fig. 3). Buchsbaum concludes from the data that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). Buchsbaum states that radioimmunoconjugates like those studied in this publication have been used in the treatment of patients having B-cell lymphoma cancer (pg. 641, left column, second paragraph).
Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of 0.5 mg/kg to 18 mg/kg AVE1642 to patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Patients were either dosed with 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib. No dose-limiting toxicities were observed in the 3, 12, or 18 mg/kg single agent arms or any of the combination therapy arms (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph).
A person of ordinary skill in the art would have recognized that both Burak and Moreau teach administration of IGF-1R targeting antibodies, including AVE1642, for the treatment of cancer. It would be recognized that Burak teaches the radioimmunoconjugate form of AVE1642, which is unlabeled in the Moreau study. Furthermore, it would be recognized that Buchsbaum teaches that the combination of a radioimmunoconjugate with the pre-administration of its “cold” (unlabeled) form results in greater tumor uptake of the radioimmunoconjugate, which could lead to increased efficacy and decreased toxicity. It would be understood that Buchsbaum teaches or suggests that combining the methods of Burak and Moreau, specifically with the pre-administration of the unlabeled antibody of Moreau prior to the radioimmunoconjugate of Burak, would have pharmacological benefits (MPEP § 2143(I)(G)). As both Burak and Moreau teach successful and safe administration of their respective antibodies and Buchsbaum teaches that the pre-administration method is an effective combination, a person of ordinary skill in the art would have a reasonable expectation of success combining the two methods/antibodies.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer using an IGF-1R targeting radioimmunoconjugate taught by Burak with the pre-administration (as taught by Buchsbaum) of the unlabeled AVE1642 antibody of Moreau. This would result in the predictable result of an effective cancer treatment method using an IGF-1R targeting radioimmunoconjugate and a cold IGF-1R targeting molecule.
Regarding claim 1, Burak teaches radioimmunoconjugates of insulin-like growth factor-1 receptor targeting monoclonal antibodies (column 1, lines 20-26). The radioimmunoconjugates include a chelating moiety and a linking group, which may be take possess several structures that read on the claimed formula of A-L-B (column 1, line 27 through column 2, line 16). Burak also teaches the use of these radioimmunoconjugates for the treatment of cancer (column 5, lines 25-38). Specific examples of this method include Examples 27 and 28, which teach methods of treating cancer in a xenograft tumor mouse model using 225Ac-labeled Compound C-HuMIGF-1R radioimmunoconjugate in single-dose or multi-dose regimens (column 58, line 56 through column 60, line 24). In these examples, all doses result in tumor growth regression or suppression, indicating therapeutically effective dosage amounts. The method of Burak also includes embodiments wherein the radioimmunoconjugate is dosed in combination with other antiproliferative / anticancer agents (column 5, lines 55-67). Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Furthermore, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). As described above, Buchsbaum suggests that modifying the anti-IGF-1R radioimmunoconjugate cancer treatment method of Burak by pre-administering an analogous cold antibody, such as the unlabeled AVE1642 of Moreau, would result in greater tumor uptake of the radioimmunoconjugate of Burak. The resulting method reads on the method of claim 1. The pre-administration of Buchsbaum reads on the scope of co-administration in this claim, as both compounds are administered as part of the same regimen and the examples of Buchsbaum teach dosing on the same day. Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 1 obvious.
Regarding claim 2, Burak teaches radioimmunoconjugates of insulin-like growth factor-1 receptor targeting monoclonal antibodies (column 1, lines 20-26). Burak teaches that the antibody or antigen-binding fragment thereof specifically binds IGF-1R and can be AVE1642 (column 2, lines 57-67). Specific examples of Burak’s method include Examples 27 and 28, which teach methods of treating cancer in a xenograft tumor mouse model using a 225Ac-labeled Compound C-HuMIGF-1R radioimmunoconjugate (column 58, line 56 through column 60, line 24). In the disclosure of Burak, HuMIGF-1R is AVE1642 (column 41, line 25). Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 2 obvious.
Regarding claim 3, Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that pre-administration of unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 3 obvious.
Regarding claims 4 and 5, Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib based on the bodyweight of the patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph), indicating a good safety profile. These dose values fall within the claimed ranges, rendering them obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claims 4 and 5 obvious.
Regarding claim 6, Burak teaches administering 0.05, 0.2, and 0.4 µCi of 225Ac-Compound C-HuMIGF-1R to Colo-205 xenograft tumor bearing mice (Example 27: column 58, line 56 through column 59, line 12; and Example 28: column 59, line 14 through column 60, line 24)). Burak also teaches that administration of 800 µg of unlabeled HuMIGF-1R antibody to the Colo-205 model was a dose at 40 mg/kg (column 58, lines 42-43). From this information, it can be determined that the Colo-205 mouse model used mice that were about 20 g in bodyweight (0.8 mg divided by 40 mg/kg). Furthermore, it is known that the conversion between Curies and Becquerels is 1 Ci = 3.7x1037 Bq. From this conversion factor, it can be calculated that Burak dosed mice at 1.85, 7.4, and 14.8 kBq doses, respectively. Dividing by the bodyweight of the mouse model results in dose values of 92.5, 370, and 740 kBq/kg. Burak teaches that the 0.05 µCi dose suppressed tumor growth in a single-dose method (column 59, lines 2-3) and caused regression of tumor growth in a multi-dose method (column 59, line 36- column 60, line 2). The 92.5 kBq/kg dose (0.05 µCi total dose) falls within the claimed range, rendering it obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 6 obvious.
Regarding claim 10, Example 20 of Burak (column 52, lines 1-23) teaches the conjugation of Compound C (Fig. 3) with HuMIGF-1R; which is AVE1642 (column 41, line 25), an IGF-1R binding antibody, (column 2, lines 57-67); and labeling this conjugate with 225Ac, thus forming a metal complex of the chelating moiety. This conjugate has the form of structure described in the first structure at the bottom of column 4, wherein B is AVE1642. This is a structure that can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a metal complex (225Ac) of DOTA (a chelating moiety), L1 is an unsubstituted C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, L3 is a C8 heteroalkyl group, and Z is -C(O)-. Furthermore, Examples 27 and 28 of Burak teach methods of treating cancer in a xenograft tumor mouse model using 225Ac-labeled Compound C-HuMIGF-1R radioimmunoconjugate (column 58, line 56 through column 60, line 24). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 10 obvious.
Regarding claim 11, in the above described Example 20 radioimmunoconjugate of Burak, 225Ac-Compound C-HuMIGF-1R (column 52, lines 1-23), the L3 group could alternatively be described as (CH2CH2O)3—C2 alkyl. Furthermore, Burak teaches that alternative embodiments of the L3 group may be optionally substituted C1-C50 alkyl, optionally substituted C1-C50 heteroalkyl, or C5-C20 polyethylene glycol (column 33, lines 37-39). The C5-C20 polyethylene glycol overlaps in scope with (CH2CH2O)2-20. Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 11 obvious.
Regarding claim 12, Burak teaches that the chelating moiety of the IGF-1R targeting radioimmunoconjugate may be DOTA, DOTMA, DOTAM, DO3AM, DOTP, DOTA-4AMP, NOTA, or HP-DO3A (column 32, lines 10-45). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 12 obvious.
Regarding claim 13, Burak teaches that the following radioisotopes may be chelated by the chelating group: 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 66Ga, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 90Y, 89Zr, 97Ru, 99mTc, 105Rh, 109Pd, 111In, 117mSn, 149Tb, 149Pm, 153Sm, 177Lu, 186Re, 188Re, 199Au, 201Tl, 203Pb, 212Pb, 212Bi, 213Bi, 225Ac, and 227Th (column 32, lines 49-53). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 13 obvious.
Regarding claim 14, Example 20 of Burak (column 52, lines 1-23) teaches the conjugation of Compound C (Fig. 3) with HuMIGF-1R; which is AVE1642, an IGF-1R binding antibody, (column 41, line 25); and labeling this conjugate with 225Ac, thus forming a metal complex of the chelating moiety. This conjugate has the form of structure described in the first structure at the bottom of column 4, wherein B is AVE1642. This is a structure that can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a metal complex (225Ac) of DOTA, L1 is C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, L3 is (CH2CH2O)m(CH2)w wherein m is 3 and w is 2, and Z is -C(O)-. Furthermore, Examples 27 and 28 of Burak teach methods of treating cancer in a xenograft tumor mouse model using 225Ac-labeled Compound C-HuMIGF-1R radioimmunoconjugate (column 58, line 56 through column 60, line 24). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 14 obvious.
Regarding claim 15, Burak teaches radioimmunoconjugate structures that read on the claimed A-L-B Formula provided in claim 1 wherein the A-L- portion of the structure is identical to claimed moiety 1 and moiety 2 (column 4, two structures at bottom of page). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 15 obvious.
Regarding claim 17, Burak teaches a radioimmunoconjugate structure that read on the claimed structure. Example 20 of Burak (column 52, lines 1-23) teaches conjugation of Compound C (Fig. 3) with HuMIGF-1R, which is AVE1642 (column 41, line 25), and labeling this conjugate with 225Ac. This conjugate has the form of structure described in the first structure at the bottom of column 4, wherein B is AVE1642, an IGF-1R binding antibody (column 2, lines 57-67). This final product reads on the claimed radioimmunoconjugate structure. Furthermore, Examples 27 and 28 of Burak teach methods of treating cancer in a xenograft tumor mouse model using 225Ac-labeled Compound C-HuMIGF-1R radioimmunoconjugate (column 58, line 56 through column 60, line 24). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 17 obvious.
Regarding claims 18-20, Burak teaches that the following radioisotopes may be chelated by the chelating group: 149Tb, 212Pb, 212Bi, 213Bi, 225Ac, and 227Th (column 32, lines 49-53). It is well understood in the art that these are alpha emitting radionuclides. Burak specifically teaches an example of using a 225Ac-labeled IGF-1R targeting radioimmunoconjugate for the treatment of colorectal tumor xenograft bearing mice (columns 58-59, Example 27). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claims 18-20 obvious.
Regarding claim 21, Burak teaches a radioimmunoconjugate structure that read on the claimed structure. Example 20 of Burak (column 52, lines 1-23) teaches conjugation of Compound C (Fig. 3) with HuMIGF-1R, which is AVE1642 (column 41, line 25), and labeling this conjugate with 225Ac. This final product reads on the claimed radioimmunoconjugate structure. Furthermore, Examples 27 and 28 of Burak teach methods of treating cancer in a xenograft tumor mouse model using 225Ac-labeled Compound C-HuMIGF-1R radioimmunoconjugate (column 58, line 56 through column 60, line 24). Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 21 obvious.
Regarding claim 22, Moreau teaches a method for the treatment of cancer comprising the administration of AVE1642 as a single agent (pg. 1, right column, second paragraph). This is a form of an IGF-1R targeting monoclonal antibody that is not radiolabeled, and is therefore considered “cold.” Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claim 22 obvious.
Regarding claims 23 and 24, Burak teaches that the method of treating cancer using the taught radioimmunoconjugate includes embodiments wherein the cancer is a solid tumor (column 5, lines 57-48). Burak further teaches that the solid tumor may be breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, or Ewing’s sarcoma. Therefore, the combined teachings of Burak, Buchsbaum, and Moreau render claims 23 and 24 obvious.
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.
Claims 1-5, 10-15, and 17-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 15-17 of U.S. Patent No. 10,093,741 in view of Buchsbaum (Buchsbaum, D. J.; et al., Cancer Res., 1992) and Moreau (Moreau, P.; et al., Leukemia, 2011).
The claims of U.S. Patent No. 10,093,741 (henceforth referred to as the ‘741 patent) are drawn to immunoconjugates and radioimmunoconjugates of AVE1642. This radioimmunoconjugate may comprise 225Ac. The claims are also drawn to methods of using these radioimmunoconjugates to treat cancer. The cancer may be a solid tumor. This method may further comprise administration of another antiproliferative agent.
The claims of the ‘741 patent are not drawn to a method including co-administering an IGF-1R targeting radioimmunoconjugate with a cold IGF-1R targeting molecule.
As described above, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). More specifically, Buchsbaum teaches administering both antibodies to mice bearing Human B-Lineage Lymphoma xenograft tumors (pg. 638, Establishment of Human B-Lineage Lymphoma Xenografts in Athymic Nude Mice and Biodistribution studies). Buchsbaum teaches injecting 100 µg unlabeled antibody 2 hours prior to dosing 2.5 µCi radiolabeled antibody (pg. 638, Results, first paragraph). Buchsbaum teaches that this pre-administration of the unlabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which 36 µg unlabeled antibody was dosed 3 hours prior to injection of 4 µg radioimmunoconjugate (pg. 639, right column, first paragraph). In this method, at three days after administration, there was more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen (pg. 639, Fig. 3). Buchsbaum concludes from the data that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). Buchsbaum states that radioimmunoconjugates like those studied in this publication have been used in the treatment of patients having B-cell lymphoma cancer (pg. 641, left column, second paragraph).
As described above, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of 0.5 mg/kg to 18 mg/kg AVE1642 to patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Patients were either dosed with 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib. No dose-limiting toxicities were observed in the 3, 12, or 18 mg/kg single agent arms or any of the combination therapy arms (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph).
A person of ordinary skill in the art would have recognized that both the ‘741 patent and Moreau teach administration of the IGF-1R targeting antibody AVE1642 for the treatment of cancer. It would be recognized that the ‘741 patent teaches the radioimmunoconjugate form of AVE1642, which is unlabeled in the Moreau study. Furthermore, it would be recognized that Buchsbaum teaches that the combination of a radioimmunoconjugate with the pre-administration of its “cold” (unlabeled) form results in greater tumor uptake of the radioimmunoconjugate, which could lead to increased efficacy and decreased toxicity. It would be understood that Buchsbaum teaches or suggests that combining the methods of the ‘741 patent and Moreau, specifically with the pre-administration of the unlabeled antibody of Moreau prior to the radioimmunoconjugate of the ‘741 patent, would have pharmacological benefits (MPEP § 2143(I)(G)). As both the ‘741 patent and Moreau teach successful and safe administration of their respective antibodies and Buchsbaum teaches that the pre-administration method is an effective combination, a person of ordinary skill in the art would have a reasonable expectation of success combining the two methods/antibodies.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer using an IGF-1R targeting radioimmunoconjugate of the ‘741 patent with the pre-administration (as taught by Buchsbaum) of the unlabeled AVE1642 antibody of Moreau. This would result in the predictable result of an effective cancer treatment method using an IGF-1R targeting radioimmunoconjugate and a cold IGF-1R targeting molecule.
Regarding instant claim 1, conflicting claim 7 of the ‘741 patent teaches a method of treating cancer comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of conflicting claim 1. The compound of conflicting claim 1 can be described as a chelating moiety connected to AVE1642 by a linker. As described by Moreau, AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Conflicting claim 15 is drawn to the method of conflicting claim 7 wherein the compound is a metal salt, which reads on the instant claim 1 limitation of a metal complex of the chelating moiety. Conflicting claim 10 describes an embodiment in which the use of the radioimmunoconjugate may further comprise administration of another antiproliferative agent. Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Furthermore, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). As described above, Buchsbaum suggests that modifying the anti-IGF-1R radioimmunoconjugate cancer treatment method of the ‘741 patent by pre-administering an analogous cold antibody, such as the unlabeled AVE1642 of Moreau, would result in greater tumor uptake of the radioimmunoconjugate of the ‘741 patent. The resulting method reads on the method of instant claim 1. The pre-administration of Buchsbaum reads on the scope of co-administration in this claim, as both compounds are administered as part of the same regimen and the examples of Buchsbaum teach dosing on the same day.
Regarding instant claim 2, conflicting claim 7 of the ‘741 patent requires the administration of the compound of conflicting claim 1, which is a conjugate of AVE1642. As described by Moreau, AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph).
Regarding instant claim 3, Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that pre-administration of unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph).
Regarding instant claims 4 and 5, Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib based on the bodyweight of the patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph), indicating a good safety profile. These dose values fall within the claimed ranges, rendering them obvious (MPEP § 2144.05(I)).
Regarding instant claim 10, conflicting claim 7 of the ‘741 patent is drawn to a method of treating cancer using the compound of conflicting claim 1. The compound of conflicting claim 1 can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a DOTA chelating moiety, L1 is an unsubstituted C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, L3 is a C8 heteroalkyl group, and Z is -C(O)-. Furthermore, conflicting claim 6 and 17 are drawn to embodiments in which 225Ac is chelated by the DOTA group, resulting in a metal complex of the chelating moiety.
Regarding instant claim 11, conflicting claim 7 of the ‘741 patent is drawn to a method of treating cancer using the compound of conflicting claim 1. As described above, the compound of conflicting claim 1 can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a DOTA chelating moiety, L1 is an unsubstituted C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, L3 is a C8 heteroalkyl group, and Z is -C(O)-. Alternatively, the L3 group could alternatively be described as (CH2CH2O)3—C2 alkyl. Furthermore, conflicting claim 6 and 17 are drawn to embodiments in which 225Ac is chelated by the DOTA group, resulting in a metal complex of the chelating moiety.
Regarding instant claim 12, conflicting claim 7 of the ‘741 patent is drawn to a method of treating cancer using the compound of conflicting claim 1. The compound of conflicting claim 1 comprises a DOTA chelating moiety. Furthermore, conflicting claim 6 and 17 are drawn to embodiments in which 225Ac is chelated by the DOTA group, resulting in a metal complex of the chelating moiety.
Regarding instant claims 13 and 18-20, conflicting claims 5-6 and 17 of the ‘741 patent are drawn to embodiments in which the radioimmunoconjugate of AVE1642 contains 111In or 225Ac. It is well understood in the art that these are alpha emitting radionuclides
Regarding instant claim 14, conflicting claim 7 of the ‘741 patent is drawn to a method of treating cancer using the compound of conflicting claim 1. The compound of conflicting claim 1 can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a DOTA chelating moiety, L1 is an unsubstituted C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, L3 is (CH2CH2O)m(CH2)w wherein m is 3 and w is 2, and Z is -C(O)-. Furthermore, conflicting claim 6 and 17 are drawn to embodiments in which 225Ac is chelated by the DOTA group, resulting in a metal complex of the chelating moiety.
Regarding instant claim 15, conflicting claim 7 of the ‘741 patent is drawn to a method of treating cancer using the compound of conflicting claim 1. The compound of conflicting claim 1 can be described by the formula A-L-B wherein B is AVE1642. In the structure of the compound of conflicting claim 1, the A-L- portion of the structure is identical to that of moiety 1 of instant claim 15.
Regarding instant claim 17, conflicting claim 7 of the ‘741 patent is drawn to a method of treating cancer using the compound of conflicting claim 1. The compound of conflicting claim 1 can be described by the formula A-L-B wherein B is AVE1642. The structure of the compound of conflicting claim 1 reads on that of instant claim 17. As described by Moreau, AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph).
Regarding instant claim 21, conflicting claim 17 of the ‘741 patent is drawn to a method of treating cancer comprising administering a compound of conflicting claim 1 (a radioimmunoconjugate of AVE1642) wherein the compound is bound to 225Ac. This version of the compound of conflicting claim 1 reads on the drawn required structure of instant claim 21.
Regarding instant claim 22, Moreau teaches a method for the treatment of cancer comprising the administration of AVE1642 as a single agent (pg. 1, right column, second paragraph). This is a form of an IGF-1R targeting monoclonal antibody that is not radiolabeled, and is therefore considered “cold.”
Regarding instant claims 23 and 24, conflicting claim 8 of the ‘741 patent is drawn to a method of treating cancer comprising administering conjugates of AVE1642 wherein the cancer may be a solid tumor. Conflicting claim 9 is drawn to more specific methods wherein the cancer may be breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, adrenocortical carcinoma, Ewing’s Sarcoma, liver cancer, neuroendocrine cancer, bladder cancer, or melanoma.
Claims 1-5, 10-15, and 17-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,433,148 in view of Buchsbaum (Buchsbaum, D. J.; et al., Cancer Res., 1992) and Moreau (Moreau, P.; et al., Leukemia, 2011).
The claims of U.S. Patent No. 11,433,148 (henceforth referred to as the ‘148 patent) are drawn to immunoconjugates and radioimmunoconjugates of IGF-1R targeting antibodies, including AVE1642. This radioimmunoconjugate may comprise 225Ac. The claims are also drawn to methods of using these radioimmunoconjugates to treat cancer. The cancer may be a solid tumor. This method may further comprise administration of another antiproliferative agent.
The claims of the ‘148 patent are not drawn to a method including co-administering an IGF-1R targeting radioimmunoconjugate with a cold IGF-1R targeting molecule.
As described above, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). More specifically, Buchsbaum teaches administering both antibodies to mice bearing Human B-Lineage Lymphoma xenograft tumors (pg. 638, Establishment of Human B-Lineage Lymphoma Xenografts in Athymic Nude Mice and Biodistribution studies). Buchsbaum teaches injecting 100 µg unlabeled antibody 2 hours prior to dosing 2.5 µCi radiolabeled antibody (pg. 638, Results, first paragraph). Buchsbaum teaches that this pre-administration of the unlabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which 36 µg unlabeled antibody was dosed 3 hours prior to injection of 4 µg radioimmunoconjugate (pg. 639, right column, first paragraph). In this method, at three days after administration, there was more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen (pg. 639, Fig. 3). Buchsbaum concludes from the data that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). Buchsbaum states that radioimmunoconjugates like those studied in this publication have been used in the treatment of patients having B-cell lymphoma cancer (pg. 641, left column, second paragraph).
As described above, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of 0.5 mg/kg to 18 mg/kg AVE1642 to patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Patients were either dosed with 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib. No dose-limiting toxicities were observed in the 3, 12, or 18 mg/kg single agent arms or any of the combination therapy arms (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph).
A person of ordinary skill in the art would have recognized that both the ‘148 patent and Moreau teach administration of an IGF-1R targeting antibody for the treatment of cancer. It would be recognized that the ‘148 patent teaches the radioimmunoconjugate form of IGF-1R targeting antibodies, including AVE1642, which is unlabeled in the Moreau study. Furthermore, it would be recognized that Buchsbaum teaches that the combination of a radioimmunoconjugate with the pre-administration of its “cold” (unlabeled) form results in greater tumor uptake of the radioimmunoconjugate, which could lead to increased efficacy and decreased toxicity. It would be understood that Buchsbaum teaches or suggests that combining the methods of the ‘148 patent and Moreau, specifically with the pre-administration of the unlabeled antibody of Moreau prior to the radioimmunoconjugate of the ‘148 patent, would have pharmacological benefits (MPEP § 2143(I)(G)). As both the ‘148 patent and Moreau teach successful and safe administration of their respective antibodies and Buchsbaum teaches that the pre-administration method is an effective combination, a person of ordinary skill in the art would have a reasonable expectation of success combining the two methods/antibodies.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer using an IGF-1R targeting radioimmunoconjugate of the ‘148 patent with the pre-administration (as taught by Buchsbaum) of the unlabeled AVE1642 antibody of Moreau. This would result in the predictable result of an effective cancer treatment method using an IGF-1R targeting radioimmunoconjugate and a cold IGF-1R targeting molecule.
Regarding instant claim 1, conflicting claim 20 of the ‘148 patent teaches a method of treating cancer comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of conflicting claim 13 followed by administration of a dose of the compound of conflicting claim 1. The compound of conflicting claim 1 can be described as a metal complex of a chelating moiety connected to an IGF-1R targeting antibody (such as AVE1642) by a linker. As described by Moreau, AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Conflicting claim 25 describes an embodiment in which the use of the radioimmunoconjugate may further comprise administration of another antiproliferative agent. Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Furthermore, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). As described above, Buchsbaum suggests that modifying the anti-IGF-1R radioimmunoconjugate cancer treatment method of the ‘148 patent by pre-administering an analogous cold antibody, such as the unlabeled AVE1642 of Moreau, would result in greater tumor uptake of the radioimmunoconjugate of the ‘148 patent. The resulting method reads on the method of instant claim 1. The pre-administration of Buchsbaum reads on the scope of co-administration in this claim, as both compounds are administered as part of the same regimen and the examples of Buchsbaum teach dosing on the same day.
Regarding instant claim 2, conflicting claim 20 of the ‘148 patent requires the administration of the compound of conflicting claim 1, which is a conjugate of an IGF-1R targeting antibody. Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph).
Regarding instant claim 3, Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that pre-administration of unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph).
Regarding instant claims 4 and 5, Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib based on the bodyweight of the patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph), indicating a good safety profile. These dose values fall within the claimed ranges, rendering them obvious (MPEP § 2144.05(I)).
Regarding instant claim 10, conflicting claim 20 of the ‘148 patent is drawn to a method of treating cancer using the compounds of conflicting claims 1 and 13. The compound of conflicting claim 1 can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a metal complex of a chelating moiety; L1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted aryl or heteroaryl; n is 1, X1 is -C(O)NR1-* or NR1wherein R1 is H, or optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted aryl or heteroaryl; L3 is optionally substituted C1-C50 alkyl, optionally substituted C1-C50 heteroalkyl; and Z is -C(O)-, -CH2-, -C(S)-, -OC(O)-, or NR1 wherein R1 is H or optionally substituted C1-C6 alkyl. Conflicting claim 13 only specifies that the chelated radionuclide is an alpha emitter, thus maintaining these other structural requirements and options.
Regarding instant claim 11, conflicting claim 20 of the ‘148 patent is drawn to a method of treating cancer using the compounds of conflicting claims 1 and 13. As described above, the compound of conflicting claim 1 can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1-. This includes embodiments such as those in conflicting claim 9, the first of which reads as an embodiment in which the L3 group could be described as (CH2CH2O)3—C2 alkyl.
Regarding instant claim 12, conflicting claim 20 of the ‘148 patent is drawn to a method of treating cancer using the compounds of conflicting claim 1 and 13. According to conflicting claim 1, the chelating moiety may be DOTA, DOTMA, DOTAM, DO3AM-acetic acid, DOTP, DOTA-4AMP, NOTA, or HP-DO3A.
Regarding instant claims 13 and 18-20, conflicting claims 5, 11, 12, and 14 of the ‘148 patent are drawn to embodiments in which the radioimmunoconjugate contains radionuclides. Conflicting claim 13 requires that the radionuclide is an alpha emitter. Specifically, conflicting claim 14 requires the alpha emitting radionuclide be 225Ac.
Regarding instant claim 14, conflicting claim 20 of the ‘148 patent is drawn to a method of treating cancer using the compounds of conflicting claims 1 and 13. The compound of conflicting claim 1 may take the form of the structures of conflicting claim 9, the first of which can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a DOTA chelating moiety, L1 is an unsubstituted C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, L3 is (CH2CH2O)m(CH2)w wherein m is 3 and w is 2, and Z is -C(O)-. Furthermore, conflicting claim 20 requires the chelator to be in the metal complex form.
Regarding instant claim 15, conflicting claim 20 of the ‘148 patent is drawn to a method of treating cancer using the compounds of conflicting claims 1 and 13. The compound of conflicting claim 1 may take the form of the structures of conflicting claim 9, which can be described by the formula A-L-B wherein B is an IGF-1R targeting antibody. In the structures of the compound of conflicting claim 9, the A-L- portion of the structure is identical to that of moiety 1 and moiety 2 of instant claim 15.
Regarding instant claim 17, conflicting claim 20 of the ‘148 patent is drawn to a method of treating cancer using the compounds of conflicting claims 1 and 13. The compound of conflicting claim 1 may take the form of the structures of conflicting claim 9, the first of which reads on the structure of instant claim 17.
Regarding instant claim 21, conflicting claim 20 of the ‘148 patent is drawn to a method of treating cancer comprising administering a compound of conflicting claims 1 and 13. The conjugate of conflicting claim 1 may be AVE1642. Furthermore, this is a requirement in the embodiment of conflicting claim 17. The chelating and linking groups may take the form as described in conflicting claim 9, the first of which reads on the instantly claimed structure. Furthermore, conflicting claim 14 requires the 225Ac bound form of the radioimmunoconjugate. This version of the compound of conflicting claim 1 reads on the drawn required structure of instant claim 21.
Regarding instant claim 22, Moreau teaches a method for the treatment of cancer comprising the administration of AVE1642 as a single agent (pg. 1, right column, second paragraph). This is a form of an IGF-1R targeting monoclonal antibody that is not radiolabeled, and is therefore considered “cold.”
Regarding instant claims 23 and 24, conflicting claim 23 of the ‘148 patent is drawn to a method of treating cancer comprising administering conjugates of IGF-1R targeting antibodies wherein the cancer may be a solid tumor. Conflicting claim 24 is drawn to more specific methods wherein the cancer may be breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, adrenocortical carcinoma, or Ewing’s Sarcoma.
Claims 1-6, 10-15, and 17-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 7-10, 12-15, 18-23, and 25-26 of copending Application No. 18/568,234 in view of Buchsbaum (Buchsbaum, D. J.; et al., Cancer Res., 1992) and Moreau (Moreau, P.; et al., Leukemia, 2011).
The claims of copending application 18/568,234 (henceforth referred to as the ‘234 application) are drawn to methods of treating cancer using 225Ac radioimmunoconjugates. Such agents may be radioimmunoconjugates of IGF-1R targeting antibodies, including AVE1642. This method may further comprise administration of another anticancer agent.
The claims of the ‘234 application are not drawn to a method including co-administering an IGF-1R targeting radioimmunoconjugate with a cold IGF-1R targeting molecule.
As described above, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). Buchsbaum concludes that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph).
As described above, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent in the treatment of patients with multiple myeloma (pg. 1, Title). Patients were either dosed with 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph).
A person of ordinary skill in the art would have recognized that both the ‘234 application and Moreau teach administration of an IGF-1R targeting antibody for the treatment of cancer. It would be recognized that the ‘234 application teaches the radioimmunoconjugate form of IGF-1R targeting antibodies, including AVE1642, which is unlabeled in the Moreau study. Furthermore, it would be recognized that Buchsbaum teaches that the combination of a radioimmunoconjugate with the pre-administration of its “cold” (unlabeled) form results in greater tumor uptake of the radioimmunoconjugate, which could lead to increased efficacy and decreased toxicity. It would be understood that Buchsbaum teaches or suggests that combining the methods of the ‘234 application and Moreau, specifically with the pre-administration of the unlabeled antibody of Moreau prior to the radioimmunoconjugate of the ‘234 application, would have pharmacological benefits (MPEP § 2143(I)(G)). As both the ‘234 application patent and Moreau teach successful and safe administration of their respective antibodies and Buchsbaum teaches that the pre-administration method is an effective combination, a person of ordinary skill in the art would have a reasonable expectation of success combining the two methods/antibodies.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer using an IGF-1R targeting radioimmunoconjugate of the ‘234 application with the pre-administration (as taught by Buchsbaum) of the unlabeled AVE1642 antibody of Moreau. This would result in the predictable result of an effective cancer treatment method comprising using an IGF-1R targeting radioimmunoconjugate and a cold IGF-1R targeting molecule.
Regarding instant claim 1, conflicting claim 10 of the copending ‘234 application is drawn to a method of treating cancer comprising administering to a subject in need thereof an effective amount of a 225Ac radioimmunoconjugate of AVE1642. The compound of conflicting claim 10 can be described as a metal complex of a chelating moiety connected to an IGF-1R targeting antibody by a linker. Conflicting claim 3 describes an embodiment in which the use of the radioimmunoconjugate may further comprise administration of another anticancer drug (checkpoint inhibitor). Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Furthermore, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). Buchsbaum concludes that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). As described above, Buchsbaum suggests that modifying the anti-IGF-1R radioimmunoconjugate cancer treatment method of the copending ‘234 application by pre-administering an analogous cold antibody, such as the unlabeled AVE1642 of Moreau, would result in greater tumor uptake of the radioimmunoconjugate of the copending ‘234 application. The resulting method reads on the method of instant claim 1. The pre-administration of Buchsbaum reads on the scope of co-administration in this claim, as both compounds are administered as part of the same regimen and the examples of Buchsbaum teach dosing on the same day.
Regarding instant claim 2, conflicting claim 10 of the copending ‘234 application requires the administration of a compound which is a radioimmunoconjugate of an IGF-1R targeting antibody. Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph).
Regarding instant claim 3, Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that pre-administration of unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph).
Regarding instant claims 4 and 5, Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib based on the bodyweight of the patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph), indicating a good safety profile. These dose values fall within the claimed ranges, rendering them obvious (MPEP § 2144.05(I)).
Regarding instant claim 6, conflicting claim 10 of the copending ‘234 application is drawn to a method of treating cancer in which a 225Ac-bound radioimmunoconjugate of AVE1642 is dosed at 10-400 kBq/kg, which encompasses the claimed range, rendering it obvious (MPEP § 2144.05(I)).
Regarding instant claims 10-15 and 17-21, conflicting claim 10 of the copending ‘234 application is drawn to a method of treating cancer comprising administering a 225Ac-bound radioimmunoconjugate of AVE1642. This radioimmunoconjugate can possess a variety of linker and chelator embodiments disclosed by conflicting claim 1 These include the embodiments described by the structures in conflicting claim 5. In the embodiment of the chelator and linker region of formula I of conflicting claim 5 being bound to AVE1642 (as is required in conflicting claim 10), this structure reads on the claimed radioimmunoconjugate structures of instant claims 10-15 and 17-21. This combined structure is identical to that of instant claim 21. The inclusion of 225Ac reads on the limitations of instant claims 13 and 18-20. The chelator and linker regions result in a structure that reads on instant claim 17, which contains moiety 1 of instant claim 15. The chelator is DOTA, which reads on instant claim 12. This embodiment of the structure can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a DOTA chelating moiety, L1 is an unsubstituted C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, and Z is -C(O)-. The L3 group can be described either as a C8 heteroalkyl group, (CH2CH2O)3—C2 alkyl, or (CH2CH2O)m(CH2)w wherein m is 3 and w is 2. Thus, this structure reads on instant claims 10, 11, and 14.
Regarding instant claim 22, Moreau teaches a method for the treatment of cancer comprising the administration of AVE1642 as a single agent (pg. 1, right column, second paragraph). This is a form of an IGF-1R targeting monoclonal antibody that is not radiolabeled, and is therefore considered “cold.”
Regarding instant claims 23 and 24, conflicting claim 23 of the copending ‘234 application is drawn to a method of treating cancer comprising administering conjugates of 225Ac radioimmunoconjugates which may include AVE1642 conjugates (see conflicting claim 10) wherein the cancer may be breast cancer, lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, adrenocortical carcinoma, neuroendocrine cancer, or Ewing’s Sarcoma. It is well known in the art that these are a solid tumors
This is a provisional nonstatutory double patenting rejection.
Claims 1-5, 10-15, 17-20, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of copending Application No. 19/482,779 in view of Buchsbaum (Buchsbaum, D. J.; et al., Cancer Res., 1992) and Moreau (Moreau, P.; et al., Leukemia, 2011).
The claims of copending application 19/482,779 (henceforth referred to as the ‘779 application) are drawn to methods of treating cancer using co-administration of a radioimmunoconjugate of structure A-L-B and a cold targeting molecule. The radiolabel of the radioimmunoconjugate may be 225Ac. The radioimmunoconjugate and cold targeting molecule may be IGF-1R targeting antibodies.
The claims of the copending ‘779 application are not drawn to a method including pre-administering a cold IGF-1R targeting molecule before administration of an IGF-1R targeting radioimmunoconjugate.
As described above, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). Buchsbaum concludes that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph).
As described above, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent in the treatment of patients with multiple myeloma (pg. 1, Title). Patients were either dosed with 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph).
A person of ordinary skill in the art would have recognized that both the ‘779 application and Moreau teach administration of an IGF-1R targeting antibody for the treatment of cancer. It would be recognized that the ‘779 application teaches the radioimmunoconjugate form of IGF-1R targeting antibodies. Furthermore, it would be recognized that Buchsbaum teaches that the combination of a radioimmunoconjugate with the pre-administration of its “cold” (unlabeled) form results in greater tumor uptake of the radioimmunoconjugate, which could lead to increased efficacy and decreased toxicity. It would be understood that Buchsbaum teaches or suggests that combining the methods of the ‘779 application and Moreau, specifically with the pre-administration of the unlabeled antibody of Moreau prior to the radioimmunoconjugate of the ‘779 application, would have pharmacological benefits (MPEP § 2143(I)(G)). As both the ‘779 application patent and Moreau teach successful and safe administration of their respective antibodies and Buchsbaum teaches that the pre-administration method is an effective combination, a person of ordinary skill in the art would have a reasonable expectation of success combining the two methods/antibodies.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer using an IGF-1R targeting radioimmunoconjugate of the ‘779 application with the pre-administration (as taught by Buchsbaum) of the unlabeled AVE1642 antibody of Moreau. This would result in the predictable result of an effective cancer treatment method comprising using an IGF-1R targeting radioimmunoconjugate and a cold IGF-1R targeting molecule.
Regarding instant claim 1, conflicting claim 11 of the copending ‘779 application is drawn to a method of treating cancer wherein embodiments include administering to a subject in need thereof an effective amount of a radioimmunoconjugate of an IGF-1R targeting antibody and co-administration of a cold targeting molecule. Conflicting claim 1 requires the radioimmunoconjugate to have a structure of A-L-B that reads on instant claim 1. Conflicting claim 1 also requires the administration of a cold targeting molecule and conflicting claim 12 requires the cold targeting molecule is an antibody. Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph). Furthermore, Buchsbaum teaches combined dosing of a radiolabeled anti-B1 monoclonal antibody with the unlabeled form of the same antibody (pg. 637, Abstract). Buchsbaum concludes that predosing unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph). As described above, Buchsbaum suggests that modifying the anti-IGF-1R radioimmunoconjugate cancer treatment method of the copending ‘779 application by pre-administering an analogous cold antibody, such as the unlabeled AVE1642 of Moreau, would result in greater tumor uptake of the radioimmunoconjugate of the copending ‘779 application. The resulting method reads on the method of instant claim 1.
Regarding instant claim 2, conflicting claim 11 of the copending ‘779 application includes embodiments that require the administration of a compound which is a radioimmunoconjugate of an IGF-1R targeting antibody. Additionally, Moreau teaches the use of the anti-IGF-1R monoclonal antibody AVE1642 as a single agent or in combination in the treatment of patients with multiple myeloma (pg. 1, Title). Moreau describes that AVE1642 is an antibody that targets IGF-1R (pg. 1, left column, last paragraph).
Regarding instant claim 3, Buchsbaum teaches injecting unlabeled antibody 2 hours prior to dosing radiolabeled antibody resulted in a greater uptake of the radioimmunoconjugate in tumor tissue at four days post-administration (pg. 638, Results, first paragraph; and pg. 639, Fig. 1). Buchsbaum teaches another method in which unlabeled antibody was dosed 3 hours prior to injection of radioimmunoconjugate, resulting in more radioimmunoconjugate uptake in tumor tissue and less uptake in the spleen at 3 days after administration (pg. 639, Fig. 3). Buchsbaum concludes from the data that pre-administration of unlabeled antibody leads to greater tumor delivery of radioimmunoconjugate (pg. 640, discussion, second paragraph).
Regarding instant claims 4 and 5, Moreau teaches administration of either 3, 6, 12, or 18 mg/kg AVE1642 alone or 0.5, 6, or 12 mg/kg AVE in combination with bortezomib based on the bodyweight of the patients (pg. 1, right column, last paragraph; and pg. 2, left column, first paragraph). Moreau describes the toxicity profile of the antibody at these doses as good (pg. 2, right column, second paragraph), indicating a good safety profile. These dose values fall within the claimed ranges, rendering them obvious (MPEP § 2144.05(I)).
Regarding instant claims 10-15 and 17-21, conflicting claim 11 of the copending ‘779 application is drawn to a method of treating cancer including embodiments comprising administering a radioimmunoconjugate of an IGF-1R targeting antibody. This radioimmunoconjugate can possess a variety of linker and chelator embodiments disclosed by conflicting claim 1 These include an embodiment described by the structure in conflicting claim 9. Conflicting claim 3 requires the radioimmunoconjugate comprises 225Ac. In the embodiment of the chelator and linker region of formula I of conflicting claim 1 being bound to an IGF-1R binding antibody (as is in the scope of conflicting claim 11), this structure reads on the claimed radioimmunoconjugate structures of instant claims 10-15 and 17-20. The inclusion of 225Ac reads on the limitations of instant claims 13 and 18-20. The chelator and linker regions result in a structure that reads on instant claim 17, which contains moiety 1 of instant claim 15. The chelator is DOTA, which reads on instant claim 12. This embodiment of the structure can be described by the formula A-L1-(L2)n-B wherein L2 has the structure -X1-L3-Z1- and wherein A is a DOTA chelating moiety, L1 is an unsubstituted C2 alkyl, n is 1, X1 is -C(O)NR1-* wherein R1 is H, and Z is -C(O)-. The L3 group can be described either as a C8 heteroalkyl group, (CH2CH2O)3—C2 alkyl, or (CH2CH2O)m(CH2)w wherein m is 3 and w is 2. Thus, this structure reads on instant claims 10, 11, and 14.
Regarding instant claim 22, Moreau teaches a method for the treatment of cancer comprising the administration of AVE1642 as a single agent (pg. 1, right column, second paragraph). This is a form of an IGF-1R targeting monoclonal antibody that is not radiolabeled, and is therefore considered “cold.”
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims are rejected.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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